An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2010.04.044

An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.

Full text of DOI:10.1016/j.tetlet.2010.04.044

Tetrahedron Letters 51 (2010) 3208–3210
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of oseltamivir phosphate (Tamiflu) via
a metal-mediated domino reaction and ring-closing metathesis
*
Pawinee Wichienukul, Sunisa Akkarasamiyo, Ngampong Kongkathip, Boonsong Kongkathip
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science,
Kasetsart University, Chatuchak, Bangkok 10900, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu)
from cheap, commercially available -ribose is described. The main features of this approach comprise a
Received 15 February 2010
Revised 23 March 2010
Accepted 12 April 2010
Available online 18 April 2010
D
metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant func-
tionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new
and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved
oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentyl-
idene ketal and stereospecific nucleophilic replacement of a triflate with an azide.
Ó 2010 Elsevier Ltd. All rights reserved.
Oseltamivir phosphate (Tamiflu, 1) (Fig. 1) is used as an orally
active drug for the treatment and the prevention of infections
due to influenza viruses. Tamiflu is hydrolyzed by an esterase en-
zyme to the corresponding carboxylic acid, which is a potent inhib-
itor of neuraminidases A and B.1 Recently, this compound was
found to be active against the swine flu virus (H1N1 human flu)
which has become a global influenza pandemic.2 Many nations
now have plans to stock a significant amount of this compound
in case of a possible influenza outbreak. As a result, concerns have
been raised about the capacity of the existing production process
to meet world demand. These arise because the current manufac-
turing process uses (À)-shikimic acid as the starting compound
which is not always readily available in consistently pure form.3
Consequently, there has been intense effort from the chemical
community in developing alternative approaches which start from
cheap and readily available substrates.4 The recent disclosure, by
Chen and co-workers, of the synthesis of the title compound from
3-pentanone in methanolic saturated HCl solution and trimethyl
orthoformate [HC(OMe)3]. The alcohol 2 was then converted into
the iodoribose derivative 3 in 79% yield by treatment with PPh3
and iodine in the presence of imidazole (Scheme 1).6
We next examined the Bernet–Vasella domino reaction7 of
iodoribose derivative 3 in the presence of Zn and ethyl 2-(bromo-
methyl)acrylate. Activated zinc dust in THF under sonication con-
ditions proved to be very reliable and consistently gave full
conversion and a very high yield of the desired diene 4. However,
the reaction proceeded slowly in THF alone. The reactivity could
be enhanced by addition of H2O as a co-solvent.
The reaction of 3 with Zn in THF/H2O (2:1) gave the desired
diene 4 along with lactone 5 resulting from cyclization of hydroxy
the readily available and inexpensive
port our own efforts in the area.
D
-ribose5 prompts us to re-
As shown by our retrosynthetic analysis (Fig. 1), we envisioned
installation of the cyclohexene ester core of Tamiflu via ring-clos-
ing metathesis of a diene generated by metal-mediated reductive
elimination of an iodoribose derivative and in situ alkylation of
an aldehyde intermediate by a metal allyl reagent. This diene can
then be converted into the cyclohexene ester by ring-closing olefin
metathesis (RCM).
The synthesis started from D-ribose with protection of the syn-
1,2-dihydroxy group as the 3-pentylidene ketal 2 by reaction with
* Corresponding author. Tel.: +66 25625444/2235; fax: +66 25793955.
E-mail address: fscibsk@ku.ac.th (B. Kongkathip).
Figure 1. Retrosynthetic analysis of oseltamivir phosphate (1) from D-ribose via a
1,2-amino hydroxy intermediate.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.044

P. Wichienukul et al. / Tetrahedron Letters 51 (2010) 3208–3210
3209
Scheme 2. Ring-closing metathesis (RCM) of diene 4.
Scheme 1. Preparation of methyl 5-deoxy-5-iodo-2,3-O-isopentylidene-b-
furanose (3).
D-ribo-
ester 4 (Table 1, entry 1). Besides zinc, the reaction with indium
was also investigated. This reaction proceeded significantly slower
than with zinc under the same conditions to give the desired diene
and a substantial amount of the alkylated by-product 6 (entry 2).
However the amount of by-product 6 could be reduced and the
yield of 4 was improved significantly to 70% by the addition of ace-
tic acid (0.01 equiv) and sonication until the intermediate aldehyde
was formed (monitoring by TLC) before the introduction of ethyl 2-
(bromomethyl)acrylate (entry 3).
Using the second-generation Grubbs’ catalyst (8), the diene 4
underwent ring-closing metathesis to provide 5-epi-shikimic acid
derivative 7 in 60% yield (Scheme 2). The 1H and 13C NMR spectra
of 7 were in agreement with those reported by Chen and co-work-
ers,5 and hence the stereochemistry of 4 could be assigned (see
Supplementary data). Moreover, we did not detect the other iso-
meric shikimic acid derivative during the RCM reaction, and thus
compound 4 is a single stereoisomer.
Our strategy for the transformation of 5-epi-shikimic acid deriv-
ative 7 into the 1,2-diamino derivative was different from reports
in the literature.3a–d,8 The secondary hydroxy group of 7 was con-
verted into an amino group by oxidation with TEMPO and trichlo-
roisocyanuric acid (TCCA) to provide the corresponding ketone,
followed by oxime formation and then reduction of the oxime with
NaBH4 catalyzed by MoO3 to give 5-amino ketal 10. Regioselective
reductive ring opening of the 5-amino ketal was best performed
employing a highly selective protocol (Et3SiH and TiCl4 in CH2Cl2
at À78 °C to À10 °C) as reported by scientists at Roche in their shi-
kimic acid route.3b However, the hydroxy amino product was diffi-
cult to separate by column chromatography. Protection of the
amino group with Boc anhydride made chromatographic separa-
tion of the protected product 11 much easier (Scheme 3).
Scheme 3. Synthesis of amino alcohol 11.
It is interesting to note that when the amino group of ketal 10
was N-Boc protected (10a), cleavage of the ketal group under the
same reaction conditions gave the other regioisomer 11a (Scheme
4).
To transform the hydroxy amino compound 11 into the 1,2-dia-
mino carboxylate 13, the hydroxy group was activated as the tri-
flate which was used in the next step without purification due to
its instability (Scheme 5). The triflate underwent SN2 displacement
with sodium azide in acetone/water (9:1) to provide the azido
amine 12 in good yield. The azide group of 12 was transformed di-
rectly into an acetamide by treatment with thioacetic acid and 2,6-
Table 1
Zinc- and indium-mediated elimination–allylation of 3
Entry
Metal
Reagents
Yield of 4b (%)
Yield of 5b (%)
Yield of 6b (%)
1
2
3
Zn
In
In
THF/H2O (2:1), sonicate, 50 °C, 3 h
THF/H2O (2:1), sonicate, 50 °C, 3 h
THF/H2O (2:1), AcOH sonicate, 50 °C, 1 h
71
45
70
22
—
—
—
30
7
a
a
AcOH (0.01 equiv) was added, the mixture was sonicated until the aldehyde intermediate formed (monitoring by TLC) then ethyl 2-(bromomethyl)acrylate was added
and the reaction was sonicated for another 2 h.
Isolated yield.
b

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P. Wichienukul et al. / Tetrahedron Letters 51 (2010) 3208–3210
Acknowledgments
S.A. is a Ph.D. student under the Royal Golden Jubilee Program,
the Thailand Research Fund (TRF) and P.W. is an M.Sc. student un-
der the Development and Promotion of Science and Technology
Talents Project (DPST). We are grateful for financial support from
the TRF, through the Royal Golden Jubilee Program. Financial sup-
port from the Center for Innovation in Chemistry (PERCH-CIC),
Commission on Higher Education, Ministry of Education and
Kasetsart University Research and Development Institute (KURDI)
are also gratefully acknowledged.
Scheme 4. Reductive opening of pentylidene ketal 10a.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.044.
References and notes
1. Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439.
2. World-Health-Organization, Swine Influenza Questions and Answers, April 26,
2009.
3. (a) 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; (b) Federspiel, M.; Fisher, R.; Henning, 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; (c) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044; (d) Harrington, P. J.;
Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res. Dev. 2004, 8, 86.
4. (a) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365; (b) Shie, J.-J.; Fang, J.-M.;
Wang, S.-Y.; Tasi, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong,
C.-H. J. Am. Chem. Soc. 2007, 129, 11892; (c) Radatus, B. K.; Murthy, K. S. K.;
Weeratunga, G.; Horne, S. E.; Kothakonda, K. K.; Wolf, E. C. G.; Wang, Z. U.S.
Patent 2008/0009639; Chem. Abstr. 2008, 148, 144973.; (d) Mandai, T.; Oshitari,
T. Synlett 2009, 783.
5. Osato, H.; Jones, I. L.; Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12, 60.
6. Classon, B.; Liu, Z. J. Org. Chem. 1988, 53, 6126.
7. Madsen, R.; Hyldtoft, L. J. Am. Chem. Soc. 2000, 122, 8444.
8. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; 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; (b) Nie, L.-D.; Shi, X.-X.; Ko, K. H.; Lu, W.-D. J.
Org. Chem. 2009, 74, 3970; (c) Nie, L.-D.; Shi, X. X. Tetrahedron: Asymmetry 2009,
20, 124.
Scheme 5. Completion of the synthesis of oseltamivir phosphate (1).
lutidine in chloroform at reflux to afford 13 (44% yield, three steps
from 11).9 Finally, the Boc protecting group of 13 was removed
with TFA in CH2Cl2 to form an amine, which was directly exposed
to 1.2 equiv of phosphoric acid in EtOH at 55 °C to afford oseltam-
ivir phosphate (1) in 75% yield (two steps).
In summary, we have accomplished an efficient synthesis of
oseltamivir phosphate in 14 steps and 5% overall yield, using cheap
and abundant D-ribose as the starting material. The key features of
the synthesis include the formation of an epi-shikimic acid ester by
combining a metal-mediated domino reaction with ring-closing
olefin metathesis (RCM). Moreover, transformation of the epi-shi-
kimic acid derivative into a 1,2-diamino compound represents a
new and efficient synthetic route for the synthesis of Tamiflu
which has the potential to be developed as an industrial process
in the future.
9. Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am. Chem. Soc.
2003, 125, 7754.