Communications

DOI: 10.1002/anie.200701754
Drug Synthesis

A Practical Synthesis of ( )-Oseltamivir**

( )-Oseltamivir phosphate (1·H3PO4, tamiflu) is a potent could best be constructed by an asymmetric Diels–Alder
inhibitor of neuraminidase and is used worldwide as a drug reaction between dihydropyridine 6 and the acrylic acid
for influenza of both type A and type B.[1] The recent spread derivative 7.
of the avian virus H5N1 has prompted governments to Our synthesis commenced with the reduction of pyridine
stockpile tamiflu as a precautionary measure against an (8) in the presence of benzyl chloroformate to give dihydro-
influenza pandemic. However, the high cost of the drug pyridine 9 (Scheme 2).[4] Asymmetric Diels–Alder reactions
makes it difficult for developing countries to stockpile between dihydropyridine derivatives and acrylic acid deriv-
tamiflu. The starting material in the current industrial syn- atives have not yet been developed to a high enough level to
thesis of oseltamivir is shikimic acid, which is obtained either be used practically in synthesis.[5] We therefore turned to a
by the extraction of Chinese star anise or by the fermentation two-step sequence involving the use of acrolein. The treat-
of genetically engineered E. coli through tedious purification ment of 9 with acrolein in the presence of the MacMillan
processes.[2] Furthermore, special production facilities are catalyst (10)[6] at room temperature led to a mixture of
needed to handle the explosive intermediates and reagents aldehydes which included the desired Diels–Alder adduct
involved. Therefore, intensive efforts have been made to 11.[7] This mixture was subjected without purification to Kraus
improve the synthesis of oseltamivir.[3] Herein, we report a oxidation to give the corresponding carboxylic acid 12 among
practical synthesis of oseltamivir. the products.[8] After the removal of basic impurities by
Our retrosynthesis of oseltamivir (1) is outlined in washing a solution of the product mixture in ethyl acetate
Scheme 1: We proposed the bicyclo[2.2.2] lactam 2 with a with dilute HCl, the carboxylic acids were extracted into an
aqueous solution of sodium bicarbonate. Upon addition of
bromine, a facile bromolactonization proceeded to give the
desired lactone 13. As acidic by-products remain in the
aqueous phase, simple extraction followed by crystallization
from methanol afforded practically pure 13 (> 99 % ee) in
26 % yield from benzyl chloroformate. Thus, neither tedious
chromatographic separations nor expensive reagents are
needed to prepare bromolactone 13.
Having developed a highly efficient route to this key
intermediate, we then focused on the further transformation
of 13 into oseltamivir. The Cbz group in 13 was exchanged for
a Boc group by hydrogenolysis in the presence of Boc2O to
give 14 (92 % yield),[9] which was oxidized with a catalytic
amount of RuO2·n H2O (10 mol %) and NaIO4 to furnish
Scheme 1. Retrosynthesis of oseltamivir (1). imide 15 in 86 % yield.[10] Ammonolysis of the lactone
followed by mesylation of the resulting alcohol afforded
leaving group X at C2 as a key precursor to 1 and envisaged mesylate 17 in 86 % yield from 15. When treated with
that 2 could be derived from carboxylic acid 3 by either a iodobenzene diacetate and allyl alcohol, amide 17 underwent
Curtius or a Hofmann rearrangement of the corresponding the Hofmann rearrangement to give allyl carbamate 18 in
amide. Lactone 4, a precursor of 3, could in turn be derived 88 % yield.[11]
from 5 by halolactonization. Finally, the bicyclic system 5 As initially anticipated, 18 underwent a series of trans-
formations upon treatment with a slight excess of sodium
[*] N. Satoh, T. Akiba, Dr. S. Yokoshima, Prof. T. Fukuyama ethoxide (2.02 equiv) at 0 8C: Thus, ethanolysis of the N-Boc
Graduate School of Pharmaceutical Sciences lactam, dehydrobromination, and aziridine formation pro-
University of Tokyo vided 19 in 87 % yield. The regioselective cleavage of
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) aziridine 19 was effected by treatment with BF3·Et2O in 3-
Fax: (+ 81) 3-5802-8694 pentanol to give ether 20 in 62 % yield.[1, 12] Removal of the
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Boc group and acetylation of the resulting amine afforded 21
[**] This research was supported financially in part by a grant for the
in 88 % yield. Finally, deprotection of the Alloc-substituted
21st Century COE Program and a Grant-in-Aid (15109001 and
16073205) from the Ministry of Education, Culture, Sports, Science, amine with a combination of Pd/C, Ph3P, and 1,3-dimethyl-
and Technology of Japan. We are indebted to Dr. Kunisuke Izawa of barbituric acid in ethanol at reflux, removal of the Pd/C
Ajinomoto Co. for an ample supply of d-phenylalanine. catalyst by filtration, concentration in vacuo, and the addition
Supporting information for this article is available on the WWW of phosphoric acid[3d] furnished crystalline oseltamivir phos-
under http://www.angewandte.org or from the author. phate (1·H3PO4) in 76 % yield. The spectroscopic data of

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2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 5734 –5736
 Angewandte
Chemie

Scheme 2. Synthesis of oseltamivir phosphate (1·H3PO4). Alloc = allyloxycarbonyl, Bn = benzyl, Boc = tert-butoxycarbonyl, Cbz = benzyloxycarbonyl,
Ms = methanesulfonyl, M.S. = molecular sieves, TFA = trifluoroacetic acid.

oseltamivir phosphate obtained by this synthetic route are [1] C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S.
consistent with those reported in the literature.[3a] Swaminathan, N. Bischofberger, M. S. Chen, D. B. Mendel, C. Y.
We believe that our synthetic route to 1 is highly practical Tai, W. G. Laver, R. C. Stevens, J. Am. Chem. Soc. 1997, 119, 681.
for a number of reasons: First, inexpensive and commonly [2] S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B.
Wirz, U. Zutter, Chimia 2004, 58, 621.
used reagents are employed. The relatively expensive catalyst
[3] a) J. C. Rohloff, K. M. Kent, M. J. Postich, M. W. Becker, H. H.
RuO2·n H2O can be recovered and reused (see reference [8] Chapman, D. E. Kelly, W. Lew, M. S. Louie, L. R. McGee, E. J.
and the Supporting Information). Furthermore, although the Prisbe, L. M. Schultze, R. H. Yu, L. Zhang, J. Org. Chem. 1998,
overall yield of lactone 13 from benzyl chloroformate is 63, 4545; b) M. Federspiel, R. Fischer, M. Hennig, H.-J. Mair, T.
rather low (26 %), this intermediate can be obtained as Oberhauser, G. Rimmler, T. Albiez, J. Bruhin, H. Estermann, C.
crystals on a large scale without tedious purification proce- Gandert, V. GKckel, S. GKtzK, U. Hoffmann, G. Huber, G.
dures. The other reactions proceed in high yields, and a Janatsch, S. Lauper, O. RKckel-StLbler, R. Trussardi, A. G.
majority of the intermediates are obtained as crystals. In Zwahlen, Org. Process Res. Dev. 1999, 3, 266; c) M. Karpf, R.
Trussardi, J. Org. Chem. 2001, 66, 2044; d) P. J. Harrington, J. D.
practice, no chromatographic purifications are required for
Brown, T. Foderaro, R. C. Hughes, Org. Process Res. Dev. 2004,
the conversion of 13 into 17 or for the conversion of 20 into 1. 8, 86; e) Y.-Y. Yeung, S. Hong, E. J. Corey, J. Am. Chem. Soc.
In conclusion, we have synthesized oseltamivir phosphate 2006, 128, 6310; f) Y. Fukuta, T. Mita, N. Fukuda, M. Kanai, M.
(1·H3PO4) in 22 % yield from the readily available lactone 13 Shibasaki, J. Am. Chem. Soc. 2006, 128, 6312; g) X. Cong, Z.-J.
(5.6 % yield from benzyl chloroformate) by using an asym- Yao, J. Org. Chem. 2006, 71, 5365; h) T. Mita, N. Fukuda, F. X.
metric Diels–Alder reaction, a bromolactonization, and a Roca, M. Kanai, M. Shibasaki, Org. Lett. 2007, 9, 259; i) K.
Hofmann rearrangement as key transformations. We believe Yamatsugu, S. Kamijo, Y. Suto, M. Kanai, M. Shibasaki,
that the overall yield of 1 prepared by the route described Tetrahedron Lett. 2007, 48, 1403; j) for a recent review of
syntheses of oseltamivir, see: V. Farina, J. D. Brown, Angew.
would be much improved in a production-scale operation and
Chem. 2006, 118, 7488; Angew. Chem. Int. Ed. 2006, 45, 7330.
that our synthesis is thus a viable alternative to the Roche– [4] a) F. W. Fowler, J. Org. Chem. 1972, 37, 1321; b) R. J. Sundberg,
Gilead synthesis in which shikimic acid is employed as the J. D. Bloom, J. Org. Chem. 1981, 46, 4836.
starting material. Furthermore, our synthetic route has great [5] For enantioselective Diels–Alder reactions of dihydropyridines,
potential for the generation of a wide range of tamiflu see: a) N. Takenaka, Y. Huang, V. H. Rawal, Tetrahedron 2002,
analogues. 58, 8299; b) H. Nakano, N. Tsugawa, R. Fujita, Tetrahedron Lett.
2005, 46, 5677; for diastereoselective reactions of chiral dihy-
Received: April 20, 2007 dropyridines, see: c) M. Mehmandoust, C. Marazano, R. Singh,
Published online: June 26, 2007 B. Gillet, M. CMsario, J.-L. Fourrey, B. C. Das, Tetrahedron Lett.
1988, 29, 4423; d) C. Marazano, S. Yannic, Y. Genisson, M.
Mehmandoust, B. C. Das, Tetrahedron Lett. 1990, 31, 1995; e) Y.

.
Keywords: antiviral agents · Diels–Alder reaction ·
domino reactions · lactones · rearrangement
Matsumura, Y. Nakamura, T. Maki, O. Onomura, Tetrahedron
Lett. 2000, 41, 7685; for diastereoselective Diels – Alder reac-
tions of chiral acrylic acid derivatives with dihydropyridines, see:

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Communications
f) C. Kouklovsky, A. PouilhNs, Y. Langlois, J. Am. Chem. Soc. Supporting Information). Oxone could also be used as a
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alcohol after reduction of the crude mixture of aldehydes (see rable by chromatography on silica gel.
the Supporting Information). The exo isomer was not detected.
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[10] In an experiment with 4.5 g of 14, 93 % of the RuO2·n H2O used
could be recovered by the addition of isopropanol to the
reaction mixture followed by filtration. The recovered material
could be reused and showed no sign of deterioration (see the

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