Efficient short step synthesis of corey's tamiflu intermediate

Article abstract of DOI:10.1021/ol7029646

Corey's tamiflu intermediate was synthesized from a bicyclolactam adduct obtained by base-catalyzed Diels-Alder reaction of N-nosyl-3-hydroxy-2-pyridone with ethyl acrylate. A compound that has the same array of functional groups with the Corey's intermediate was obtained in four steps from the DA adduct in 47% overall yield. The intermediate itself was also prepared efficiently by simply changing the protective group.

Full text of DOI:10.1021/ol7029646

ORGANIC
LETTERS
2008
Vol. 10, No. 5
815-816
Efficient Short Step Synthesis of
Corey’s Tamiflu Intermediate
Nsiama Tienabe Kipassa, Hiroaki Okamura,* Kengo Kina, Toshiyuki Hamada, and
Tetsuo Iwagawa
Department of Chemistry and Bioscience, Faculty of Science, Kagoshima UniVersity,
1-21-35 Korimoto, Kagoshima 890-0065, Japan
okam@sci.kagoshima-u.ac.jp
Received December 8, 2007
ABSTRACT
Corey’s tamiflu intermediate was synthesized from a bicyclolactam adduct obtained by base-catalyzed Diels−Alder reaction of N-nosyl-3-
hydroxy-2-pyridone with ethyl acrylate. A compound that has the same array of functional groups with the Corey’s intermediate was obtained
in four steps from the DA adduct in 47% overall yield. The intermediate itself was also prepared efficiently by simply changing the protective
group.
Tamiflu (oseltamivir phosphate) 1 is a potent neuraminidase
inhibitor and the most widely used anti-influenza drug. Since
its development in 1996 by Gilead Science, Inc. and
launching by F. Hoffman-La Roche, Ltd., 42 million people
have been treated with Tamiflu until November 2006.1
Roche’s group has already developed its practical synthetic
route for commercial supply.2 However, more a efficient
process using easily available starting material and safer
reactions is still required for stockpiling the drug in prepara-
tion for a possible flu pandemic, and thus active researches
have been carried out.3,4 In addition, since the emergence of
influenza viruses with reduced sensitivity to neuraminidase
inhibitors have been reported recently,5 syntheses of modified
Tamiflu are also of high interest.
Our research group found a unique base-catalyzed Diels-
Alder (DA) reaction of 3-hydroxy-2-pyridones that gave
sterically controlled and highly functionalized bicyclolactams
4 as products.6 These compounds seemed to be good building
blocks for aminocyclitols having C7N structures,7 and indeed,
(()-validamine and its epimers were synthesized from the
DA adduct in short steps.8
Since Tamiflu is also structurally related to aminocyclitols,
we planed its short and efficient synthesis. Considering the
known synthetic pathway, Corey’s synthesis seemed to be
superior because no expensive starting material and no hard-
to-deal-with azide reagent were needed,3 and if the steps
could be reduced, the process would be much more attractive
as a practical production method. In the Corey’s synthesis,
the intermediate 2a has a simple C7N structure (see Figure
1), and thus we chose it as a primary target of our synthesis
(1) Factsheet Tamiflu. F. Hoffman-La Roche, Ltd., November 17, 2006.
(2) Albrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz,
B.; Zutter, U. Chimia 2004, 58, 621-629.
(3) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
6310-6311.
(4) (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 6312. (b) Cong, X.; Yao, Z.-J. J. Org. Chem.
2006, 71, 5365. (c) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki,
M. Org. Lett. 2007, 9, 259. (d) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403. (e) Satoh, N.; Akiba,
T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734-
5736. (f) Bromfield, K. M.; Grade´n, H.; Hagberg, D. P.; Olsson, H.; Kann,
N. Chem. Commun. 2007, 3183-3185. (g) Kraus, G. A.; Goronga, T.
Synthesis 2007, 1765-1767.
(5) Reece, P. A. J. Med. Virol. 2007, 79, 1577-1586.
(6) Okamura, H.; Nagaike, H.; Iwagawa, T.; Nakatani, M. Tetrahedron
Lett. 2000, 41, 8317-8321.
(7) Mahud, T. Nat. Prod. Rep. 2003, 20, 137-166.
(8) Okamura, H.; Nagaike, H.; Kipassa, N. T.; Iwagawa, T.; Nakatani,
M. Heterocycles 2006, 68, 2587-2594.
10.1021/ol7029646 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/26/2008

Scheme 1. Synthesis of Tamiflu Intermediates
Figure 1. Tamiflu 1 and Corey’s intermediate 2a.
using the DA adduct 4b as the starting material. Here, we
report a short and efficient synthesis of (()-2a and its
equivalent (()-2b.
The starting material 4b was prepared by the base-
catalyzed DA reaction of 3b and ethyl acrylate in good yield.9
Chemoselective reduction of the lactam carbonyl group was
achieved by NaBH4 in THF to give diol 5b. After oxidative
cleavage of the 1,2-diol moiety, the corresponding ketone
was obtained as a relatively unstable mixture of two
diastereomers and one enol tautomer (6b and 6b′). Reduction
of the mixture using NaBH4 followed by elimination of the
resulting alcohol by mesylation gave 2b that has the same
array of functional groups as does Corey’s intermediate (2a).3
Changing the protective group from Ns (2-nitrobenzen-
sulfonyl) to Boc was nicely accomplished by mild depro-
are important factors for industrial preparations, and thus the
synthesis described here could be considered as a practical
method.
10
tection using thioglycolic acid and K2CO3 followed by a
Although the resulting products in this synthesis were all
racemate, asymmetric synthesis of 4b has been currently
investigated in our group. Until now, we have already
reported the asymmetric DA reaction of 3-hydroxy-2-pyrone
and acrylates having chiral auxiliaries12 in the presence of
cinchona alkaloids as chiral catalysts. Considering the
structural similarity of the substrates and products, this
approach would be promising to give an optically active
compound related to 4b13 that will provide efficient asym-
metric synthesis Tamiflu 1 and its related compounds.
Boc protection in aqueous solution,11 and the formation of
2a was established by 1H NMR. Unfortunately, purification
of 2a was difficult due to a contamination of side products
of the deprotection.
An alternative synthetic pathway for 2a in pure form was
next examined. The conversions of functional groups were
essentially the same as those of the above-mentioned
synthetic route, and the only change was deprotection of the
Ns group and introduction of Boc protective group at the
earlier stage of the synthesis (4b f 5b f 5a). After obtaining
the Boc-protected compound 5a, oxidative cleavage and
subsequent reduction-elimination were again successfully
accomplished to give pure 2a.
Acknowledgment. We thank Prof. Tsutomu Katsuki and
Assistant Professor Tatsuya Uchida, Kyushu University, for
HRMS measurements and elemental analyses.
As shown in Scheme 1, the DA adduct 4b was easily
obtained from an aqueous “green” DA reaction that was
possible to scale-up until multigram quantity without sig-
nificant loss of the yield. All the subsequent processes for
2b were only four steps that required regular reactions using
inexpensive reagents and easy operations. Availability of the
appropriate starting material and ease of the synthetic steps
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
shown in Scheme 1. This material is available via the Internet
at http://pubs.acs.org.
OL7029646
(12) Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani, M. Tetrahedron
Lett. 1998, 39, 1211-1214.
(13) As a preliminary examination, we found that the asymmetric DA
reaction of 3a and chiral acrylate derivative gave optically active product
up to 91% de. Further optimization of the reaction conditions is currently
being investigated.
(9) The details of the base-catalyzed DA reaction of 3b are mentioned
in the Supporting Information.
(10) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353-359.
(11) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 8, 3259-
3262.
816
Org. Lett., Vol. 10, No. 5, 2008