LETTER
Synthesis of Tamiflu
C
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(+)-10 in lieu of ( )-10 through the relevant steps in
Scheme 2, optically active Tamiflu [(+)-1] should be at-
tainable in a comparable yield.13
In conclusion, a novel approach to the core structure of
antiflu agent Tamiflu/Oseltamivir is developed. A litera-
ture Diels–Alder reaction was employed as a rapid entry
into the desired fully functionalized cyclohexene architec-
ture, which opens up a previously unreachable possibility
of using pyrrole nitrogen as the source of the amino group
in the end product. Such a strategy was made feasible here
mainly because of successful realization of removal of the
superfluous alkenyl bromine atom in the Diels–Alder
product with NaBH4 along with selective saturation of the
C–C double bond conjugated to the ester functionality and
the b-elimination of the N-Boc that collapsed the bridged
framework into the fully functionalized cyclohexene.
Apart from the conciseness of the synthetic sequence, the
present approach is also merited by the fact that all the
steps up to ( )-10 could be completed with only one chro-
matography at the end of the sequence. Another notewor-
thy feature of the present approach is the use of cyclic
sulfite instead of epoxide as substrate in the introduction
of the second nitrogen atom because the yields with the
cyclic sulfite were apparently higher. From the known
( )-14 following the literature steps it should be possible
to obtain ( )-1 in 12% overall yield in totally twelve steps.
The ( )-10 could also be resolved into optically active
components via corresponding N-acyl oxazolidin-2-
thione. Use of (+)-10 in lieu of ( )-10 in the same synthet-
ic sequence should allow for the synthesis of optically ac-
tive Tamiflu [(+)-1]. Compared the existing routes in the
literature, the present one is remarkably practical because
of use of common/inexpensive starting materials and re-
agents. It should make a good complement to its prece-
dents.
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Supporting Information for this article is available online at
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Acknowledgment
(7) Andersen, N.-G.; Maddaford, S.-P.; Keay, B.-A. J. Org.
Chem. 1996, 61, 2885.
Financial support from the National Natural Science Foundation of
China (20672129, 20621062, 20772143) and the Chinese Academy
of Sciences (‘Knowledge Innovation’, KJCX2.YW.H08) is grate-
fully acknowledged.
(8) For a similar elimination, see: Regis, L.-T.; Liu, Y.-Z.;
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References and Notes
(1) Information about avian flu and H5N1 virus can be found in:
(2) (a) Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H. J.;
Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.;
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E. J. J. Am. Chem. Soc. 2006, 128, 6310. (d) Fukuta, Y.;
(10) (a) Sun, X.-L.; Wu, Y.-L. Acta Chim. Sin. 1996, 54, 826.
(b) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang,
L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.;
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J. Am. Chem. Soc. 1997, 119, 681.
(11) For a facile synthesis of this auxiliary, see: Wu, Y.-K.; Yang,
Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990.
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