Communications

DOI: 10.1002/anie.200804883
Domino Reactions

High-Yielding Synthesis of the Anti-Influenza Neuramidase Inhibitor

( )-Oseltamivir by Three “One-Pot” Operations**
Hayato Ishikawa, Takaki Suzuki, and Yujiro Hayashi*

A great deal of attention has been paid both in the scientific been reported, previous methods do not meet all these
literature and the general media to the high potential risk of a requirements, and developing a method which does so
worldwide spread of avian H5N1 influenza virus, the death remains a great challenge for the chemical community.
rate of which is over 50 %.[1] Indeed, should this virus acquire One-pot operations are effective for carrying out several
the ability to become capable of spreading easily and directly transformations and forming several bonds in a single pot,
from human to human it could very possibly cause a while at the same time cutting out several purification steps,
disastrous pandemic. ( )-Oseltamivir phosphate (Tamiflu), minimizing chemical waste generation, and saving time. To
a neuraminidase inhibitor used in the treatment of both simplify the synthesis we investigated the preparation of
type A and type B human influenza,[2] is one of the most Tamiflu by a small number of one-pot operations. Our
promising therapeutics, and many nations have plans to stock strategy was to construct a key, fully functionalized ethyl
a significant amount of this compound in case of a possible cyclohexenecarboxylate intermediate in a single-pot opera-
influenza outbreak. Moreover, the recent emergence of tion as the first step; after this, the remainder of the synthesis
Tamiflu-resistant virus strains has prompted the chemical consists simply of functional group manipulations, also
community to develop medicines effective against the carried out in one-pot operations.
mutated virus.[3] To meet these demands, intensive efforts The first key reaction relied on organocatalysis, a
have been devoted to the development of efficient prepara- relatively new, rapidly developing technology in synthetic
tions of this life-saving drug[1, 2, 4] and of its derivatives. organic chemistry.[5] Diphenylprolinol silyl ether 4,[6] which
For our synthesis of Tamiflu, we set the following was developed independently by our group[7] and Jørgensens
objectives, because meeting these requirements would allow group,[8] acts as an effective organocatalyst, promoting many
a large amount to be prepared in a short time and at low cost: kinds of asymmetric reactions with excellent enantioselectiv-
1) The number of synthetic reactions should be not more than ities. We have already reported the highly enantioselective
ten, and the number of separate operations should be as few Michael reactions of aldehydes and nitroalkenes catalyzed by
as possible. 2) The overall yield should be over 50 %. 3) Only ether 4,[7a] which was also elegantly employed by Enders and
inexpensive reagents should be employed. Preparing a co-workers in a domino reaction with a,b-enals to prepare
molecule of this complexity, possessing three contiguous tetrasubstituted cyclohexenecarbaldehydes.[9] We applied our
chiral centers, in no more than ten synthetic reactions in over reaction to the present synthesis using the three simple
50 % overall yield is a very challenging goal. Even if each starting materials alkoxyaldehyde 2, nitroalkene 3, and
individual reaction of a sequence proceeds in 90 % yield—an diethyl vinylphosphonate derivative 5; subsequent treatment
excellent yield in organic synthesis—the overall yield falls to with p-toluenethiol afforded the heavily functionalized ethyl
35 % after ten reactions (0.910 = 0.35). The best yield yet cyclohexanecarboxylate 6 in good yield (70 %) in a single-pot
achieved for the total synthesis of Tamiflu is approximately operation (Scheme 1). This crucial reaction requires some
35 %.[4b, d] Moreover, in order to supply Tamiflu to developing comment: The first reaction of 2 and 3, which is catalyzed by
countries where influenza might spread, production costs diphenylprolinol silyl ether 4, provides the Michael adduct 8
should be kept low. This requires that only inexpensive (Figure 1) in quantitative yield with excellent enantioselec-
reagents be used. Although several syntheses of Tamiflu have tivity if we quench the reaction at this stage. Only 5 mol % of
the catalyst is sufficient to promote the reaction, which makes
[*] Dr. H. Ishikawa, T. Suzuki, Prof. Dr. Y. Hayashi it highly practical.
Department of Industrial Chemistry, Faculty of Engineering The next step involves a domino reaction as nitroalkane 8
Tokyo University of Science reacts with vinylphosphonate 5 by a Michael reaction, and the
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan) phosphonate generated undergoes an intramolecular
Fax: (+ 81) 3-5261-4631 Horner–Wardsworth–Emmons reaction with the formyl
E-mail: hayashi@ci.kagu.tus.ac.jp
group to generate ethyl cyclohexenecarboxylate 9. Although
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
this proceeds well, not only the desired 9 but also by-products
Prof. Dr. Y. Hayashi
such as 10 and 11 are obtained. Hydroxy phosphonate 10 can
Research Institute for Science and Technology
Tokyo University of Science (Japan) be isolated as a result of the anti arrangement of its hydroxy
[**] This work was supported in part by Grant-in-Aid for Creative and diethoxyphosphoryl groups, which is unfavorable for
Scientific Research from The Ministry of Education, Culture, Sports, elimination; 11 arises from a second Michael reaction, this
Science, and Technology (MEXT). time of 9 with 5. We found that the undesired products 10 and
Supporting information for this article is available on the WWW 11 can be transformed successfully into the desired cyclo-
under http://dx.doi.org/10.1002/anie.200804883. hexene 9 by treating the mixture of 9, 10, and 11 in situ with

1304  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2009, 48, 1304 –1307
 Angewandte
Chemie

Scheme 1. The total synthesis of ( )-oseltamivir (1). TFA = trifluoroacetic acid, TMS = trimethylsilyl, tol = tolyl.

and 11 undergoes a retro-Michael reaction; in both cases

target 9 is generated.
As diester 9 is obtained as a mixture of diastereomers in
which the undesired (5R)-9 isomer predominates, we exam-
ined the isomerization. Although both acid- and base-
mediated conversion of (5R)-9 to the desired (5S)-9 was
partially successful, we have developed a more efficient
transformation, which is the last stage of the first one-pot
operation: Treatment of the (5S)-9/(5R)-9 mixture with p-
toluenethiol in the presence of Cs2CO3 gives the Michael
product in excellent yield, with the desired 5S isomer
predominating. In this reaction, (5R)-9 and (5S)-9 equilibrate,
and a thiol-Michael addition reaction proceeds stereoselec-
tively and predominantly from (5R)-9. Although the Michael
adduct (5R)-6 is first formed, it is easily isomerized into (5S)-
6, which is more stable than (5R)-6 under basic conditions.
Thus, starting from the mixture of (5R)-9 and (5S)-9, the
desired isomer (5S)-6 is obtained in good yield.
The remaining transformations required are the conver-
sion of a tert-butoxycarbonyl group into an acetylamino
moiety, and reduction of the nitro group into an amine moiety.
Deprotection of the tert-butyl ester was successfully per-
formed by treatment of 6 with CF3CO2H. Excess reagent was
removed under reduced pressure, and the crude carboxylic
Figure 1. The synthetic intermediates of ( )-oseltamivir (1). acid was converted into the acyl azide by addition of first
oxalyl chloride, then NaN3 in aqueous acetone. In this way,
acyl azide 7, which is pure enough to be used directly in the
next reactions, was prepared from 6 in a single pot.
Cs2CO3 in EtOH. Compound 10 undergoes a retro-aldol The next three reactions were also conducted in one pot.
reaction followed by Horner–Wardsworth–Emmons reaction, When 7 was treated with AcOH in Ac2O at room temper-

Angew. Chem. Int. Ed. 2009, 48, 1304 –1307  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 1305
Communications
ature, a domino reaction consisting of a Curtius rearrange-
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.
Keywords: antiviral agents · domino reactions · organocatalysis ·
oseltamivir · Tamiflu
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