High-yielding synthesis of the anti-influenza neuramidase inhibitor (-)-oseltamivir by three "One-Pot" operations

Article abstract of DOI:10.1002/anie.200804883

Taking shortcuts: A remarkably short and high-yielding asymmetric total synthesis of (-)-oseltamivir takes advantage of organocatalysis and single-pot domino operations. The target, known as the drug Tamiflu, is prepared efficiently in a short time, and a

Full text of DOI:10.1002/anie.200804883

Communications
DOI: 10.1002/anie.200804883
Domino Reactions
High-Yielding Synthesis of the Anti-Influenza Neuramidase Inhibitor
(À)-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
literature and the general media to the high potential risk of a
worldwide spread of avian H5N1 influenza virus, the death
rate of which is over 50%.[1] Indeed, should this virus acquire
the ability to become capable of spreading easily and directly
from human to human it could very possibly cause a
disastrous pandemic. (À)-Oseltamivir phosphate (Tamiflu),
a neuraminidase inhibitor used in the treatment of both
type A and type B human influenza,[2] is one of the most
promising therapeutics, and many nations have plans to stock
a significant amount of this compound in case of a possible
influenza outbreak. Moreover, the recent emergence of
Tamiflu-resistant virus strains has prompted the chemical
community to develop medicines effective against the
mutated virus.[3] To meet these demands, intensive efforts
have been devoted to the development of efficient prepara-
tions of this life-saving drug[1,2,4] and of its derivatives.
For our synthesis of Tamiflu, we set the following
objectives, because meeting these requirements would allow
a large amount to be prepared in a short time and at low cost:
1) The number of synthetic reactions should be not more than
ten, and the number of separate operations should be as few
as possible. 2) The overall yield should be over 50%. 3) Only
inexpensive reagents should be employed. Preparing a
molecule of this complexity, possessing three contiguous
chiral centers, in no more than ten synthetic reactions in over
50% overall yield is a very challenging goal. Even if each
individual reaction of a sequence proceeds in 90% yield—an
excellent yield in organic synthesis—the overall yield falls to
35% after ten reactions (0.910 = 0.35). The best yield yet
achieved for the total synthesis of Tamiflu is approximately
35%.[4b,d] Moreover, in order to supply Tamiflu to developing
countries where influenza might spread, production costs
should be kept low. This requires that only inexpensive
reagents be used. Although several syntheses of Tamiflu have
been reported, previous methods do not meet all these
requirements, and developing a method which does so
remains a great challenge for the chemical community.
One-pot operations are effective for carrying out several
transformations and forming several bonds in a single pot,
while at the same time cutting out several purification steps,
minimizing chemical waste generation, and saving time. To
simplify the synthesis we investigated the preparation of
Tamiflu by a small number of one-pot operations. Our
strategy was to construct a key, fully functionalized ethyl
cyclohexenecarboxylate intermediate in a single-pot opera-
tion as the first step; after this, the remainder of the synthesis
consists simply of functional group manipulations, also
carried out in one-pot operations.
The first key reaction relied on organocatalysis, a
relatively new, rapidly developing technology in synthetic
organic chemistry.[5] Diphenylprolinol silyl ether 4,[6] which
was developed independently by our group[7] and Jørgensenꢀs
group,[8] acts as an effective organocatalyst, promoting many
kinds of asymmetric reactions with excellent enantioselectiv-
ities. We have already reported the highly enantioselective
Michael reactions of aldehydes and nitroalkenes catalyzed by
ether 4,[7a] which was also elegantly employed by Enders and
co-workers in a domino reaction with a,b-enals to prepare
tetrasubstituted cyclohexenecarbaldehydes.[9] We applied our
reaction to the present synthesis using the three simple
starting materials alkoxyaldehyde 2, nitroalkene 3, and
diethyl vinylphosphonate derivative 5; subsequent treatment
with p-toluenethiol afforded the heavily functionalized ethyl
cyclohexanecarboxylate 6 in good yield (70%) in a single-pot
operation (Scheme 1). This crucial reaction requires some
comment: The first reaction of 2 and 3, which is catalyzed by
diphenylprolinol silyl ether 4, provides the Michael adduct 8
(Figure 1) in quantitative yield with excellent enantioselec-
tivity if we quench the reaction at this stage. Only 5 mol% of
the catalyst is sufficient to promote the reaction, which makes
it highly practical.
[*] Dr. H. Ishikawa, T. Suzuki, Prof. Dr. Y. Hayashi
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
The next step involves a domino reaction as nitroalkane 8
reacts with vinylphosphonate 5 by a Michael reaction, and the
phosphonate generated undergoes an intramolecular
Horner–Wardsworth–Emmons reaction with the formyl
group to generate ethyl cyclohexenecarboxylate 9. Although
this proceeds well, not only the desired 9 but also by-products
such as 10 and 11 are obtained. Hydroxy phosphonate 10 can
be isolated as a result of the anti arrangement of its hydroxy
and diethoxyphosphoryl groups, which is unfavorable for
elimination; 11 arises from a second Michael reaction, this
time of 9 with 5. We found that the undesired products 10 and
11 can be transformed successfully into the desired cyclo-
hexene 9 by treating the mixture of 9, 10, and 11 in situ with
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
Prof. Dr. Y. Hayashi
Research Institute for Science and Technology
Tokyo University of Science (Japan)
[**] This work was supported in part by Grant-in-Aid for Creative
Scientific Research from The Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804883.
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Scheme 1. The total synthesis of (À)-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
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.
Figure 1. The synthetic intermediates of (À)-oseltamivir (1).
Cs2CO3 in EtOH. Compound 10 undergoes a retro-aldol
reaction followed by Horner–Wardsworth–Emmons reaction,
The next three reactions were also conducted in one pot.
When 7 was treated with AcOH in Ac2O at room temper-
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ature, a domino reaction consisting of a Curtius rearrange-
ment and amide formation proceeded to afford 12.[10] It is a
synthetic merit that the Curtius rearrangement proceeds at
room temperature; reaction of the acyl azide does not require
heating, which decreases potential hazards. Nitro compound
12 was treated with Zn/HCl in EtOH to provide amine 13.
After ammonia had been bubbled into the reaction mixture to
form the ZnII–NH3 complex, addition of K2CO3 promoted the
retro-Michael reaction of the thiol to afford oseltamivir (1),
which was purified by acid/base extraction and obtained in
82% yield from 6. The properties of synthetic (À)-oseltamivir
are identical to those reported in the literature (1H and
13C NMR spectra, IR spectrum, Rf value, optical rotation).[4k,n]
It should be noted that all the synthetic transformations from
7 to 1 could be performed in the same reaction vessel. The
intermediate 12 is a solid and can be purified by crystalliza-
tion.
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In summary, an efficient, enantioselective total synthesis
of (À)-oseltamivir has been accomplished, demonstrating the
power of asymmetric reactions catalyzed by organocatalysts,
in particular diphenylprolinol silyl ether 4. The present
synthesis has several noteworthy features: 1) A highly
functionalized chiral cyclohexane framework of the correct
configuration is synthesized in the first one-pot operation,
which consists of a succession of reactions, including a
diphenylprolinol silyl ether mediated, asymmetric Michael
reaction, a domino Michael reaction/Horner–Wardsworth–
Emmons reaction combined with retro-aldol and retro-
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catalyzed isomerization. 2) Three reactions occur in the third
one-pot operation: a Curtius rearrangement, the reduction of
a nitro group to an amine, and a retro-Michael reaction of the
thiol. 3) The Curtius rearrangement proceeds at room tem-
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4) The domino reaction consisting of a Curtius rearrangement
and amide formation is a direct method for the synthesis of 12.
This synthesis requires nine reactions, a total of three
separate one-pot operations, and one purification by column
chromatography. The total yield of (À)-oseltamivir from
nitroalkene 3 is 57%. All the reagents are inexpensive. The
metal-based reagents employed in the present total synthesis
contain either alkali-metal ions (Na, K, and Cs) or nontoxic
Zn. No special care is needed to exclude water or air. Thus,
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The synthetic route itself is completely different from
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for agents effective against Tamiflu-resistant viruses. We hope
that further refinement of the present method will make it
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Received: October 6, 2008
Published online: January 2, 2009
Keywords: antiviral agents · domino reactions · organocatalysis ·
.
oseltamivir · Tamiflu
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