A concise and flexible synthesis of the potent anti-influenza agents tamiflu and tamiphosphor

Article abstract of DOI:10.1002/anie.200801959

(Chemical Equation Presented) Tamiflu and the highly potent neuraminidase inhibitor tamiphosphor have been synthesized in 11 steps and greater than 20% overall yields from an haloarene (1S,2S)-cis-diol. The key transformations include a regio- and stereoselective bromoamidation, and a palladium-catalyzed carbonylation or phosphonylation reaction (see scheme; tamiflu: A = CO ₂Et, B = NH₃⁺H₂PO₄ ^-, tamiphosphor: A = PO(ONH₄)₂, B = NH ₂).

Full text of DOI:10.1002/anie.200801959

Communications
DOI: 10.1002/anie.200801959
Natural Products Synthesis
A Concise and Flexible Synthesis of the Potent Anti-Influenza Agents
Tamiflu and Tamiphosphor**
Jiun-Jie Shie, Jim-Min Fang,* and Chi-Huey Wong
Influenza remains a major health problem. The worldwide
occurrences of avian flu have increased public awareness of
the potential for global influenza pandemics. Tamiflu (oselta-
mivir phosphate, 1·H3PO4; Scheme 1),[1] a popular drug for
effective inhibitor (Ki = 19 nm) of the H274Y mutant of H5N1
neuraminidase.[3] Furthermore, our preliminary study indi-
cates that tamiphosphor is also orally bioavailable and
protects mice against lethal influenza viruses. By comparison
of the survival rate and mean survival time of infected mice
(data not shown), tamiphosphor is found to be more effective
than tamiflu against the H1N1 human influenza virus and at
least equally effective against the recombinant H5N1
(NIBRG14) virus.
The current industrial synthesis of tamiflu relies on
naturally occurring shikimic acid as a starting material.[4]
However, the availability of consistently pure shikimic acid
may be problematic. One of the drawbacks of this large-scale
synthesis lies in the manipulation of the potentially explosive
azide reagent and intermediates. Several new synthetic
methods for the preparation of tamiflu have been developed
without using shikimic acid.[5] To establish the cyclohexene-
carboxylate core structure of tamiflu, various types of Diels–
Alder reactions have been applied. For example, Karpf and
co-workers[5a,c] have carried out the Diels–Alder reaction
between an appropriately functionalized furan and acrylate,
followed by enzymatic resolution, to obtain the chiral
intermediate for the synthesis of tamiflu. In one approach
by Shibasaki and co-workers,[6a] the Diels–Alder reaction of 1-
trimethylsilyloxy-1,3-butadiene with fumaryl chloride was
utilized to construct the core structure; however, separation
of the racemic mixture of a key intermediate (by HPLC on a
chiral stationary phase) was required. Alternatively, the
catalytic enantioselective Diels–Alder reactions developed
by the research groups of Corey[7] and Fukuyama[8] afforded
the required chiral cyclohexenecarboxylates for the synthesis
of tamiflu. In another approach by the research group of
Shibasaki,[6b–d] a meso-aziridine derivative of 1,4-cyclohexa-
diene was prepared and subjected to a catalytic asymmetric
ring-opening reaction with trimethylsilyl azide, which served
as the platform methodology for the synthesis of tamiflu.
Karpf and co-workers used Ru/Al2O3-catalyzed hydrogena-
tion of a substituted isophthalic diester to provide the
cyclohexane core where all the substituents and the diester
are disposed cis to one another.[5a,c] The meso diester was then
enzymatically hydrolyzed to an optically active monoacid,
which serves as the key intermediate for the synthesis of
Scheme 1. Retrosynthetic strategy for anti-influenza agents starting
from bromoarene cis-1,2-dihydrodiol (5). Boc=tert-butyloxycarbonyl.
the treatment of influenza, is an orally administrated prodrug
which is readily hydrolyzed by hepatic esterases to give the
corresponding carboxylic acid 2 as the active inhibitor of
neuraminidase on the influenza virus. As the side effects of
tamiflu cause teenage patients to suffer from mental disor-
ders,[2] and with the emergence of drug-resistant strains of
avian flu, the development of new chemical entities to combat
influenza viruses are urgently needed for the battle against
the threat of pandemic flu.
We recently reported that tamiphosphor (3) is a promising
drug against both avian flu and human influenza.[3] Tami-
phosphor, in which the carboxyl group in oseltamivir is
replaced with a phosphonate group, interacts strongly with
the three arginine residues of neuraminidase, and is more
potent against the wild-type neuraminidases of H1N1 and
H5N1 viruses. In addition, the guanidine analogue 4 is an
[*] Prof. J.-M. Fang
Department of Chemistry
National Taiwan University, Taipei 106 (Taiwan)
Fax: (+886)2-2363-7812
E-mail: jmfang@ntu.edu.tw
[9]
tamiflu. Kann and co-workers demonstrated the synthesis
Dr. J.-J. Shie, Prof. J.-M. Fang, Prof. C.-H. Wong
The Genomics Research Center
Academia Sinica, Taipei, 11529 (Taiwan)
of tamiflu by starting with the amination of a chiral cationic
iron complex of cyclohexadienecarboxylate, which was
obtained by separation of the diastereomers formed with
(1R,2S)-2-phenylcyclohexanol. Trost and Zhang reported a
palladium-catalyzed asymmetric allylic amination of 5-oxa-
bicyclo[3.2.1]hexen-4-one as a key step in the synthesis of
tamiflu.[10]
[**] We thank the National Science Council for financial support, and the
Advanced Instrumentation Center of the National Taiwan University
for X-ray diffraction analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801959.
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Chemie
We have reported the
synthesis of tamiflu and
tamiphosphor using d-
xylose as an inexpensive
starting material.[3] The
cyclohexene core of the
target compounds is con-
structed by an intramolec-
ular Horner–Wadsworth–
Emmons reaction.[11] Even
though this flexible syn-
thetic method provides
both tamiflu and tamiphos-
phor in reasonable overall
yields
(5–13%),
the
lengthy reaction pathway
(18 or 19 steps) is not
ideal for a large-scale syn-
thesis. Herein, we explore a
more concise and practical
synthetic route to tamiflu
(1·H3PO4) and tamiphos-
phor (3; Scheme 1). The
enantiopure starting mate-
rial used in our procedure,
bromoarene cis-1,2-dihy-
drodiol (5), is commercially
available and is easily pro-
duced on large scales by
microbial oxidation of bro-
mobenzene.[12] As a result
of their unique combina-
tions of functionality, the
haloarene cis-dihydrodiols
have been successfully
applied to the synthesis of
various natural products
Scheme 2. Concise synthesis of 1·H3PO4 and 3. DABCO=1,4-diazabicyclo[2.2.2]octane, DIAD=diisopropyl
azodicarboxylate, DMP=dimethoxypropane, DPPA=diphenylphosphoryl azide, LHMDS=lithium hexamethyl-
disilazide, NBA=N-bromoacetamide.
and related molecules.[12] In addition, the bromine atom can
be transformed into various functional groups, including
carboxylate and phosphonate, at a late stage of the synthetic
sequence. Thus, the proposed synthetic strategy is versatile in
that the common intermediates, for example 12 and 15, are of
pivotal importance to prepare tamiflu, tamiphosphor, and
other derivatives. Such late-stage functionalization is partic-
ularly appealing from a medicinal chemistry point of view.
Based on this synthetic plan, the acetonide of 5 was
subjected to a SnBr4-catalyzed bromoacetamidation reaction
with N-bromoacetamide (NBA) in CH3CN at 08C[13] to give
bromoamide 6 in a regio- and stereoselective manner
(Scheme 2). The structure of 6 was confirmed by X-ray
diffraction analysis (see the Supporting Information). The
reaction most likely proceeds by formation of a bromonium
ion on the less hindered face, followed by a selective backside
attack of the acetamide moiety at the allylic C5-position. In
the presence of LHMDS (1.1 equiv), bromoamide 6 was
converted into aziridine 7, which underwent a BF3-mediated
ring-opening reaction with 3-pentanol to give compound 8 in
73% yield. After removal of the protecting group, the cis-diol
9 was treated with a-acetoxyisobutyryl bromide to afford the
corresponding trans-2-bromocyclohexyl acetate 10. By anal-
ogy to precedented examples,[14] this reaction might involve
formation of an intermediate acetoxonium ion and a backside
attack by a bromide ion at the allylic C2-position. The
reaction of 10 with LiBHEt3 (super-hydride; 3 equiv) cleanly
afforded 11 in 82% yield (from 9) by simultaneous reduction
of the acetyl group and the bromine atom at the C1- and C2-
positions, respectively. The hydroxy group of 11 was success-
fully substituted by an azido group with inversion of config-
uration upon treatment with diphenylphosphoryl azide
(DPPA) according to the Mitsunobu method to give 12 in
84% yield.[3] A small amount (2%) of diene 13, which is the
side product generated by elimination of a water molecule,
was also observed. The pivotal compound 12 was subjected to
organometallic coupling reactions to incorporate the desired
carboxyl or phosphonyl groups. Thus, the reaction of 12 with
[Ni(CO)2(PPh3)2] in the presence of EtOH gave the ethyl
ester 14a in 81% yield.[15] On the other hand, phosphonyla-
tion of 12 with diethyl phosphite was achieved by using a
catalytic amount of [Pd(PPh3)4] to afford the phosphonate
14b in 83% yield.[16] After reduction of the azido group of 14a
and 14b to an amine moiety, tamiflu and tamiphosphor were
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Communications
respectively synthesized according to our previously reported
procedures.[3]
The above synthetic method was further improved by the
reaction sequence using the readily available starting material
bromoarene cis-1,2-dihydrodiol (5), which can be supplied
from the microbial oxidation of bromobenzene. All reactions
were handled without using potentially hazardous intermedi-
ates or toxic reagents, and as most of the reactions occurred in
a regio- and stereoselective fashion to give crystalline
products throughout the synthesis (6, 9, 11, 12, 14a, 15, 17a,
17b, 1·H3PO4, and 3), the isolation procedures were relatively
simple and cost effective. Even though only a gram-scale
synthesis is demonstrated in this study, the large-scale syn-
thesis of tamiflu and tamiphosphor looks promising and will
be useful for the development of anti-influenza drugs.
development of an azide-free process.[17] We found that
tetrabutylammonium cyanate was a good source for the
amine functionality. Alcohol 11 was treated with Bu4NOCN/
PPh3/DDQ to give an isocyanate intermediate,[18] which was
subsequently treated with tBuOH to give carbamate 15 in
78% yield (Scheme 3). A Pd-catalyzed coupling reaction with
Received: April 25, 2008
Keywords: asymmetric synthesis · chiral pool · drug design ·
.
synthesis design · total synthesis
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