A new and efficient asymmetric synthesis of oseltamivir phosphate(Tamiflu) from D-mannose

Article abstract of DOI:org/10.1016/j.tetlet.2012.08.143

Oseltamivir phosphate (Tamiflu) was synthesized from D-mannose through a short and practical synthetic route. A unique feature of the route is that the bulky 3-pentyloxy group and adjacent acetamide of Tamiflu were introduced at an early stage of the synthesis by copper-catalyzed regioselective ringopening of the 2,3-pentylidene ketal of D-lyxofuranoside. The D-lyxofuranoside ethylphosphonate precursor was then cyclized via an intramolecular Horner-Wadsworth-Emmons reaction to furnish the Tamiflu skeleton.

Full text of DOI:org/10.1016/j.tetlet.2012.08.143

Tetrahedron Letters 53 (2012) 6209–6211
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new and efficient asymmetric synthesis of oseltamivir phosphate
(Tamiflu) from D-mannose
⇑
Nutthawat Chuanopparat, Ngampong Kongkathip, Boonsong Kongkathip
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry, Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University,
Chatuchak, Bangkok 10900, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Oseltamivir phosphate (Tamiflu) was synthesized from D-mannose through a short and practical syn-
Received 25 June 2012
Revised 22 August 2012
Accepted 31 August 2012
Available online 7 September 2012
thetic route. A unique feature of the route is that the bulky 3-pentyloxy group and adjacent acetamide
of Tamiflu were introduced at an early stage of the synthesis by copper-catalyzed regioselective ring-
opening of the 2,3-pentylidene ketal of D-lyxofuranoside. The D-lyxofuranoside ethylphosphonate precur-
sor was then cyclized via an intramolecular Horner–Wadsworth–Emmons reaction to furnish the Tamiflu
skeleton.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Oseltamivir phosphate
Avian flu
Mannose
Horner–Wadsworth–Emmons reaction
Reductive ring-opening
Oseltamivir phosphate (Tamiflu, 1) is a potent inhibitor of viral
neuraminidase and is used worldwide as a drug for the treatment
and prevention of both type A and type B influenza.1 The recent
spread of the avian virus, H5N1 and the swine flu virus (H1N1 hu-
man flu) has prompted many nations to stockpile Tamiflu in the
case of a possible influenza outbreak.2 However, only developing
countries can afford to stockpile this drug due to the high cost of
the Tamiflu production process.
production costs should be low. This requires that only inexpensive
starting materials and reagents be used.
Our group is currently involved in developing alternative syn-
thetic methods for Tamiflu.14a In a recent disclosure by us14b and
other researchers,14c
D-ribose was used to synthesize the title com-
pound. Our synthesis was based on a metal-mediated domino
reaction and ring-closing metathesis to construct the cyclohexene
ester core structure, followed by functional group manipulation to
afford Tamiflu. Although this synthesis had some merits such as
the novel method for constructing the cyclohexene core of the
target compound, it used an expensive Ru catalyst which would
hamper the large-scale preparation of oseltamivir phosphate. After
an extensive study, we have exploited a short, practical synthesis
Currently, Tamiflu is produced and supplied by Roche using
(À)-shikimic acid as the starting material, which is not always
readily available in consistently pure form.3 Production of (À)-shikimic
acid with a consistent purity, is both time-consuming and costly.
Therefore, significant efforts have been made to improve the syn-
thesis of Tamiflu. For example, several new synthetic methods
have been developed without using shikimic acid. Commercially
of oseltamivir phosphate starting from
D-mannose which is a
less-expensive material. Herein, we report the details. The key fea-
ture of our new synthetic process is that the bulky 3-pentyloxy
group and the adjacent acetamide of Tamiflu were introduced at
an early stage of the synthesis by employing catalytic ring-opening
available starting materials such as (À)-quinic acid,3
L
-serine,4
xylose,5 a mesoaziridine,6 a substituted cyclohexadiene7 a lactone,8 a
pyridine,9 2,6-dimethoxyphenol,10
D L
-mannitol,11 -methionine,12 ethyl
benzoate,13 -ribose,14 and diethyl tartrate15 have been used for the
D
of
-mannose, and the resulting OH was transformed into an
acetamide.
As shown by our retrosynthetic analysis (Fig. 1), we envisioned
a 2,3-pentylidene ketal of D-lyxofuranoside, derived from
synthesis of Tamiflu. Among those, monosaccharides such as xylose,
glucose, ribose, mannose, and arabinose are important chiral raw
materials available in nature. They are not only less-expensive, but
also possess chiral centers, therefore it is quite easy to find the most
appropriate substrate to fit the synthetic plan. Moreover, in order to
supply Tamiflu to developing countries where influenza might spread,
D
that construction of the cyclohexene ester 2, a core of Tamiflu could
be accomplished via intramolecular Horner–Wadsworth–Emmons
olefination16 of the phosphoryl ester which in turn could be pre-
pared from the reaction of functionalized 5-aldolyxofuranoside 3
and diethylphosphonoacetate. The functionalized furanoside could
⇑
Corresponding author. Tel.: +66 2 5625444x2235; fax: +66 2 5625444x2119.
E-mail address: fscibsk@ku.ac.th (B. Kongkathip).
be derived from the 2,3-pentylidene ketal of D-lyxofuranoside 6 by
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.143

6210
N. Chuanopparat et al. / Tetrahedron Letters 53 (2012) 6209–6211
EtO2C
P(O)(OEt)2
wasobservedwhenthehydroxyparentcompound6wasused(entry
3). These results indicated that the direction of ring-cleavage might
be influenced by the hydroxy group at C-5. In order to investigate the
effect of the functional group at C-5 in this reaction, the silyl ether 8
and the aldehyde analog 5 were examined. Moreover, Cu(OTf)2,
whichhasbeenreportedtobe aneffectivecatalystfortheregioselec-
tive ring-opening of 4,6-O-benzylidene acetal in hexapyranoside
systems,19 was also tested in our investigation. We found that when
using Et3SiH in the presence of Cu(OTf)2 in acetonitrile, reductive
ring-opening of ketal 5 did not proceed, and only starting material
was recovered (entry 4). This might be due to Cu(OTf)2 being a weak-
er Lewis acid than TiCl4. When Cu(OTf)2 was used in combination
with BH3ÁTHF, a stronger reductant, ketal ring-opening proceeded
to give diol 11 and alcohol 6 (entry 5). The results indicated that
the aldehyde was reduced to an alcohol under these conditions. Sim-
ilar results were obtained when the acetate and silyl derivatives 7
and 8 were examined (entries 6 and 7). TLC monitoring of the reac-
tion revealed that the acetoxy and silyl groups were removed under
the reaction conditions to give the corresponding alcohols which
then proceeded to undergo ketal ring-opening. To prove our
assumption alcohol 6 was subjected to catalytic ring-opening under
the same conditions. Indeed, only isomer 11 was obtained exclu-
sively from the reaction (entry 8).
O
CO2Et
O
CO2Et
O
OH
AcHN
AcHN
AcHN
O
O
NH2.H3PO4
OH
O
1
Tamiflu ( )
2
oseltamivir phosphate
HO
O
OBn
OH
H
OH
O
OBn
HO
HO
HO
AcHN
OH
O
O
H
H
3
H
H
6
D-mannose
Figure 1. Retrosynthetic analysis of oseltamivir phosphate (1) from D-mannose via
regioselective ring-opening of a ketal.
O
O
O
O
OH
R
OBn
D-mannose
O
O
O
O
This regioselectivity is attributed to the preferential complexa-
tion of the 5-hydroxy group and the adjacent ketal oxygen with the
copper reagent to form a bidentate complex (Fig. 2), which would
favor C3–O bond cleavage to give O-benzyl-2-O-isopentylidene-5-
5. R = CHO
6. R = CH2OH
4
Ac2O, py, rt
7.
8.
R = CH2OAc
R = CH2OSiMe3
Me3SiCl, py, rt
a-D
-lyxomannofuranoside (11).
Having achieved the crucial regioselective cleavage of the ketal
Scheme 1. Synthesis of O-benzyl-2,3-O-isopentylidene-
a
-
D
-lyxofuranosides.
group, selective protection of diol 11 was performed using
TBDMSCl to give 13 in good yield (Scheme 2). Treatment of 13 with
trifluoromethane sulfonic anhydride in the presence of pyridine at
0 °C afforded the triflate derivative, which was subsequently re-
acted with sodium azide in acetone-water to give 3-azidofuranose
14. The azide group of 14 was transformed into an amino moiety
by treatment with PPh3 which was then acetylated to give acetam-
ide 15. Removal of the silyl protecting group by treatment with
regioselective opening of the ketal followed by azide substitution of
the resulting hydroxy group, reduction, and acetylation.
The synthesis (Scheme 1) was started with diacetal formation
from
to give 2,3:5,6-di-O-pentylidene-
D
-mannose using a modified method described by Whistler17
a-D-mannofuranose (4), which
was subsequently converted, without isolation into aldehyde
5 and then reduced into alcohol 6; the overall yield of 6 from
D
-mannose was 30% (Scheme 1).18
Our initial plan was to convert 6 into its acetate 7 followed by
O
H
cleavage of the ketal group employing a highly selective protocol
involving TiCl4/Et3SiH, as in the shikimic acid route, developed by
Mair and co-workers.3b Unfortunately, the reaction afforded poor
selectivity (9:10 = 1:1) for the desired product 9 either at À78 °C or
at 0 °C (Table 1, entries 1 and 2). However improved regioselectivity
O
O
O
Cu
TfO
TfO
OBn
3
2
Figure 2. Transition state during ketal cleavage mediated by Cu(OTf)2.
Table 1
Reductive ring-opening of the pentylidene ketals 5–8
O
O
O
R
OBn
OBn
R
OBn
OH
conditions
R
+
HO
O
O
O
O
5 8
-
10
R = CH2OAc
9
R = CH2OAc
R = CH2OH
12 R = CH2OH
11
Entry
Substrate
Conditions
Yield (%) 9
20
18
—
Yield (%) 10
Yield (%) 11
Yield (%) 12
Yield (%) 6
1
2
3
4
5
6
7
8
7: R = CH2OAc
7: R = CH2OAc
6: R = CH2OH
5: R = CHO
TiCl4, Et3SiH, CH2Cl2, –78 °C, 5 min
TiCl4, Et3SiH, CH2Cl2, 0 °C, 5 min
TiCl4, Et3SiH, CH2Cl2, –78 °C, 5 min
Cu(OTf)2, Et3SiH, MeCN, rt, 2 h
Cu(OTf)2, BH3ÁTHF, rt, 2 h
20
20
—
—
—
40
—
—
15
—
—
—
Starting material was recovered
5: R = CHO
—
—
—
—
—
—
—
—
60
55
59
75
—
—
—
—
20
30
31
10
7: R = CH2OAc
8: R = CH2OSiMe3
6: R = CH2OH
Cu(OTf)2, BH3ÁTHF, rt, 10 min
Cu(OTf)2, BH3ÁTHF, rt, 10 min
Cu(OTf)2, BH3ÁTHF, rt, 2 h

N. Chuanopparat et al. / Tetrahedron Letters 53 (2012) 6209–6211
6211
HO
by Horner–Wadsworth–Emmons olefination afforded the Tamiflu
skeleton. Throughout the synthesis, well-established, highly effi-
cient reactions were employed.
TBDMSO
TBDMSCl, imidazole,
DMAP, CH2Cl2, 82%
O
O
1) Tf2O, Py,
CH2Cl2, 0 °C
OBn
OBn
O
HO
O
HO
2) NaN3
acetone/H2O
(9:1), rt,
Acknowledgments
13
11
(89% over 2 steps)
N.C. is a Ph.D. student under the Royal Golden Jubilee Program,
the Thailand Research Fund (TRF). We are grateful for financial
support from the TRF, through the Royal Golden Jubilee Program.
Financial support from the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Commission on Higher Education, Minis-
try of Education and the Kasetsart University Research and Devel-
opment Institute (KURDI) is also gratefully acknowledged.
TBDMSO
TBDMSO
1. PPh3, THF, rt., 4 h
then H2O, Et3N, rt.,
O
O
OBn
OBn
O
O
2. Ac2O, pyridine, 0 °C to
rt., 2 h
( 70% over 2 steps)
AcHN
N3
14
15
HO
1) (COCl)2, DMSO, Et3N,
CH2Cl2, -78 °C, 2 h,
O
Supplementary data
OBn
TBAF, THF,
0 °C to rt.,
4 h, 95%
AcHN
O
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.143.
2) (EtO)2(O)PCH2CO2Et,
TiCl4, Et3N, CH2Cl2, 0 oC, 2 h
16
3) 10% Pd/C, EtOH, rt., 4 d
(33% over 3 steps)
References and notes
O
O
P
CO2Et
EtO
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Et3N, rt, overnight,
81%.
CO2Et
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1
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N3
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2) 20% H3PO4/EtOH
50 °C, 30 min, 0 °C,
82%
NHAc
19
Scheme 2. Completion of the synthesis of oseltamivir phosphate 1.
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TBAF gave the hydroxy compound 16 in excellent yield. Oxidation
of 16 using Swern conditions yielded the corresponding aldehyde,
Knoevenagel condensation of which with ethyl dimethoxyphos-
phoryl acetate followed by hydrogenation gave the C1-elongated
phosphonate 17 in 33% yield over the three steps.
Intramolecular Horner–Wadsworth–Emmons olefination of 17
using sodium hydride in THF afforded 4b-acetamido shikimate
18 in moderate yield. The second amino group was introduced into
18 by activation of the 5b-hydroxy group as the mesylate followed
by azide substitution with sodium azide to give azido acetamido
shikimate 19. Finally, azide 19 was reduced by treatment with tri-
phenylphosphine and water to form an amine, which was directly
exposed to 1.2 equiv of phosphoric acid in ethanol at 50 °C to af-
ford Tamiflu (1) in 82% yield.
In summary, we have achieved a new asymmetric synthesis of
Tamiflu in 13 steps and 5% overall yield from cheap and abundant
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Chem., Int. Ed. 2005, 44, 1665–1666.
3-pentyloxy group and the adjacent acetamide of Tamiflu were
introduced at an early stage of the synthesis by regioselective ketal
ring-opening of
D-lyxofuranoside using Cu(OTf)2 as the catalyst.
Condensation with diethylphosphonoacetate and then cyclization