A facile access to antiflu agent tamiflu/oseltamivir

Article abstract of DOI:10.1055/s-0029-1217740

A practical approach to Tamiflu is developed featuring the construction of the carbocycle core of the target molecule through a Diels-Alder reaction with concurrent introduction of one of the nitrogen atoms. Incorporation of another nitrogen atom was achi

Full text of DOI:10.1055/s-0029-1217740

LETTER
A
A Facile Access to Antiflu Agent Tamiflu/Oseltamivir
S
ynthesis of
Tami
a
a
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: ylwu@mail.sioc.ac.cn; E-mail: yikangwu@mail.sioc.ac.cn
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Avenue, Changchun, Jilin 130012, P. R. of China
b
Received 16 June 2009
allow for synthesis of racemic Tamiflu in twelve steps and
12% overall yield if using the last four steps in Kann’s2k
and Corey’s2c route, respectively. In combination of reso-
lution of a key intermediate (10), enantiopure (+)-Tamiflu
Abstract: A practical approach to Tamiflu is developed featuring
the construction of the carbocycle core of the target molecule
through a Diels–Alder reaction with concurrent introduction of one
of the nitrogen atoms. Incorporation of another nitrogen atom was
achieved via a high-yielding regioselective ring opening of a cyclic would be also obtainable in comparable yields.
sulfite.
The Diels–Alder reaction between pyrrole and acrylate
Key words: Diels–Alder reactions, eliminations, enantiomeric
resolution, epoxides, antiviral agents
was recognized as a rapid entry into the desired molecular
architecture at an early stage of development of Tamiflu.3
However, because the cycloaddition failed to take place as
anticipated, this seemingly highly straightforward strate-
Over the last decade the avian flu virus H5N1 has gradu-
ally developed into a serious life threat around the world.1
Although now the patients can be treated effectively by
oral administration of Tamiflu [1, the phosphate of Osel-
tamivir (2)], an inhibitor of neuraminidase, the supply of
the semisynthetic drug apparently cannot meet the mas-
sive and still increasing global demand because the start-
ing material (–)-shikimic acid (3) itself is a limited natural
resource (Figure 1).
gy was completely abandoned by subsequent investiga-
tors. We were deeply impressed by the potentially high
efficiency of the Diels–Alder approach and felt that it de-
served further investigations. In a literature study we no-
ticed that Rainier4a and Trudell4b had reported a similar
Diels–Alder addition, where a bromo-substituted acetyl-
enecarboxylate was utilized. Although the product carried
an unwanted bromine atom, it might be conveniently re-
moved with NaBH4 in DMSO when saturation of the
C–C double bond in conjugate with the ester group as ob-
served with some more or less related molecular set-
ups.4c,5 If this debromination really worked out, it would
be possible to reactivate the abandoned cycloaddition
O
CO2Et
O
CO2Et
AcHN
AcHN
Boc
NH2⋅H3PO4
NH2
(–)-Oseltamivir (2)
Boc
N
N
(+)-Tamiflu (1)
CO2Et
CO2Et
90 °C
CO2Et
NaBH4
HO
HO
CO2H
+
exo-7
25%
N
60%
(ref. 4a,b)
Boc
Br
DMSO
74%
Br
(–)-Shikimic acid (3)
6
Boc
N
OH
4
5
Figure 1 The structures of Tamiflu and shikmic acid
CO2Et
endo-7
In world-wide exhaustive efforts to gain facile access to
Tamiflu an array of synthetic routes2 has been developed.
However, while all these approaches demonstrate certain
interesting novel chemistries many of them involved ex-
pensive/toxic reagents or starting materials that are not
readily available. It appears that an ideal synthesis of
Tamiflu is still to be found. Further investigations are war-
ranted, especially now when swine flu (A-H1N1) takes
tighter grips worldwide. Herein, we wish to report a
Diels–Alder reaction based new approach which would
49%
t-BuOH
H2O
Boc
N
HO
HO
OsO4
EtCOEt
94%
NMO
96%
PTSA
CO2Et
8
LiHMDS
THF
CO2Et
Boc
O
O
N
O
O
–78 to 0 °C
80%
CO2Et
NHBoc
( )-10
9
SYNLETT 2009, No. x, pp 000A–000D
x
x
.xx.
2
0
0
9
Advanced online publication: xx.xx.2009
DOI: 10.1055/s-0029-1217740; Art ID: W09309ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

B
H. Sun et al.
LETTER
strategy. With these thoughts in mind, we began the ex- might stem from the steric crowding associated with the
plorations on the new approach.
neighboring NHBoc group. However, use of protecting
groups of smaller sizes (such as acetyl or trifluoroacetyl
group) or simply an unprotected amino group still failed
to raise the content of the desired isomer in the product
mixtures to more than 50%. For this reason, we next
switched to the alternative strategy in Scheme 2, leaving
construction of the 3-pentyl ethereal linkage to a later
stage.
Our synthesis emerged with the facile cycloaddition be-
tween the 46 and 57 as described in the literature4
(Scheme 1). To our delight, the bromine atom indeed
could be removed with NaBH4/DMSO5 when saturating
the conjugated C–C double bond, giving endo-74c and
exo-7 formed in 49% and 25% isolated yield, respectively.
The isolated major isomer endo-7 was then exposed to
OsO4/NMO (N-methylmorpholine N-oxide) in t-BuOH– The new plan started with removal of the ketal protecting
H2O to afford the corresponding endo-diol 8 (96%). Fur- group in 10 with PTSA in MeOH. The resulting diol 12
ther treatment of 8 with 3-pentanone in the presence of a was converted into dimesylate 13 with MsCl/Et3N in
catalytic amount of PTSA led to ketal 9 (94%), which on CH2Cl2, which on treatment with NaN3/DMF led to the
exposure to LiHMDS in THF at –78 to 0 °C led to the key known azide 15, an advanced intermediate in Kann’s2k
intermediate racemic 10 in 80% yield.8 In preparative synthesis. As the yields of these steps were not satisfacto-
runs, the diastereomeric mixtures of 7, 8, and 9 could be ry, we also examined an alternative route to 15.
used without need for separation of the isomers and the ra-
cemic 10 was isolated in a comparable overall yield (24%)
In the event, the diol 12 was converted into cyclic sulfite
13¢ via reaction with SOCl2. The nitrogen atom was then
by only one column chromatography at the end of the
introduced by a regioselective opening of the cyclic
whole sequence.
sulfite10 at the allylic position with azide anion giving 14,
also an advanced intermediate in Kann’s2k synthesis.
CO2Et
CO2Et
Thus, starting from 14 using the remaining steps of
Kann2k and Corey,2c racemic Tamiflu [( )-1] would be ob-
tained in twelve steps from 4 and 5 with 12% overall
yield.
HO
O
O
O
TiCl4
Et3SiH
( )-11
( )-10
95%
NHBoc
NHBoc
80% PTSA, MeOH
CO2Et
EtO2C
S
CO2H
O
CO2Et
O
SOCl2
LiOH
HO
HO
O
S
NH
HN
Bn
O
THF–H2O
91%
Et3N
O
( )-13'
O
( )-17
BocHN
Boc
( )-12
100%
O
O
18
NHBoc
NHBoc
( )-10
NaN3, DMF
N3
95%
60% MsCl, Et3N
CO2Et
EDCI, DMAP
96%
CO2Et
67%
MsO
S
O
S
O
HO
NaN3
DMF
( )-14
O
O
O
MsO
N
O
N
O
( )-13
NHBoc
+
NHBoc
O
Bn
Bn
(1:1)
NHBoc
NHBoc
19
20
N3
CO2Et
MsCl, Et3N
CH2Cl2
97%
1) Ph3P, Et3N
MsO
(ref. 2k)
CO2Et
(ref. 2k)
( )-15
O
O
CH2Cl2
73%
DMAP, EtOH
2) Ac2O, pyridine
NHBoc
(+)-10
(ref 2c)
NHBoc
CO2Et
H3PO4
EtOH
Scheme 3
Cu(OTf)2
EtCH(OH)Et
AcN
( )-1
( )-16
Access to (+)-10 was gained through the sequence shown
in Scheme 3. Separation of the enantiomers was achieved
through derivation with optically active chiral auxiliary
18. Thus, hydrolysis of the ester functionality led to the
corresponding free carboxylic acid ( )-17. Catenation of
17 with 1811 was achieved with the aid of EDCI [1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide] and DMAP.
The resulting diastereomers 19 and 20 were readily sepa-
rated by column chromatography on silica gel. The isomer
with desire stereochemistry (19) was then transformed
(+)-10 through a DMAP-mediated ethanolysis.12 With
NHBoc
Scheme 2
In an attempt to make full use of the 3-pentylidene pro-
tecting group, we tried to cleave the ketal functionality by
reduction with TiCl4/Et3SiH9 (Scheme 2), which was ex-
pected to result in a 3-pentyl ether motif. A clean reaction
was indeed observed under such conditions. However, the
3-pentyl group turned out to be on a wrong hydroxyl
group (11). We suspected that the undesired selectivity
Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

LETTER
Synthesis of Tamiflu
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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.
(3) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi,
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Supporting Information for this article is available online at
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Acknowledgment
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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
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Synlett 2009, No. x, A–D © Thieme Stuttgart · New York

D
H. Sun et al.
LETTER
(13) The absolute configuration of (+)-10 was established by
(12) For similar cleavages of the auxiliaries by DMAP-catalyzed
alcoholysis, see: (a) Wu, Y.-K.; Sun, Y.-P.; Yang, Y.-Q.;
Hu, Q.; Zhang, Q. J. Org. Chem. 2004, 69, 6141. (b) Su,
D.-W.; Wang, Y.-C.; Yan, T.-H. Tetrahedron Lett. 1999, 40,
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comparison of the spectroscopic data of the 15 thus derived
with those reported in the literature (ref. 2k).
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