A concise synthetic approach toward tamiflu (oseltamivir phosphate): Cis-aziridine as the key synthon and RCM

Article abstract of DOI:10.1039/c3ra47210h

The key synthon cis-aziridine has been efficiently utilised for the synthesis of oseltamivir phosphate, using Wittig olefination, Barbier addition, Mitsunobu reaction and ring closing metathesis (RCM) as key essentials.

Full text of DOI:10.1039/c3ra47210h

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A concise synthetic approach toward tamiflu
(oseltamivir phosphate): cis-aziridine as the key
synthon and RCM†
Cite this: RSC Adv., 2014, 4, 11417
Received 2nd December 2013
Accepted 7th February 2014
*
Subhash P. Chavan, Prakash N. Chavan and Lalit B. Khairnar
DOI: 10.1039/c3ra47210h
www.rsc.org/advances
The key synthon cis-aziridine has been efficiently utilised for the the synthetic precursor (À)-shikimic acid, whose natural source
synthesis of oseltamivir phosphate, using Wittig olefination, Barbier is limited. The 30 kg of dried star anise plant provides 1 kg
addition, Mitsunobu reaction and ring closing metathesis (RCM) as key (À)-shikimic acid through extraction method. Whereas 30% of
essentials.
its total requirement supplied by fermentation process.5
Recently many synthetic groups focused on the alternative
synthetic strategies from the cheap and more readily available
starting materials which resulted in the different synthetic
routes for the synthesis of the tamiu.6
The constant and continuous world-wide threat of seasonal
inuenza to human and animal health is a cause for concern
due to the mortality and mobility of the viral strains.1 Neur-
aminidase inhibition is necessary for stopping the spread of the
viral infection from the infected host cell. These surface glyco-
proteins cleave the sialic acid complex, which invade the lead of
the viron in new cells. The molecules which were investigated
for blocking the neuraminidase active site, help the inhibition
of the viral infection and avoid the viron aggregation. Two of
these molecules such as zanamivir (Relenza®) and oseltamivir
phosphate (Tamiu®) are the drugs available in the market for
the treatment and prevention of the seasonal inuenza caused
by mutant viral strains (Fig. 1).
The zanamivir has low bioavailability and is administrated
by inhalation which could be problematic in case of patients
suffering from the respiratory disease. Whereas the oseltamivir
phosphate (tamiu) is given in the form of an oral prodrug and
it has high bioavailability.
Tamiu is effective against both H5N1 and H1N1 viral
strains but its dose should be administered within 36–48 h aer
inuenza symptoms detection.2 The rst report for tamiu
synthesis by Gilead science3 and Roche's4 processes from the
(À)-shikimic acid is utilized for industrial scale synthesis of
tamiu.
Shibasaki and co-workers reported different approaches
based on asymmetric aziridine opening, Diels–Alder reaction
and ring closing metathesis.7 Whereas Corey et al. reported the
synthesis of tamiu involving a Diels–Alder reaction8 while
Hayashi's report on three “one-pot” operational strategy for
tamiu synthesis is the highest yielding protocol so far fro the
tamiu.9 There are also other synthetic routes reported for the
tamiu synthesis which involve L-serine, D-xylose, D-ribose,
D-mannitol, L-methionine and D-tartarate chiral starting mate-
rials as alternatives to the (À)-shikimic acid.10 However these
synthetic strategies suffer from several limitations, which
include the utilization of expensive starting materials,
hazardous chemicals, tedious reaction conditions, azide inter-
mediates and low yielding reaction steps. Due to this there is
still a need to design and develop new synthetic routes which
overcome the drawbacks of the reported strategies. The main
task is to substitute the raw material of current manufacturing
One of the major factors which restrict the large scale
production of neuraminidase inhibitor drugs is the shortage of
Organic Chemistry Division, National Chemical Laboratory, Dr Homi Bhabha Road,
Pune-411008, Maharashtra, India. E-mail: sp.chavan@ncl.res.in; Fax: +91-20-
25892629; Tel: +91-20-25902286
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data and copies of 1H and 13C-NMR spectra for the compounds.
See DOI: 10.1039/c3ra47210h
Fig. 1 Neuraminidase inhibitors.
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process. The increasing demand of the tamiu on worldwide
seasonal pandemics of inuenza puts increasing pressure to
fulll this need.
Since its discovery by Gabriel in 1888, aziridines are
synthetically attractive intermediates and the building blocks
for the synthesis of natural products.11 They have been exten-
sively explored for the construction of stereogenic centers con-
taining nitrogen compounds. Tamiu contains ether, vicinal
trans diamine as three contiguous chiral centers in the cyclo-
hexene structure. Hence, the well-organized and accurate
placement of these groups is essential for its synthesis. The
aziridine ring can be used to access the trans diamine. We
herewith report the synthetic approach towards oseltamivir
phosphate from the D-mannitol as an inexpensive and abun-
dant chiral starting material involving aziridine as key
precursor.
Retrosynthetic analysis is shown in Scheme 1. Aziridine 2
was considered a key precursor, which could be obtained by
intramolecular RCM of bis-olen 3. Bis olen 3 in turn could be
obtained from the aziridine 4 by consecutive DIBALH reduction,
one carbon Wittig olenation, acetonide deprotection, oxidative
cleavage of diol and Barbier addition. The aziridine 4 is the key
synthon which could be easily prepared from D-mannitol.12
According to retrosynthetic plan, the synthesis began with
cis-aziridine 4, which was easily prepared from the D-mannitol
and benzhydril amine in good yield using the reported
protocol.12 The aziridine ester 4 was reduced to the corre-
sponding aldehyde 5 using DIBAL-H at À78 ꢀC (Scheme 2). The
resultant aldehyde 5 without purication was directly subjected
to one carbon Wittig homologation using KOtBu in toluene to
furnish olen 6 in 65% yield over two steps. Our next task was to
obtain the RCM precursor 3a from the olen 6 by appropriate
chemical transformation.
Accordingly, acetonide deprotection of olen 6 was carried
out with TMSOTf in DCM to afford diol 7 in 85% yield. Diol 7
was subjected to oxidative cleavage using NaIO4 in DCM to
afford aldehyde 8. The crude aldehyde 8 was directly subjected
to the Barbier addition of ethyl 2-(bromomethyl)-acrylate/Zn in
THF/aq NH4Cl to furnish the diastereomeric mixture of 3a : 3b
in 3 : 2 ratio in 94% yield. The diastereomers 3a and 3b
were separated by careful ash chromatography using
Scheme 2 Synthesis of aziridine 2.
pet.ether–ethyl acetate (90 : 10) as eluent. The undesired
stereoisomer 3a was readily converted to the desired 3b by
Mitsunobu inversion followed by ester hydrolysis with NaOEt/
EtOH to afford 3b in 69% yield.13
The relative stereochemistry of diastereomer 3a and 3b was
conrmed by transforming the compound 3b to 10 by ring
closing metathesis using Grubbs' II generation catalyst in
reuxing DCM to furnish cyclohexene aziridine 9, which on
mesylation furnished the corresponding mesylate 10. The data
of mesylate 10 was found to be in good agreement with the
documented data for 10 synthesized by different route.14 From
this the stereochemistry of compound 3b as well as 3a as
assigned. According to our retrosynthetic plan, remaining job
was to convert the aziridine 10 to intermediate 2, which was
carried out by the treatment with 3-pentanol in the presence of
Scheme 1 Retrosynthetic analysis for tamiflu 1.
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BF3$Et2O, which resulted into the regio and stereospecic ring
opening of aziridine 10 and in situ re-aziridination to afford
intermediate 2 in 80% yield (Scheme 2). Since the conversion of
intermediate 2 to aziridine 11 and from aziridine 11 to tamiu 1
are reported in the literature,4a,b,14 this constitutes for the formal
synthesis of tamiu 1.
2 A. Graul, P. A. Leeson and J. Castaner, Drugs Future, 1999, 24,
1189.
3 (a) C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang,
S. Swaminathan, N. Bischoerger, M. S. Chen,
D. B. Mendel, C. Y. Tai, W. G. Laver and R. C. Stevens, J.
Am. Chem. Soc., 1997, 119, 681; (b) C. U. Kim, W. Lew,
M. A. Williams, H. Wu, L. Zhang, X. Chen, P. A. Escarpe,
D. B. Mendel, W. G. Laver and R. C. Stevens, J. Med. Chem.,
1998, 41, 2451.
4 (a) M. Karpf and R. Trussardi, J. Org. Chem., 2001, 66, 2044;
(b) J. C. Rohloff, K. M. Kent, M. J. Postich, M. W. Becker,
H. H. Chapman, D. E. Kelly, W. Lew, M. S. Louie,
L. R. McGee, E. J. Prisbe, L. M. Schultze, R. H. Yu and
L. Zhang, J. Org. Chem., 1998, 63, 4545; (c) S. Abrecht,
P. Harrington, H. Iding, M. Karpf, R. Trussardi, B. Wirz
and U. Zutter, Chimia, 2004, 58, 621.
We would like to stress that although synthesis of tamiu has
been earlier reported from D-mannitol,10d,e it required 16 and 18
steps respectively. Our synthesis requires only 13 purication
steps. It may be further pointed out that the previous two syntheses
in addition to chiral pool strategy employ catalytic asymmetric
dihydroxylation to install additional chirality. Our synthesis on the
contrary exploits the existing chiral center of mannitol and utilizes
it for introducing the desired chirality without resorting any
further asymmetric catalysis. In addition to this our synthesis does
not generate undesired isomers, as is the case with other two
syntheses, except 3a which in turn can be readily transformed to
the desired isomer 3b. The aziridine intermediate 11 can be readily
transformed to tamiu by azide free route following the procedure
described in ref. 4a, in 5.5% overall yield which is better than the
one reported by Mandai et al.10d
5 G. Flores, January 4, 2006, http://www.the-scientist.com/?
articles.view/articleNo/23583/title/Getting-around-u-drug-
shortage/.
6 (a) J. Magano, Chem. Rev., 2009, 109, 4398; (b) J. Magano,
Tetrahedron, 2011, 67, 7875.
7 (a) Y. Fukuta, T. Mita, N. Fukuda, M. Kanai and M. Shibasaki,
J. Am. Chem. Soc., 2006, 128, 6312; (b) T. Mita, N. Fukuda,
F. X. Roca, M. Kanai and M. Shibasaki, Org. Lett., 2007, 9,
259; (c) K. Yamatsugu, S. Kamijo, Y. Suto, M. Kanai and
M. Shibasaki, Tetrahedron Lett., 2007, 48, 1403; (d)
K. Alagiri, M. Furutachi, K. Yamatsugu, N. Kumagai,
T. Watanabe and M. Shibasaki, J. Org. Chem., 2013, 78, 4019.
8 Y. Y. Yeung, S. Hong and E. J. Corey, J. Am. Chem. Soc., 2006,
128, 6310.
Conclusions
In conclusion a novel, practical and formal synthesis of tamiu
has been accomplished starting with inexpensive and abundant
chiral material viz. D-mannitol in 5.5% overall yields. The key
building block cis-aziridine is utilised in the synthesis to x the
desired stereocenters of the neuraminidase inhibitor drug osel-
tamivir phosphate. This notable synthetic attempt involved Wittig
olenation and Barbier reaction to access acyclic diene precursor
and which was converted to cyclohexene, the core skeleton of
9 H. Ishikawa, T. Suzuki and Y. Hayashi, Angew. Chem., Int. Ed.,
2009, 48, 1304.
tamiu by ring closing metathesis (RCM). The undesired diaste- 10 (a) X. Cong and Z. J. Yao, J. Org. Chem., 2006, 71, 5365; (b)
reomer of Barbier reaction was fruitfully converted into the
desired isomer using Mitsunobu conditions. The synthetic route
is concise, involving inexpensive reagents throughout the
synthesis and involves high yielding reaction steps.
J. J. Shie, J. M. Fang, S. Y. Wang, K. C. Tsai, Y. S. E. Cheng,
A. S. Yang, S. C. Hsiao, C. Y. Su and C. H. Wong, J. Am.
Chem. Soc., 2007, 129, 11892; (c) H. Osato, I. L. Jones,
A. Chen and C. L. L. Chai, Org. Lett., 2010, 12, 60; (d)
T. Mandai and T. Oshitari, Synlett, 2009, 783; (e) J. S. Ko,
J. E. Keum and S. Y. Ko, J. Org. Chem., 2010, 75, 7006; (f)
T. Oshitari and T. Mandai, Synlett, 2009, 787; (g) J. Weng,
Y. B. Li, R. B. Wang, F. Q. Li, C. Liu, A. S. C. Chan and
G. Lu, J. Org. Chem., 2010, 75, 3125.
Acknowledgements
PNC & LBK thank to CSIR New Delhi, India for SRF. We also
thank U. R. Kalkote & H. B. Borate for helpful discussion and
SPC thanks CSIR, INDIA and ORIGIN for research funding.
11 S. Gabriel, Chem. Ber., 1888, 21, 1049.
12 A. L. Williams and J. N. Johnston, J. Am. Chem. Soc., 2004,
126, 1612.
Notes and references
´
¨
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13 P. Tapolcsanyi, J. Woling, E. Mernyak and G. Schneider,
1 R. G. Webster, A. S. Monto, T. J. Braciale and R. A. Lamb,
Monatshee fur Chemie, 2004, 135, 1129.
Textbook of Inuenza, Oxford, UK: Blackwell Science, 1998, 14 K. Ishiwata, S. Terashima and K. Ujita, EP1229022 B1, or
pp. 219–264.
EP1229022, A4 or EP1229022 A1, Aug 7, 2002.
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RSC Adv., 2014, 4, 11417–11419 | 11419