Synthesis of the anti-influenza agent (-)-oseltamivir free base and (-)-methyl 3-epi-shikimate

Article abstract of DOI:10.1039/c2ob25635e

A new enantioselective synthesis of the anti-influenza agent (-)-oseltamivir free base (7.1% overall yield; 98% ee) and (-)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has been described from readily available raw materials. Sharpless asymmetric epoxidation and diastereoselective Barbier allylation of an aldehyde are the key reactions employed in the incorporation of chirality, while the cyclohexene carboxylic ester core was constructed through a ring closing metathesis reaction.

Full text of DOI:10.1039/c2ob25635e

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 3988
www.rsc.org/obc
COMMUNICATION
Synthesis of the anti-influenza agent (−)-oseltamivir free base and (−)-methyl
3-epi-shikimate†
Varun Rawat, Soumen Dey and Arumugam Sudalai*
Received 28th March 2012, Accepted 11th April 2012
DOI: 10.1039/c2ob25635e
asymmetric epoxidation (AE), diastereoselective Barbier allyla-
tion and ring closing metathesis (RCM) as the key reactions.
Based on retrosynthetic analysis, we visualized that epoxide 3
can be considered as the key precursor in the synthesis of
Tamiflu 1 and (−)-methyl 3-epi-shikimate 2 (Fig. 1).
A new enantioselective synthesis of the anti-influenza agent
(−)-oseltamivir free base (7.1% overall yield; 98% ee) and
(−)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has
been described from readily available raw materials. Sharp-
less asymmetric epoxidation and diastereoselective Barbier
allylation of an aldehyde are the key reactions employed in
the incorporation of chirality, while the cyclohexene car-
boxylic ester core was constructed through a ring closing
metathesis reaction.
Results and discussion
Initially, epoxy aldehyde (−)-78 was prepared in 64.5% yield
from commercially available cis-2-butene-1,4-diol 4 in three
steps: (i) monosilylation of diol 4 (TBSCl, imid., 73%), (ii) AE
of allylic alcohol 5 [Ti(OiPr)4, (−)-DET, anhydrous TBHP,
93%], (iii) oxidation of epoxy alcohol (+)-6 (TEMPO, BAIB,
95%) (Scheme 1). Wittig olefination of (−)-7 with
Introduction
Oseltamivir phosphate (Tamiflu, 1) is an orally effective neura-
minidase inhibitor,1 widely used for the treatment and prevention
of human influenza (H1N1) and avian influenza (H5N1) infec-
tions.2 The anti-influenza drug 1 was initially discovered by
Gilead Sciences and subsequently licensed to Roche for pro-
duction. The commercial manufacturing process of Tamiflu
employs (−)-shikimic acid,3 a natural product isolated from the
Chinese star anise plant, as the raw material. However, the
supply of (−)-shikimic acid of consistent purity is problematic
due to seasonal and geographical constraints. As a consequence,
several methods for its synthesis have been documented in the
literature.3–5 Among the strategies reported, the one from Haya-
shi’s group (9 steps, 57% yield) turns out to be the best so far.6
However, some of the existing routes are less attractive due to
certain drawbacks such as use of expensive starting materials,
chiral building blocks and low yields. In order to meet the
increasing demand for Tamiflu 1 worldwide, its alternative syn-
thesis from readily available and less expensive starting materials
is mandatory.
Fig. 1 Oseltamivir phosphate (1), methyl 3-epi-shikimate (2) and their
precursor 3.
In continuation of our interest in the asymmetric synthesis of
bioactive molecules,7 we report, in this communication, an
efficient synthesis of (−)-oseltamivir free base and (−)-methyl 3-
epi-shikimate 2, a unnatural methyl ester of shikimic acid, from
readily available starting materials by employing Sharpless
Chemical Engineering and Process Development Division, National
Chemical Laboratoty, Pashan Road, Pune 411008, India.
E-mail: a.sudalai@ncl.res.in; Fax: +91-02025902676
†Electronic supplementary information (ESI) available: Experimental
details and spectral data of all the new compounds. See DOI: 10.1039/
c2ob25635e
Scheme 1 Initial efforts in the synthesis of 1.
3988 | Org. Biomol. Chem., 2012, 10, 3988–3990
This journal is © The Royal Society of Chemistry 2012

View Online
Table 1 Optimization studies for selective catalytic hydrogenation of
alkyne 19: role of additivesa
Ph3PvCHCO2Et gave α,β-unsaturated epoxy ester 8 in 92%
yield. Regioselective ring opening of 8 at the allylic position,
with azide ion in the presence of NH4Cl, was accomplished in
85% yield to give azido alcohol 9. Staudinger reaction (Ph3P,
toluene) followed by N-acetylation (Ac2O, DMAP, Et3N)
afforded protected aziridine 10 in 81% yield. Regioselective ring
opening of 10 with 3-pentanol in presence of 1.5 equivalent of
BF3·OEt2 proceeded smoothly to furnish α,β-unsaturated epoxy
ester 11 as the exclusive product in 75% yield. On desilylation
Entry Solvent
Additives
Yield of 20b (%)
1
2
3
4
MeOH
Quinoline (10 mol%)
Quinoline (1.2 equiv.)
Pyridine (1.2 equiv.)
Quinoline (1.2 equiv.)
Pyridine (1.2 equiv.)
26
23
34
22
16
DMF
5
6
7
1,10-Phenanthroline (1.2 equiv.) 14
EtOAc
Quinoline (1.2 equiv.)
Pyridine (1.2 equiv.)
Pyridine–1-octene
57
64
95
33
with TBAF, 11 unexpectedly gave the furan derivative 12,9
a
8
9c
10
Michael adduct, as the major product (65%) along with the
desired alcohol 13 in minor amounts (17% yield). Since the
yield of 13 was miserably low, an alternative route to 1 was
undertaken as shown in Scheme 2.
Benzene Pyridine (1.2 equiv.)
a H2 (1 atm), Lindlar’s catalyst (5 wt%), dry solvent, 25 °C, 6 h.
b Isolated yield. c py–1-octene–EtOAc (1 : 1 : 10).
In the second approach, antipode epoxy alcohol (−)-6 was
readily prepared in 96% ee10 in two steps as described above: (i)
monosilylation, (ii) AE using (+)-DET as chiral source
(Scheme 2). Oxidation of (−)-6 (TEMPO, BAIB) gave the alde-
hyde (+)-7, which was subjected to Barbier allylation with ethyl
2-(bromomethyl)acrylate to afford the homoallylic alcohol 14 in
64% yield (dr = 4 : 1). The syn-stereochemistry in 14 was estab-
lished unambiguously from 2D NMR studies.11
The hydroxyl group in 14 was then protected (MOMCl,
DIPEA, 90%) and the TBS group in 15 deprotected (TBAF,
THF) to produce 16, which was then subjected to oxidation
(IBX/DMSO) to give the labile aldehyde 17. Several attempts to
perform Wittig olefination (n-BuLi, PPh3 CH3I−, THF) of 17 to
+
produce diene 18 were quite unsuccessful, due to its rapid
decomposition under the strongly basic conditions.
Scheme 3 Synthesis of oseltamivir free base.
Alternatively, the crude aldehyde 17 was subjected to Sey-
ferth–Gilbert homologation using the Bestman–Ohira reagent12
in the presence of K2CO3 and MeOH, which gave the terminal
alkyne 19 in 82% yield with a completely transesterified methyl
ester in 2 h. To prevent the transesterification process, the
Seyferth–Gilbert homologation was carried out in EtOH;
however no reaction took place even after 6 h.
Next, a systematic study of selective catalytic hydrogenation
[H2 (1 atm), Lindlar’s catalyst, additives, solvents] of alkyne 19
to alkene 20 was undertaken and the results are summarized in
Table 1. As can be seen, the ethyl acetate and pyridine
combination gave good yields (64%) of diene 20; however
higher selectivity (95%) to 20 could be achieved with a pyri-
dine–1-octene combination. The cyclohexene core 3 was then
constructed smoothly in 90% yield via a RCM strategy using
Grubbs II catalyst under high dilution (Scheme 3). Conversion
of 3 to aziridine 22 was achieved in three steps as before (see
Scheme 1) with an overall yield of 67%: (i) epoxide opening
with azide, (ii) formation of aziridine and (iii) its N-acetylation.
Regioselective ring opening of aziridine 22 with 3-pentanol
followed by simultaneous MOM deprotection and transesterifica-
tion using 2 N HCl in EtOH afforded the key amino alcohol 23,
whose spectral data were in complete agreement with reported
values.4a,g Amino alcohol 23 was then converted to oseltamivir
free base in three steps by following the reported procedures:4a
(i) mesylation of alcohol 23, (ii) displacement of mesylate with
azide ion, (iii) reduction of azide with Lindlar’s catalyst.
Several epimers of shikimic acid (e.g. methyl 3-epi-shikimate
2) form the constituents of various natural products of biological
importance and their syntheses have attracted considerable atten-
tion.13a We thus envisioned that, the cyclic epoxide 3 could be
considered as an important precursor for the synthesis of 2.
Thus, 3 was readily converted into the desired triol 2 through a
two step reaction sequence: (i) epoxide opening (H2SO4,
THF–H2O); (ii) MOM deprotection of 24 (2 N HCl, MeOH)
(Scheme 4). The comparison of spectral data of 2 with the
reported values13b,c further establishes the absolute configuration
of cyclic epoxide 3.
Scheme 2 Synthesis of dienic epoxy ester 20.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3988–3990 | 3989

View Online
E. J. Prisbe, L. M. Schultze, R. H. Yu and L. Zhang, J. Org. Chem.,
1998, 63, 4545; (b) M. Federspiel, R. Fisher, M. Henning, H. J. Mair,
T. Oberhauser, G. Rimmler, T. Albiez, J. Bruhin, H. Estermann,
C. Gandert, V. Gockel, S. Gotzo, U. Hoffmann, G. Huber, G. Janatsch,
S. Lauper, O. Rockel-Stabler, R. Trussardi and A. G. Zwahlen, Org.
Process Res. Dev., 1999, 3, 266; (c) M. Karpf and R. Trussardi, J. Org.
Chem., 2001, 66, 2044 and references cited therein; (d) P. J. Harrington,
J. D. Brown, T. Foderaro and R. C. Hughes, Org. Process Res. Dev.,
2004, 8, 86.
Scheme 4 Synthesis of methyl 3-epi shikimate 2.
4 (a) X. Lu, F.-F. Wang, N. Quan, X.-X. Shi and L.-D. Nie, Tetrahedron:
Asymmetry, 2011, 22, 1692; (b) S. Raghavan and V. S. Babu, Tetrahe-
dron, 2011, 67, 2044; (c) B. M. Trost and T. Zhang, Chem.–Eur. J., 2011,
17, 3630; (d) T. Tanaka, Q. Tan, H. Kawakubo and M. Hayashi, J. Org.
Chem., 2011, 76, 5477; (e) H. Ishikawa, B. Bondzic and Y. Hayashi,
Eur. J. Org. Chem., 2011, 6020; (f) M. Trajkovic, Z. Z. Ferjancic and
R. N. Saicic, Org. Biomol. Chem., 2011, 9, 6927; (g) D. S. Gunasekera,
Synlett, 2012, 573; (h) H.-K. Kim and K.-J. J. Park, Tetrahedron Lett.,
2012, 53, 1561 and references cited therein.
5 For review articles on synthetic strategies to oseltamivir, see:
(a) J. Magano, Tetrahedron, 2011, 67, 7875; (b) J. Magano, Chem. Rev.,
2009, 109, 4398; (c) M. Shibasaki and M. Kanai, Eur. J. Org. Chem.,
2008, 1839; (d) V. Farina and J. D. Brown, Angew. Chem., Int. Ed., 2006,
45, 7330.
Conclusion
In conclusion, we have described a new enantioselective syn-
thesis of the anti-influenza agent (−)-oseltamivir free base (7.1%
overall yield; 98% ee) and (−)-methyl 3-epi-shikimate 2 (16%
overall yield; 98% ee) starting from readily available cis-1,4-
butene diol. Key steps employed are the AE, diastereoselective
Barbier allylation and RCM. This method comprises of opera-
tionally simple yet efficient reactions with the use of inexpensive
and non-toxic reagents, amenable for commercial exploitation.
6 H. Ishikawa, T. Suzuki and Y. Hayashi, Angew. Chem., Int. Ed., 2009, 48,
1304.
Acknowledgements
7 (a) V. Rawat, P. V. Chouthaiwale, V. B. Chavan, G. Suryavanshi and
A. Sudalai, Tetrahedron Lett., 2010, 51, 6565; (b) I. N. Chaithanya Kiran,
R. S. Reddy, G. Suryavanshi and A. Sudalai, Tetrahedron Lett., 2011, 52,
438; (c) D. Devalankar, P. V. Chouthaiwale and A. Sudalai, Tetrahedron:
Asymmetry, DOI: 10.1016/j.tetasy.2012.02.004.
8 The Jorgensen’s asymmetric epoxidation proceeded in poor yields (15%)
to give (−)-7; M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang and
K. A. Jorgensen, J. Am. Chem. Soc., 2005, 127, 6964.
We thank CSIR, UGC and DST, New Delhi (sanction no.
SR/S1/OC-67/2010) for financial support. Authors also thank Dr
V. V. Ranade, Head, CE-PD for his constant encouragement and
support.
9 G. Reddipalli, M. Venkataiah, M. K. Mishra and N. W. Fadnavis, Tetrahe-
dron: Asymmetry, 2009, 20, 1802.
References
10 See ESI.†.
1 (a) A. L. Cheam, I. G. Barr, A. W. Hampson, J. Mosse and A. C. Hurt,
Antiviral Res., 2004, 63, 177; (b) B. J. Smith, J. L. McKimm-Breshkin,
M. McDonald, R. T. Fernley, J. N. Varghese and P. M. Colman, J. Med.
Chem., 2002, 45, 2207; (c) 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; (d) C. U. Kim, W. Lew,
M. A. Williams, H. Liu, L. Zhang, S. Swaminathan, N. Bischofberger,
M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver and R. C. Stevens,
J. Am. Chem. Soc., 1997, 119, 681.
11 The relative stereochemistry of 14, 3 and 24 was confirmed by COSY and
NOESY studies. A significant COSY and NOESY correlation was
observed between H4 and H3 in 14 and 3, while no correlation is
observed between H4 and H3 in 24.
2 (a) A. C. Hurt, P. Selleck, N. Komadina, R. Shaw, L. Brown and
I. G. Barr, Antiviral Res., 2007, 73, 228; (b) L. Werner, A. Machara,
B. Sullivan, I. Carrera, M. Moser, D. R. Adams and T. Hudlicky, J. Org.
Chem., 2011, 76, 10050; (c) A. Abbott, Nature, 2005, 435, 407;
(d) G. Laver and E. Garman, Science, 2001, 293, 1776; (e) J. D. Bloom,
L. I. Gong and D. Baltimore, Science, 2010, 328, 1272.
.
12 S. Müller, B. Liepold, G. J. Roth and H. J. Bestmann, Synlett, 1996, 521.
13 (a) L. Sánchez-Abella, S. Fernández, N. Armesto, M. Ferrero and
V. Gotor, J. Org. Chem., 2006, 71, 5396; (b) R. Brettle, R. Cross,
M. Frederickson, E. Haslam, F. S. MacBeath and G. M. Davies, Tetrahe-
dron, 1996, 52, 10547; (c) N. Armesto, M. Ferrero, S. Fernández and
V. Gotor, Tetrahedron Lett., 2000, 41, 8759.
3 (a) J. C. Rohloff, K. M. Kent, M. J. Postish, M. W. Becker,
H. H. Chapman, D. E. Kelly, W. Lew, M. S. Louie, L. R. McGee,
3990 | Org. Biomol. Chem., 2012, 10, 3988–3990
This journal is © The Royal Society of Chemistry 2012