A chemoenzymatic synthesis of the anti-influenza agent Tamiflu

Article abstract of DOI:10.1016/j.tetlet.2008.09.130

The anti-influenza drug Tamiflu is synthesized from enzymatically derived, enantiomerically pure, and readily available cis-1,2-dihydrocatechol.

Full text of DOI:10.1016/j.tetlet.2008.09.130

Tetrahedron Letters 49 (2008) 7018–7020
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Tetrahedron Letters
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A chemoenzymatic synthesis of the anti-influenza agent TamifluÒ
*
Maria Matveenko, Anthony C. Willis, Martin G. Banwell
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
The anti-influenza drug TamifluÒ is synthesized from enzymatically derived, enantiomerically pure, and
readily available cis-1,2-dihydrocatechol.
Article history:
Received 10 September 2008
Accepted 22 September 2008
Available online 26 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Acylaziridine
Anti-influenza
cis-1,2-Dihydrocatechol
Synthesis
TamifluÒ
TamifluÒ (1, also known as oseltamivir phosphate) is marketed
by Roche, and is used as an orally available agent for both the treat-
ment and the prevention of infections due to influenza viruses.1 In
vivo, the compound undergoes esterase-mediated hydrolysis to the
corresponding carboxylic acid, which is a potent inhibitor of neu-
raminidases A and B, key enzymes required for viral replication.
While certain of its derivatives have recently been found to be
more efficacious,2 and may exhibit reduced side-effects,3 TamifluÒ
remains a frontline agent for the treatment of human influenza. It
is also active against the avian virus H5N1.4 Accordingly, and given
the continuous threat of the outbreak of influenza pandemics, offi-
cially sanctioned stockpiling of the drug has taken place in a num-
ber of countries.5 As a result, concerns have been raised about the
capacity of the existing production process to meet peak demand.6
These arise because the current industrial synthesis7 starts from
shikimic acid, a compound that is not always readily available in
consistently pure form.6 The need to use potentially hazardous
azides in the production process7 represents another drawback
associated with the existing synthesis.6 Consequently, there has
been a significant number of recent efforts directed toward the
development of alternative and robust routes to TamifluÒ.8 Among
the various approaches pursued, some have involved the use of
Diels–Alder chemistry to assemble the cyclohexene core of target
1.9 Catalytic enantioselective variants of this basic strategy have
recently been described by both the Corey and co-workers10 and
Fukuyama groups.11 In an alternative approach, the meso-trick12
has been used to prepare various enantiopure cyclohexane precur-
sors13,14 while both a metal-mediated15 and an elegant metal-
catalyzed16 routes to TamifluÒ have also been described. The
recent disclosure, by Fang et al.,17 of two syntheses of the title
compound from the readily available and enantiomerically pure
cis-1,2-dihydrocatechol 218 prompts us to report our own efforts
in the area.
NHAc
OH
OH
O
NH2•H3PO4
Br
CO2Et
1
2
The route we have used in establishing a formal total synthesis of
TamifluÒ (1) is shown in Scheme 1, and it begins with the stereo-
selective conversion of compound 2 into the previously reported
PMP-acetal 3.19 Reductive cleavage of the latter material with
DIBAL-H resulted in a ca. 6:1 and inseparable mixture of compound
4 and its regio-isomer (85% combined yield from compound 2). In
anticipation of effecting a copper-catalyzed intramolecular aziri-
dination reaction of a type recently described by Fleming and co-
workers,20 compound 4 was treated successively with 1,10-carbon-
yldiimidazole (CDI) and hydroxylamine (generated in situ by react-
ing the corresponding hydrochloride salt with imidazole). In this
manner, a chromatographically separable mixture of the PMB
ether of o-bromophenol (21% at 88% conversion) and the desired
N-hydroxycarbamate 5 (56% at 88% conversion) was obtained.
The structure of compound 5 was confirmed by single-crystal
X-ray analysis, details of which will be presented elsewhere. O-
Tosylation of compound 5 using p-toluenesulfonyl chloride and tri-
ethylamine then gave compound 6 which could be obtained in
* Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M. G. Banwell).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.130

M. Matveenko et al. / Tetrahedron Letters 49 (2008) 7018–7020
p-MBDMA,
7019
(+)-camphor sulfonic acid,
toluene,
DIBAL-H, Et3N,
toluene,
OH
OH
O
O
OPMB
OH
0 °C, 1.5 h
–78 to –30 °C, 5 h
PMP
85% from 2
Br
Br
Br
2
3
4
(i) CDI, MeCN, 0 °C, 1 h
(ii) NH2OH•HCl, imidazole, 56% at 88% conversion
0 to 18 °C, 16 h
OPMB
OPMB
Cu(MeCN)4PF6, K2CO3,
O
MeCN, 3-pentanol,
0 to 18 °C, 16 h
OPMB
O
NH
O
N
O
43% from 6
Br
Br
OR
Br
O
N
O
O
H
p-TsCl, Et3N,
Et2O, 0 to 18 °C, 16 h
79%
8
7
5 (R=H)
6 (R=Ts)
LiOH
1,4-dioxane/water,
100 °C, 48 h
85%
NHR
NHAc
OH
NHAc
HCl/CH3OH
O
OPMB
OH
five steps17
O
O
NH2•H3PO4
35 °C, 16 h
90%
OH
Br
Br
CO2Et
AcCl, Et3N
0 to 18 °C, 1 h
99%
9 (R=H)
10 (R=Ac)
11
1
Scheme 1.
pure form and in 79% yield after column chromatography. In the
pivotal step of the reaction sequence, a solution of N-tosyloxy car-
bamate 6 in a 1.5:1 v/v mixture of 3-pentanol and acetonitrile was
treated with potassium carbonate and with a catalytic amount of
Cu(CH3CN)4PF6,21 and the ensuing mixture maintained at 25 °C
for 16 h. After workup and flash chromatography, the cyclic carba-
mate 8 was obtained in 43% yield. Presumably, this product is gen-
erated through the regioselective nucleophilic ring-opening of the
intermediate and highly strained acylaziridine 7 by 3-pentanol.
While compound 8 could be N-acylated using acetyl chloride in
the presence of Hünig’s base, the product of this process could not
be ring-opened in the desired manner using any one of a number of
nucleophiles including ammonia. As a result, carbamate 8 was
treated with lithium hydroxide in 1,4-dioxane/water at 100 °C for
48 h. In this way, the amino alcohol 9 was obtained in 85% yield.
N-Acylation of compound 9 was accomplished under standard con-
ditions to give acetamide 10 in 99% yield, and the PMB group with-
in the latter compound was then cleaved with aqueous acid to give
diol 11 (90%).22 The spectral data recorded on this compound
matched those reported by Fang et al.,17 but final confirmation of
its structure followed from a single-crystal X-ray analysis.23 The
derived ORTEP plot is shown in Figure 1.
TamifluÒ. A related azide-free synthesis, again using compound 11
as an intermediate and involving the same number of steps, has
also been described by Fang and co-workers.17 On this basis, the
present work represents a 16 step and enantioselective synthesis
of TamifluÒ from bromobenzene, the precursor to cis-1,2-dihydro-
C16
C14
C10
O15
N13
C9
C8
C2
O7
O17
C11
C1
C6
C3
C4
C12
C5
The acquisition of compound 11 constitutes a formal total syn-
thesis of TamifluÒ (1) because it is a key intermediate associated
with both of Fang’s routes17 to this target. Thus, this group was
selectively able to remove the allylic hydroxyl within compound
11 and then convert, with accompanying inversion of stereo-
chemistry, the remaining hydroxyl residue into an azido group.
Ni[0]-promoted carboethoxylation of the alkenyl bromide moiety
followed by hydrogenolytic cleavage of the azido group, and reac-
tion of the resulting primary amine with phosphoric acid then gave
O18
Br19
Figure 1. Structure of compound 11 with labelling of selected atoms. Anisotropic
displacement ellipsoids display 30% probability levels. Hydrogen atoms are drawn
as circles with small radii.

7020
M. Matveenko et al. / Tetrahedron Letters 49 (2008) 7018–7020
10. (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310; See also:
(b) Kraus, G. A.; Gorgonga, T. Synthesis 2007, 1765; (c) Kipassa, N. T.; Okamura,
H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815.
11. Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46,
5734.
12. (a) Laumen, K.; Schneider, M. Tetrahedron Lett. 1984, 25, 5875. and references
therein; (b) Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1984, 106, 3695.
13. (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 6312; (b) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M.
Org. Lett. 2007, 9, 259; (c) Morita, M.; Sone, T.; Yamatsugu, K.; Sohtome, Y.;
Matsunaga, S.; Kanai, M.; Watanabe, Y.; Shibasaki, M. Bioorg. Med. Chem. Lett.
2008, 18, 600.
catechol 2. Given the capacity for the large-scale production of diol
2 from this arene,24 the present work has the potential to provide a
useful new route to compound 1. We are currently working on a
second generation synthesis of TamifluÒ that exploits the capacity
of the route described here to deliver selectively the mono-pro-
tected forms 9 and 10 of diol 11. Results will be reported in due
course.
Acknowledgments
14. Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73, 4895. and
references therein.
15. Bromfield, K. M.; Gradén, H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem.
Commun. 2007, 3183.
We thank the Institute of Advanced Studies and the Australian
Research Council for financial support.
16. Trost, B. M.; Zhang, T. Angew. Chem., Int. Ed. 2008, 47, 3759.
17. Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5788.
Supplementary data
18. Compound
2 can be obtained from the Aldrich Chemical Co. (Catalogue
Experimental procedures, product characterization, and 1H or
13C NMR spectra for compounds 4–6 and 8–11 are provided. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.09.130.
Number 489492) or from Questor, Queen’s University of Belfast, Northern
Ireland (see: http://questor.qub.ac.uk/newsite/contact.htm). For reviews on
methods for generating cis-1,2-dihydrocatechols by microbial dihydroxylation
of the corresponding aromatics, as well as on the synthetic applications of
these metabolites, see: (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichim.
Acta 1999, 32, 35; (b) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.;
McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vögtle, M. Pure Appl. Chem. 2003, 75,
223; (c) Johnson, R. A. Org. React. 2004, 63, 117.
References and notes
19. Matveenko, M.; Banwell, M. G.; Willis, A. C. Tetrahedron 2008, 64, 4817.
20. Liu, R.; Herron, S. R.; Fleming, S. A. J. Org. Chem. 2007, 72, 5587. and references
therein.
21. Various copper catalysts were examined for their capacity to effect this
transformation, and Cu(CH3CN)4PF6 proved to be the most effective.
22. Selected physical and spectral data for compound 11 are presented in the
Supplementary data.
1. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.;
Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R.
C. J. Am. Chem. Soc. 1997, 119, 681; (b) Lew, W.; Chen, X.; Kim, C. U. Curr. Med.
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references therein.
2. Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang, A.-S.; Hsiao,
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5. See, for example: http://www.roche.com/med-cor-2006-04-19.
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8. For a recent survey of activities in this area see: Shibasaki, M.; Kanai, M. Eur. J.
Org. Chem. 2008, 1839. and references therein.
23. X-ray crystal data for compound 11: C13H22BrNO4, M = 336.23, T = 200(1) K,
monoclinic, space group P21, Z = 2, a = 8.1118(3), b = 6.9730(2),
c = 13.3490(4) Å, b = 98.0424(17)° V = 747.64(4) Å3, Dx = 1.493 g cmꢀ3
,
3414
(I)]; Rw = 0.044 (all
data), S = 0.99. Images were measured on a Nonius Kappa CCD diffractometer
(MoK graphite monochromator, k = 0.71073 Å). Crystallographic data for
unique data (2hmax = 55°); R = 0.025 [for 2899 with I > 2.0
r
a
,
compound 11 have been deposited with the Cambridge Crystallographic Data
Center (CCDC no. 701227). These data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email:
data_request@ccdc.cam.ac.uk, fax: +44 1223 336033, or via http://
www.ccdc.cam.ac.uk/data_request/cif).
9. Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2007, 48, 1403.
24. See, for example: Ballard, D. G. H.; Courtis, A.; Shirley, I. M.; Taylor, S. C.
Macromolecules 1988, 21, 294.