A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid

Article abstract of DOI:10.1021/ja0616433

A short synthetic pathway has been developed for the synthesis of oseltamivir (1) or the enantiomer (ent-1). The intermediates and conditions for this process are summarized in Scheme 1. The synthesis provides a number of advantages: (1) use of inexpensiv

Full text of DOI:10.1021/ja0616433

Published on Web 04/25/2006
A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza
Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid
Ying-Yeung Yeung, Sungwoo Hong, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received March 9, 2006; E-mail: corey@chemistry.harvard.edu
The recent emergence of the avian virus H5N1 raises the
possibility of a pandemic wave of life-threatening flu that requires
prompt action.1 A four-pronged effort to avert widespread disease
is now underway that consists of the following components: (1)
worldwide surveillance of both wild and domesticated birds with
quick culling of the latter, (2) development of recombinant vaccines
against the H5N1 virus and its mutated forms whose production
can be scaled up rapidly,2 (3) procedures for quarantine, and (4)
ramped up production of the orally effective, synthetic neuramidase
and explosive azide-containing intermediates. The route described
herein has been used for the synthesis of oseltamivir and also its
enantiomer.
inhibitor oseltamivir phosphate (Tamiflu) (1).3 This paper describes
a total synthesis of 1 that would appear to have a number of
advantages over existing processes and the potential to increase
the rate of production.
Heroic efforts by synthetic chemists at Gilead Sciences, Inc.4
and F. Hoffman-La Roche, Ltd.5 have resulted in the development
of several synthetic pathways to 1, culminating in the current
production method.5 That process falls short of the ideal for several
reasons: (1) the starting point in the synthesis is either (-)-shikimic
or (-)-quinic acid, which are complex relatively expensive and of
The synthesis of 1 is summarized in Scheme 1. We have
limited availability, and (2) two steps involve potentially hazardous
previously described the reaction of butadiene with trifluoroethyl
Scheme 1
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C O M M U N I C A T I O N S
acrylate in the presence of the S-proline-derived catalyst ent-2 to
form the adduct ent-3.6 Because we had a large supply of the
S-catalyst 2, the R-adduct ent-3, and racemic 3, these were used in
developing the experimental conditions for the synthetic route.
These procedures were then applied to the enantioselective synthesis
of 1.7 The initial Diels-Alder step is easily carried out at room
temperature on a multigram scale in excellent yield (97%) and with
>97% ee; recovery of the chiral ligand corresponding to 2 is simple
and efficient. Ammonolysis of 3 produced amide 4 quantitatively.
Iodolactamization of 4 using the Knapp protocol8 generated lactam
5, which was transformed by N-acylation with tert-butylpyrocar-
bonate into the tert-butoxycarbonyl (Boc) derivative 6 in very high
yield. Dehydroiodination of 6 occurred cleanly with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to give 7, which was allylically bromi-
nated using N-bromosuccinimide to generate 8 very efficiently. The
structure of (()-8 was confirmed by single-crystal X-ray diffraction
analysis (see Supporting Information). Treatment of 8 with cesium
carbonate in ethanol afforded the diene ethyl ester 9 quantitatively.
The next step in the synthetic sequence was a novel SnBr4-
catalyzed bromoacetamidation reaction which was completely regio-
and stereoselective using N-bromoacetamide (NBA) in CH3CN at
-40 °C that converted the diene 9 to the bromodiamide 10, the
structure of which was verified by single-crystal X-ray diffraction
analysis (of the racemic methyl ester). We surmise that this
interesting process involves the transfer of Br+ from an SnBr4-
NBA complex to the γ,δ-bond of the diene ester 9 followed by
nucleophilic attack on the intermediate bromonium ion. Other
applications of this useful process will be described in a separate
publication. Cyclization of 10 to the N-acetylaziridine was rapid
and efficient using in situ generated tetra-n-butylammonium hex-
amethyldisilazane and provided the bicyclic product 11. Reaction
of 11 in 3-pentanol solution containing a catalytic amount of cupric
triflate at 0 °C occurred regioselectively to generate the ether 12,9
identical by NMR, IR, TLC, and mp with an authentic sample.5
Finally, removal of the Boc group and salt formation with
phosphoric acid in ethanol afforded 1‚H3PO4 (Tamiflu).
This research is continuing to increase the yields for steps 9 f
10 f 11 f 12. It is our hope that the process described herein
will be of value in improving the supply of oseltamivir and in
reducing the cost. With regard to the latter, the process described
herein is in the (unpatented) public domain.
Acknowledgment. We are grateful to Drs. Martin Karpf and
Klaus Mu¨ller of Roche Research/Basel for their encouragement and
to Roche/Boulder for a reference sample of Tamiflu.
Supporting Information Available: Experimental conditions and
characterization data for the transformations and compounds shown in
Scheme 1. X-ray crystallographic data for (()-8 and the methyl ester
of (()-10. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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(2) Gao, W.; Soloff, A. C.; Lu, X.; Montecalvo, A.; Nguyen, D. C.; Matsuoka,
Y.; Robbins, P. D.; Swayne, D. E.; Donis, R. O.; Katz, J. M.; Barratt-
Boyes, S. M.; Gambotto, A. J. Virol. 2006, 80, 1959-1964.
(3) Pollack, A. New York Times, Nov 5, 2005, pp B1 and B13.
(4) (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, G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681-690. (b)
Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H.
H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.;
Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545-
4550.
(5) For an authoritative review of the area and a summary of the extensive
studies at Roche, see: Albrecht, S.; Harrington, P.; Iding, H.; Karpf, M.;
Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621-629.
(6) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388-6390.
(7) Catalyst 2, its enantiomer, and the (S)- and (R)-amino alcohol precursors
are available from Sigma Aldrich Co.
(8) (a) Knapp, S.; Gibson, F. S. Organic Syntheses; Wiley & Sons: New
York, 1998; Collect. Vol. IX, pp 516-521. (b) Knapp, S.; Levorse, A. T.
J. Org. Chem. 1988, 53, 4006-4014.
(9) The yield for the transformation 11 f 12 has not been optimized, with
regard to catalyst and temperature.
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