New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester

Article abstract of DOI:10.1021/jo800264d

(Chemical Equation Presented) A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via S_N2 substitution of the corresponding triflate 18 with NaN₃ followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of ～30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.

Full text of DOI:10.1021/jo800264d

New, Efficient Synthesis of Oseltamivir Phosphate (Tamiflu) via
Enzymatic Desymmetrization of a meso-1,3-Cyclohexanedicarboxylic
Acid Diester
Ulrich Zutter,* Hans Iding, Paul Spurr, and Beat Wirz
F. Hoffmann-La Roche Ltd., Pharmaceuticals DiVision, Technical Sciences, Synthesis & Process Research
and Biocatalysis, CH-4070 Basel, Switzerland
ulrich.zutter@roche.com
ReceiVed February 13, 2008
A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate
1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol
10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-
4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-
diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase
afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and
a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the
second amino function via SN2 substitution of the corresponding triflate 18 with NaN3 followed by azide
reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and
an overall yield of ∼30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization
of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.
Introduction
sufficient quantities of shikimic acid became available either
by extraction from Chinese star anise or alternatively by
fermentation, further research work at Roche and in academia5–11
focused on alternative syntheses using cheaper or more readily
available starting materials. Meanwhile interesting laboratory-
scale syntheses, e.g., via enantioselective Diels-Alder reactions5,9
or by desymmetrization of meso-aziridines6 have been reported.
Oseltamivir phosphate 1 is the orally active prodrug of the
potent and selective inhibitor 2 of influenza neuraminidases A
and B.1 After its discovery at Gilead Sciences, Foster City (CA),
the carboxylic ester 1 was developed in collaboration with Roche
as an orally active drug for the treatment and prevention of
influenza infections. In 1999, oseltamivir phosphate 1 was
successfully launched under the trade name Tamiflu. Process
research and development work at Roche aiming at a scalable
process was based mainly on the drug discovery route and the
kilolaboratory synthesis from Gilead Science, which used either
naturally occurring quinic acid 3 or shikimic acid 4 as starting
materials (Scheme 1).2 The resulting commercial manufacturing
process commences from shikimic acid 4 and takes advantage
of the key epoxide 5 used in the Gilead synthesis.3,4 Although
(2) 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.
(3) (a) Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H.-J.; Oberhauser, T.;
Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Go¨ckel, V.;
Go¨tzo¨, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Ro¨ckel-Sta¨bler,
O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. DeV. 1999, 3, 266. (b)
Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044, and references therein.
(c) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process
Res. DeV. 2004, 8, 86.
(4) For a summary of process research and development work at Roche, see:
(a) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.;
Zutter, U. Chimia 2004, 58, 621. (b) Abrecht, S.; Cordon Federspiel, M.;
Estermann, H.; Fischer, R.; Karpf, M.; Mair, H.-J.; Oberhauser, T.; Rimmler,
G.; Trussardi, R.; Zutter, U. Chimia 2007, 61, 1, and references therein.
(5) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310.
(1) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen,
X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem.
1998, 41, 2451. (b) 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.
10.1021/jo800264d CCC: $40.75
Published on Web 06/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4895–4902 4895

Zutter et al.
SCHEME 1. Synthesis of 1 Starting from Quinic Acid 3 and Shikimic Acid 4
SCHEME 2. Desymmetrization Concept
Herein we describe a new efficient synthesis of oseltamivir
phosphate 1 and its enantiomer ent-1 starting from cheap 2,6-
dimethoxyphenol 10.12
4-acetyl-amino group under inversion of configuration would
complete the synthesis. Should the less favored (R)-monoacid
ent-8 be produced instead, the required inversion of configu-
ration into the proposed intermediate 9 might be possible via
ammonolysis (or hydrazinolysis) of the ester function and
esterification of the acid (Route B).
Results and Discussion
Synthetic Strategy. The concept of the synthesis described
herein is based on two key transformations: the cis-hydrogena-
tion of a trihydroxyisophthalic acid derivative of type 6 and
the desymmetrization of the resultant all-cis meso-diester 7 by
an enzymatic hydrolysis, which was anticipated to afford in
potentially quantitative yield either the optically active (S)-
monoacid 8 or the enantiomeric (R)-monoacid ent-8 (Scheme
2). If the preferred (S)-monoacid 8 would be formed, introduc-
tion of the 5-amino functionality was planned via a Hofmann
(or Curtius) degradation of the corresponding amide (or hy-
drazide) 9 (Route A). Subsequent formation of the cyclohexene
double bond via a 1,2-elimination and introduction of the
Synthesis of Diethyl Isophthalate 6a and 6b. The first part
of the synthesis starts from readily available and cheap 2,6-
dimethoxyphenol 10, which was etherified with 3-pentyl me-
sylate using KOtBu in DMSO (Scheme 3). To minimize
competitive elimination of the mesylate to 2-pentene, KOtBu
was added slowly over 4 h to a solution of the phenol 10 and
2 equiv of the mesylate. Bromination of the crude 3-pentylether
11 with 2 equiv of N-bromosuccinimide provided the crystalline
dibromide 12 with high selectivity (GC <1% dibromo isomer
and tribromo side product). Subsequent Pd-catalyzed ethoxy-
carbonylation with carbon monoxide (10 bar CO, 110 °C) and
KOAc in EtOH provided the diethyl isophthalate derivative 6a,
which was distilled to ensure an optimal quality for the ensuing
hydrogenation step. Methyl ether cleavage with 2 equiv of
MgBr2 in refluxing THF gave the corresponding diphenol 6b
as an alternative substrate for the aromatic ring hydrogenation.
Aromatic Ring Hydrogenation of 6a and 6b. The hydro-
genation of the isophthalic acid derivatives 6a and 6b was
examined with a variety of catalysts such as Rh, Ru, and Pt on
Al2O3 or charcoal support as well as with Raney-Ni. While Pt
and Raney-Ni proved to be inactive, hydrogenation of the
dimethoxy derivative 6a with both Rh and Ru catalysts led
to the desired all-cis meso-diester 7a. Best results were
obtained with 5% Ru-Al2O3 in EtOAc (100 bar H2, 60 °C),
(6) (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 6312. (b) Mita, T.; Fukuda, N.; Roca, X.; Kanai, M.;
Shibasaki, M. Org. Lett. 2007, 9, 259.
(7) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetra-
hedron Lett. 2007, 48, 1403.
(8) Bromfield, K. M.; Grade´n, H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem.
Commun. 2007, 3183.
(9) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int.
Ed. 2007, 46, 5734.
(10) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. E.; Yang,
A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 11892.
(11) For recent reviews on the synthesis of oseltamivir phosphate 1, see: (a)
Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330. (b) Shibasaki,
M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
(12) Iding, H.; Wirz, B. ; Zutter, U., F. Hoffmann-La Roche AG, EP 1146036-
A2 (priority date 10.04.2000).
4896 J. Org. Chem. Vol. 73, No. 13, 2008

New, Efficient Synthesis of OseltamiVir Phosphate
SCHEME 3. Synthesis of Isophthalate 6a and Hydrogenation and Desymmetrization of Diester 7a and 7b
providing 7a in over 80% yield after crystallization from
hexane. According to GC analysis (area %), the crude reaction
mixture consisted of ∼90% of the desired 7a and only small
amounts of a few side products whereof the two des-methoxy
side products were identified (GC <1.5%). Considering that
10 diastereomers (6 racemates + 4 mesoforms) were
theoretically possible, the diastereoselectivity of this aromatic
ring hydrogenation was quite remarkable.13 In contrast, no
suitable catalyst could be found for the hydrogenation of the
corresponding diphenol 6b. Hydrogenation over 5%
Rh-Al2O3, (100 bar H2, EtOAc, 100 °C) afforded a complex
product mixture containing only ∼10% (GC) of the dihy-
droxy-meso-diester 7b. Instead, cleavage of the two methyl
ether groups in 7a with TMS-iodide generated in situ
(Me3SiCl, NaI, cat. H2O) afforded the desired dihydroxy-
meso-diester 7b in nearly quantitative yield so that both meso-
diesters 7a and 7b could be readily accessed and the
enzymatic monohydrolysis studied.
Enzymatic Desymmetrization of All-cis meso-Diesters
7a and 7b. The enzymatic desymmetrization of cis-1,3-
cyclohexanedicarboxylic acid diesters has already been described
in the literature.14 An extensive enzyme screening revealed that
the most selective hydrolysis of dihydroxy-meso-diester 7b was
effected by pig liver esterase (PLE, Fluka), affording the desired
(S)-monoacid 8b with high enantiomeric excess (96-98% ee)
and in nearly quantitative yield. Quite remarkably, the enzyme
readily tolerated 10% substrate concentration, even at 35 °C,
probably owing to the insolubility of the substrate as well as
the hydrophilic nature of the product.15
On the other hand, hydrolysis of the corresponding dimethoxy-
meso-diester 7a with commercial lipases from Aspergillus
oryzae, Thermomyces lanuginosa, or Mucor miehei afforded the
monoacid ent-8a with high selectivity and enantiomeric purity
(A. oryzae quant yield, >99.9% ee) albeit with the wrong
configuration for the further transformation into 1 via direct
Curtius degradation. The absolute configuration of ent-8a was
assigned after O-demethylation with TMS-iodide by transfor-
mation of the resultant (R)-monoacid ent-8b into the enantiomer
ent-1 of oseltamivir phosphate 1 (see Experimental Section).16
Transformation of the (S)-Mono-Acid 8b into Oselta-
mivir Phosphate 1. The final part of the synthesis required the
introduction of the 1,2-cyclohexene double bond, the 5-amino,
and the 4-acetylamino functionalities with the required config-
uration (Scheme 4). Treatment of the hydroxy-acid 8b with
diphenylphosphoryl azide (DPPA) and Et3N effected a Curtius
degradation, a rearrangement known to proceed with retention
of configuration, and provided the crystalline oxazolidinone 13
via intramolecular trapping of the isocyanate intermediate by
the adjacent hydroxyl group.17 The subsequent transformation
to the desired cyclohexenol 17 and the corresponding triflate
18 thereof was initially accomplished via Boc-protection,
dehydration of the ꢀ-hydroxy ester function in 14 with triflic
anhydride and DMAP (2.2 equiv Tf2O, 4.5 equiv DMAP)
followed by cleavage of the cyclic carbamate in 15 with catalytic
Cs2CO3 in ethanol.18 The moderate overall yield for the stepwise
transformation 13 f 18 of 45% prompted us to investigate a
more efficient alternative. Above all, the observation that the
carbonate 16 was an intermediate in the base-catalyzed etha-
nolysis of Boc-oxazolidinone 15 encouraged us to test whether
(13) (a) Bailey, W. J.; Economy, J. J. Org. Chem. 1957, 23, 1002. (b) Gensler,
W. J.; Solomon, P. H. J. Org. Chem. 1973, 38, 1726–1731. (c) Nielsen, A.-T.;
Christian, S. L.; Moor, D. W. J. Org. Chem. 1987, 52, 1656–1662. (d)
Burgstahler, A. W.; Bithos, Z. J. Org. Synth. 1973, 3, 591–595. An examination
of the literature revealed that the hydrogenation of unsubstituted isophthalic esters
like dimethyl isophthalate13a (Ra-Ni, neat, 300 bar, 150 °C) produces cis-trans
mixtures of the corresponding 1,3-cyclohexanedicarboxylic acid diesters.
Hydrogenation of substituted isophthalic esters, e.g., dimethyl
5-hydroxyisophthalate13b (Rh-Al2O3, MeOH, 3.5 bar, 25 °C) or triethyl benzene-
1,3,5-tricarboxylate13c (PtO2, AcOH, 3.5 bar, 25 °C) as well as gallic acid13d
(Rh-Al2O3, EtOH, 180 bar, 70 °C) deliver predominantly the all-cis isomers.
(14) Boaz, N. E. Tetrahedron: Asymmetry 1999, 10, 813.
(15) For larger scale experiments a PLE “technical grade” (Roche Diagnostics,
cat. no. 11681800103) was successfully employed.
(16) In fact, as the absolute configuration of ent-8a was unknown and ent-
8a was obtained as the first product of desymmetrization, ent-1 was synthesized
before 1.
J. Org. Chem. Vol. 73, No. 13, 2008 4897

Zutter et al.
SCHEME 4. Conversion of Mono-Acid 8b to Oseltamivir Phosphate 1
an analogous intramolecular alcoholysis of the Boc-activated
cyclic carbamate in 14 would generate the cyclic carbonate
intermediate 19 with the R-hydrogen and the ꢀ-carbonate leaving
group optimally set up to undergo a base-induced decarboxy-
lative elimination reaction. Indeed, treatment of 14 with a
catalytic amount of NaH or KOtBu in refluxing toluene effected
a highly selective transformation affording cyclohexenol 17 with
both the double bond and the Boc-protected amino group
introduced correctly.
decarboxylative elimination shortcut was easily implemented
in a “one-pot” procedure for the conversion of the oxazolidinone
13 into the triflate 18. Thus, treatment of 13 with (Boc)2O and
2 mol % DMAP in toluene provided Boc-oxazolidinone 14,
which upon heating with 0.5 mol % NaH furnished cyclohexenol
17. Subsequent esterification of crude 17 with Tf2O and pyridine
gave after crystallization from isopropyl ether the triflate 18 in
85% overall yield starting from 13, nearly doubling the yield
of the previous stepwise protocol.
The 4-amino functionality was incorporated via a SN2
substitution of the triflate 18 with NaN3 in aqueous acetone at
ambient temperature, providing the azide 20 with full inversion
of configuration (Scheme 4). Azide substitution of less powerful
sulfonate leaving groups such as nosylate or mesylate in DMSO
at 50 °C afforded lower yields and more 1,3-cyclohexadiene
Whereas no intermediate could be detected during this
transformation in refluxing toluene, under milder conditions
(EtOAc, 10 mol % NaH, 70 °C, 17 h) a trace was seen by TLC
that was then isolated by chromatography and identified as the
proposed carbonate intermediate 19 (NMR and MS).19 This
(17) The desymmetrization concept discussed at the beginning included a
synthesis of 1 via both enantiomeric monoacids 8b and ent-8b (Scheme 2).
Alternatively, the desired oxazolidinone 13 should be accessible using the (R)-
monoacid ent-8b via ammonolysis (or hydrazinolysis) and Hofmann (or Curtius)
degradation of the resultant amide (or hydrazide) followed by esterification:
(19) An independent synthesis of the carbonate intermediate 19 was
accomplished as follows:
MS and elemental analysis of compound 19: ESI-MS (m/z) 438 (M + Na+, 32),
433 (M + NH4+, 75), 360 (M + H+-C 4H8, 100). Anal. Calcd for C20H33NO8:
C, 57.82; H, 8.01; N, 3.37; O, 30.81. Found: C, 57.53; H, 7.87; N, 3.32; O,
1
(18) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
4898 J. Org. Chem. Vol. 73, No. 13, 2008
30.57. H/13C NMR spectra, see Supporting Information.

New, Efficient Synthesis of OseltamiVir Phosphate
2836, 1594, 1492, 1252 cm-1. 1H NMR (CDCl3, 250 MHz) δ 0.97
(t, J ) 7.4 Hz, 6H), 1.54-1.70 (m, 4H), 3.81 (s, 6H), 4.02 (quint,
J ) 6.0 Hz, 1H), 6.56 (d, J ) 8.3 Hz, 2H), 6.95 (t, J ) 8.3 Hz,
1H). EI-MS (m/z) 224 (M+•, 5), 154 (M+• - C5H10, 100). Anal.
Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.60; H, 9.10.
1,5-Dibromo-3-(1-ethylpropoxy)-2,4-dimethoxybenzene (12).
Crude 3-pentyl aryl ether 11 (44.9 g, 0.20 mol) dissolved in DMF
(60 mL) was added to a stirred solution of NBS (73.4 g, 0.40 mol)
in DMF (160 mL) at 0 °C over 1 h. After stirring at room
temperature for 18 h, the red-brown reaction mixture was diluted
with EtOAc (400 mL) and washed three times with 5% brine (400,
200, 200 mL). All aqueous layers were extracted with EtOAc (200
mL), and the combined organic layers were stirred with charcoal
(4 g) for 1 h. Filtration and evaporation gave the crude product
(78.7 g) which was dissolved in 80% EtOH/H2O (400 mL) at 50
°C. After cooling and stirring at -20 °C for 18 h, the suspension
was filtered, and the crystalline residue was washed with cold 80%
EtOH/H2O and dried (35 °C/1 mbar/18 h), affording 68.9 g (90%)
light yellow dibromide 12, mp 47-48 °C. IR (nujol) ν 1559, 1271,
side product (triflate ∼10%, mesylate ∼50% 1,3-cyclohexadiene
side product). Azide reduction (Bu3P-H2O or H2/Ra-Co)
followed by acetylation with Ac2O, removal of the Boc
protecting group with HBr in AcOH and salt formation with
H3PO4 gave oseltamivir phosphate 1 with ∼30% overall yield
in 10 steps starting from 2,6-dimethoxyphenol. The enantiomeric
purity of 1 determined by chiral HPLC of the Boc-derivative
21 was >99.9% ee (see Experimental Section).
Conclusion
In summary, a new enantioselective synthesis of the anti-
influenza neuraminidase inhibitor oseltamivir phosphate 1
starting from cheap 2,6-dimethoxyphenol 10 has been ac-
complished. Key steps of this approach were the cis-hydrogena-
tion of the trihydroxyisophthalic acid derivative 6a and the
desymmetrization of the dihydroxy-meso-diester 7b by enan-
tioselective hydrolysis with pig liver esterase, affording the (S)-
monoacid 8b. Subsequent Shioiri-Yamada-Curtius degradation
followed by a unique decarboxylative elimination reaction of
Boc-oxazolidinone 14 gave cyclohexenol 17, which was con-
verted to the target molecule 1 by substitution of the corre-
sponding triflate 18 with NaN3, azide reduction, N-acetylation,
and deprotection. This practical and efficient 10-step synthesis
provided the enantiomerically pure oseltamivir phosphate 1 in
∼30% overall yield without any chromatographic purification
and compares favorably with recently published syntheses.5–11
Hydrolysis of the dimethoxy-meso-diester 7a with Aspergillus
oryzae lipase followed by demethylation afforded the (R)-
monoacid ent-8b, which can be transformed into the enantiomer
ent-1 of oseltamivir phosphate in a similar manner to that
described above.
1
1005 cm-1. H NMR (CDCl3, 250 MHz) δ 0.96 (t, J ) 7.4 Hz,
6H), 1.50-1.75 (m, 4H), 3.86 (s, 6H), 4.24 (quint, J ) 6.0 Hz,
1H), 7.46 (s, 1H). EI-MS (m/z) 380 (M+•, 4), 310 (M+• - C5H10,
55). Anal. Calcd for C13H18Br2O3: C, 40.87; H, 4.75; Br, 41.82.
Found: C, 40.61; H, 4.54; Br, 41.52.
5-(1-Ethylpropoxy)-4,6-dimethoxyisophthalic Acid Diethyl
Ester (6a). An autoclave (380 mL) charged with the dibromide 12
(38.2 g, 100 mmol), potassium acetate (39.3 g, 400 mmol), ethanol
(200 mL), palladium(II) acetate (0.11 g, 0.5 mmol), and 1,3-
bis(diphenylphosphino)propane (0.25 g, 0.6 mmol) was pressurized
and vented four times with carbon monoxide (CO, 10 bar) and then
heated to 110 °C. After stirring (600 rpm) at 110 °C for 15 h under
a CO pressure of 10 bar, the autoclave was cooled to room
temperature and vented. The reaction mixture was poured into a
stirred mixture of hexane (100 mL) and aqueous 5% NaHCO3 (200
mL), and the aqueous layer was extracted with hexane (100 mL).
Both organic layers were washed with 1 M HCl (100 mL),
combined, and dried (Na2SO4). After filtration and evaporation of
the solvent, the oily residue (35.7 g) was vacuum-distilled providing
the diethyl ester 6a (34.9 g, 95%) as a colorless oil, bp 140 °C/
Experimental Section
Methanesulfonic Acid 1-Ethyl-propyl Ester. To a stirred
solution of 3-pentanol (176.3 g, 2.0 mol) in pyridine (200 mL) at
0 °C was added methanesulfonyl chloride (252.0 g, 2.2 mol) over
1 h. After stirring at room temperature for 1 h, water (100 mL)
was added, and stirring was continued for 1 h. The reaction mixture
was diluted with EtOAc (1000 mL) and washed with 1 M HCl
(1600 mL) and brine (500 mL). The aqueous layers were extracted
with EtOAc (500 mL), and the combined organic layers were dried
over Na2SO4 and filtered. Evaporation of the solvent and drying
(50 °C/1 mbar) afforded crude 3-pentylmesylate (313.4 g, 94%) as
a yellow oil which was used without purification in the next step.
1
0.02 mbar. IR (film) ν 1729, 1594, 1230, 1040 cm-1. H NMR
(CDCl3, 250 MHz) δ 0.95 (t, J ) 7.5 Hz, 6H), 1.39 (t, J ) 7.1 Hz,
6H), 1.50-1.80 (m, 4H), 3.95 (s, 6H), 4.23 (quint, J ) 6.0 Hz,
1H), 4.37 (q, J ) 7.1 Hz, 4H), 7.99 (s, 1H). EI-MS (m/z) 368 (M+,
10), 323 (M+• - C2H5O, 40), 298 (M+• - C5H10, 100). Anal. Calcd
for C19H28O7: C, 61.94; H, 7.66. Found: C, 61.89; H, 7.50.
All-cis-5-(1-ethylpropoxy)-4,6-dimethoxycyclohexane-1,3-di-
carboxylic Acid Diethyl Ester (7a). The autoclave (500 mL) was
charged with the diethyl ester 6a (36.8 g, 100 mmol), 5% Ru-Al2O3
catalyst (36.8 g, Heraeus no. 1738), and EtOAc (250 mL). The
reaction mixture was stirred (1000 rpm) and heated to 60 °C under
a pressure of 100 bar H2 for 24 h. After cooling to room
temperature, the autoclave was vented and flushed with Ar, and
the black suspension was filtered. Evaporation of the solvent and
drying (50 °C/1 mbar) afforded a white, crystalline residue (35.1
g) which was dissolved in hexane (530 mL) at 50 °C. Crystallization
was effected at -20 °C for 6 h, and after filtration, washing with
cold hexane, and drying (50 °C/1 mbar/6 h), the all-cis-diester 7a
(30.8 g, 82%) was isolated as white needles, mp 108-109 °C. IR
1
IR (film) ν 2975, 2943, 2884, 1436, 1348, 1176, 912 cm-1. H
NMR (CDCl3, 250 MHz) δ 0.98 (t, J ) 7.4 Hz, 6H), 1.74 (quint,
J ) 7.4, 4H), 3.01 (s, 3H), 4.61 (quint, J ) 6.0 Hz, 1H). Anal.
Calcd for C6H14O3S: C, 43.35; H, 8.49; S, 19.29. Found: C, 43.18;
H, 8.44; S, 19.15.
2-(1-Ethylpropoxy)-1,3-dimethoxybenzene (11). To a stirred
solution of 2,6-dimethoxyphenol 10 (38.5 g, 0.25 mol) and 3-pentyl
mesylate 9 (83.1 g, 0.50 mol) in DMSO (500 mL) was added at 50
°C a solution of potassium tert-butylate (56.1 g, 0.50 mol) in DMSO
(500 mL) over 4 h, during which the reaction mixture turned brown
and viscous. Additional potassium tert-butylate (2.8 g, 0.025 mol)
was added, and stirring at 50 °C was continued for 1 h to complete
the reaction. The mixture was cooled to room temperature, diluted
with EtOAc (500 mL), and washed with 1 M HCl (600 mL). The
aqueous layer was extracted with EtOAc (250 mL), and both organic
layers were washed with water. The combined organic layers were
dried (Na2SO4), and the solvent was evaporated to give 56.2 g
(100%) crude 3-pentyl aryl ether 11 after drying (50 °C/1 mbar)
as an orange oil which was used without purification in the next
step (crude 11 can be distilled, bp 90 °C/0.03 mbar). IR (film) ν
1
(nujol) ν 1734, 1465, 1190, 1087 cm-1. H NMR (CDCl3, 250
MHz) δ 0.93 (t, J ) 7.5 Hz, 6H), 1.27 (t, J ) 7.1 Hz, 6H),
1.50-1.68 (m, 4H), 1.90-2.01 (m, 1H), 2.17-2.41 (m, 3H), 3.27
(t, J ) 3 Hz, 1H), 3.41 (quint, J ) 6.0 Hz, 1H), 3.53 (s, 6H), 4.02
(br s, 2H), 4.18 (m, 4H). ESI-MS (m/z) 375 (M + H+, 100), 305
(M + H+ - C5H10, 50). Anal. Calcd for C19H34O7: C, 60.94; H,
9.15. Found: C, 60.79; H, 9.30.
All-cis-5-(1-ethylpropoxy)-4,6-dihydroxycyclohexane-1,3-di-
carboxylic Acid Diethyl Ester (7b). To a suspension of NaI (60.0
g, 400 mmol) in acetonitrile (200 mL) was added water (0.36 g,
20 mmol), and after 30 min of stirring at 40 °C trimethylchlorosilane
J. Org. Chem. Vol. 73, No. 13, 2008 4899

Zutter et al.
(43.5 g, 400 mmol) was added all at once. Stirring was continued
at 40 °C for 30 min, then the all-cis-diester 7a (37.4 g, 100 mmol)
was added in one portion, and the reaction was completed at 40
°C for 14 h. The orange reaction mixture was cooled to room
temperature, diluted with EtOAc (500 mL), and washed with water
(250 mL). Following decolorization with Na2S2O3 (2.5 g), the
organic layer was washed with 10% brine (2 × 100 mL), and all
three aqueous layers were extracted sequentially with EtOAc (100
mL). The combined organic layers were dried (Na2SO4), filtered,
and evaporated. The crystalline residue (34.9 g) was dissolved in
refluxing methylcyclohexane (200 mL) and recrystallized with
stirring at -20 °C for 16 h. Filtration, washing with cold
methylcyclohexane and drying (50 °C/1 mbar/6 h) gave the all-
cis-dihydroxy diester 7b (33.6 g, 97%) as a white powder, mp
115-116.5 °C. IR (nujol) ν 3410, 1730, 1252, 1105 cm-1. 1H NMR
(CDCl3, 400 MHz) δ 0.95 (t, J ) 7.6 Hz, 6H), 1.29 (t, J ) 7.2 Hz,
6H), 1.53-1.65 (m, 4H), 2.00-2.07 (m, 1H), 2.28-2.45 (m, 3H),
3.21 (t, J ) 2.8 Hz, 1H), 3.42 (quint, J ) 6.0 Hz, 1H), 3.52 (d, J
) 5.6 Hz, 2H), 4.22 (m, 4H), 4.46 (br s, 2H). ESI-MS (m/z) 347
(M + H+, 100), 277 (M + H+ - C5H10, 50). Anal. Calcd for
C17H30O7: C, 58.94; H, 8.73. Found: C, 58.73; H, 8.55.
J ) 6.0 Hz, 1H), 3.54 (t, J ) 4.0 Hz, 1H), 3.71 (m, 1H), 4.21 (m,
2H), 4.45 (s, 1H), 4.67 (t, J ) 5.2 Hz, 1H), 5.65 (s, 1H). ESI-MS
(m/z) 316 (M + H+, 10), 246 (M + H+ - C5H10, 100). Anal. Calcd
for C15H25NO6: C, 57.13; H, 7.99; N, 4.44. Found: C, 57.19; H,
7.86; N, 4.49.
(3R,4S,5S)-5-tert-Butoxycarbonylamino-3-(1-ethylpropoxy)-
4-hydroxycyclohex-1-enecarboxylic Acid Ethyl Ester (17). (a)
Boc protection. A suspension of the oxazolidinone 13 (15.77 g,
50 mmol), di-tert-butyl dicarbonate (12.0 g, 55 mmol), and
4-dimethylaminopyridine (0.12 g, 1 mmol) in toluene (250 mL)
was stirred at room temperature for 4 h. After 2 h, the suspension
became a colorless solution, and after 3 h, full conversion was
indicated by TLC. A sample was worked up for analysis of Boc-
oxazolidinone 14 (ca. 2 mL was washed with 2 mL of 0.5 M HCl
and 2 mL of 10% brine. Evaporation of the organic layer gave
1
0.15 g of viscous oil). [R]20 ) +60.8 (c 1.0; CHCl3). H NMR
D
(CDCl3, 400 MHz) δ 0.90 and 0.93 (t, J ) 7.6 Hz, 3H each), 1.30
(t, J ) 7.2 Hz, 3H), 1.55 (s, 9H), 1.55-1.65 (m, 4H), 2.11 (“q”,
1H), 2.35 (“d”, 1H), 2.38-2.47 (m, 1H), 2.59 (s, 1H), 3.44 (quint,
J ) 6.0 Hz, 1H), 3.52 (t, 1H), 4.17-4.30 (m, 3H), 4.46 (s, 1H),
4.57 (t, 1H). Anal. Calcd for C20H33NO8: C, 57.82; H, 8.01; N,
3.37. Found: C, 57.97; H, 8.12; N, 3.05. (b) Decarboxylative
elimination. To the colorless solution of 14 was added NaH (10
mg 60% NaH dispersion in oil, ∼0.25 mmol), and the reaction
mixture was refluxed for 1.5 h (during which CO2 was evolved).
Evaporation of the solvent gave crude, semicrystalline cyclohexenol
17 (19.6 g) which was used without purification in the next step.
Purified sample: [R]20D ) -52.5 (c 1.0; CHCl3). IR (nujol) ν 3557,
All-cis-(1R,3S,4S,5S,6R)-5-(1-ethylpropoxy)-4,6-dihydroxycy-
clohexane-1,3-dicarboxylic Acid 1-Ethyl Ester (8b). To a vigor-
ously stirred suspension of the all-cis-dihydroxy diester 7b (34.4
g, 100 mmol) in TRIS buffer pH 8.0 (390 mL, 10 mM; prepared
from tris(hydroxymethyl)-aminomethane and deionized water,
adjusted to pH 8.0 with 0.1 M HCl) was added at 35 °C pig liver
esterase (3.4 mL PLE suspension, Fluka no. 46063). Stirring at 35
°C was continued at pH 8.0, which was controlled by the addition
of 1.0 M NaOH with a pH-stat (during the course of the reaction
the suspension became an opaque solution). After 46 h of stirring
with a total consumption of 103.3 mL of 1.0 M NaOH (103.3 mol
) 1.04 equiv), the pH of the reaction mixture was adjusted to 2.0
with 25% HCl (ca. 13 mL), and the reaction mixture extracted with
dichloromethane (3 × 330 mL). The combined organic layers were
dried (Na2SO4), and the solvent was evaporated, affording after
drying (40 °C/5 mbar) 31.2 g (98.2%) of crude monoacid 8b as a
colorless gum, which was used without purification in the next step.
Enantiomeric ratio (er) ) 98.2:1.8, determined by chiral GC of
the methyl ester derivative (CH2N2) with a BGB-172 column (15
1
3365, 1717, 1680, 1653, 1523, 1248 cm-1. H NMR (CDCl3, 400
MHz) δ 0.93 (t, J ) 7.6 Hz, 6H), 1.45 (s, 9H), 1.50-1.65 (m,
4H), 2.34 and 2.60 (ABX, JAB ) 17.5 Hz, JAX ) 10 Hz, JBX ) 5.6
Hz, 1Heq + 1Hax), 2.54 (s, 1H), 3.43 (quint, J ) 6.0 Hz, 1H), 3.87
(q, J ) 6.0 Hz, 1H), 4.04 (s, 1H), 4.15 (s, 1H), 4.20 (q, J ) 7.2
Hz, 2H), 5.18 (d, J ) 9.2 Hz, 1H), 6.67 (s, 1H). ESI-MS (m/z) 372
(M + H+, 10), 272 (M + H+ - C4H8 - CO , 100). Anal. Calcd
2
for C19H33NO6: C, 61.43; H, 8.95; N, 3.77. Found: C, 61.30; H,
8.88; N, 3.80.
(3R,4S,5S)-5-tert-Butoxycarbonylamino-3-(1-ethylpropoxy)-
4-trifluoromethanesulfonyloxy-cyclohex-1-enecarboxylic Acid
Ethyl Ester (18). To a solution of crude cyclohexenol 17 (19.6 g,
50 mmol) and pyridine (8.05 mL, 100 mmol) in dichloromethane
(250 mL) at -10 °C was added trifluoromethanesulfonic anhydride
(8.66 mL ) 14.81 g, 52.5 mmol) over 15 min, and stirring was
continued for 2.5 h. To the cold reaction mixture was added under
stirring 1 M HCl (50 mL), and then the organic layer was separated
and washed with 10% brine (2 × 50 mL). The aqueous layers were
extracted with dichloromethane (50 mL), and the combined organic
layers were dried (Na2SO4). Evaporation of the solvent afforded a
yellow, crystalline residue (24.9 g) which was dissolved in hot
isopropyl ether (375 mL, 60 °C). Small amounts of insoluble, brown
particles adhering to the glass wall were removed by decanting the
yellow solution. Crystallization at room temperature and then -20
°C gave after filtration and drying 21.4 g (85%) of yellowish,
m × 0.25 mm). [R]20 ) +7.2 (c 1.0; CHCl3). IR (film) ν
D
3600-2450 (br), 1729, 1270, 1195, 1114 cm-1. 1H NMR (DMSO-
d6, 400 MHz) δ 0.89 (t, J ) 7.2 Hz, 6H), 1.19 (t, J ) 6.8 Hz, 6H),
1.40-1.56 (m, 4H), 1.67 and 2.00 (ABX2, JAB ) 14 Hz, JAX ) 2
Hz, JBX ) 13.2 Hz, 1Heq + 1Hax), 2.38-2.58 (m, 2H), 3.28 (t, J )
2.0 Hz, 1H), 3.34 (quint, J ) 6.0 Hz, 1H), 4.08 (m, 2H), 4.24 (br
d, 2H), 5.14 (br s, 2H), 12.0 (br s, 1H). ESI-MS (m/z) 317 (M -
H-, 100), 271 (M - H- - EtOH, 50). Anal. Calcd for C15H26O7:
C, 56.59; H, 8.23. Found: C, 56.45; H, 8.26.
(3aS,5R,6R,7R,7aS)-7-(1-Ethylpropoxy)-6-hydroxy-2-oxoocta-
hydrobenzooxazole-5-carboxylic Acid Ethyl Ester (13). To a
stirred solution of the monoacid 8b (31.2 g, from 100 mmol of
all-cis-dihydroxy diester 7b) in dichloromethane (200 mL) was
added Et3N (10.1 g, 100 mmol) followed by diphenylphosphoryl
azide (29.0 g, ca. 100 mol; assay ∼95%) in one portion. After
refluxing at ∼41 °C for 16 h, the clear reaction mixture was diluted
with dichloromethane (200 mL) and washed with 1 M HCl (300
mL), 5% NaHCO3 (300 mL), and 5% brine (3 × 300 mL). All
aqueous layers were extracted sequentially with dichloromethane
(200 mL), the combined organic layers were dried (Na2SO4), and
the solvent was evaporated. The white, crystalline residue (34.6 g)
was dissolved in refluxing nBuOAc (300 mL) and crystallized with
stirring at -20 °C for 16 h. Filtration, washing with cold nBuOAc,
and drying (50 °C/10 mbar/16 h) gave white, crystalline oxazoli-
crystalline triflate 18, mp 119-120 °C (dec.). [R]20 ) -79.4 (c
D
1.0; CHCl3). IR (nujol) ν 3379, 1711, 1689, 1525, 1413, 1211 cm-1
.
1H NMR (CDCl3, 400 MHz) δ 0.90 and 0.93 (t, J ) 7.6 Hz, 3H
each), 1.31 (t, J ) 7.2 Hz, 3H), 1.45 (s, 9H), 1.50-1.68 (m, 4H),
2.32 and 2.69 (ABX, JAB ) 18.0 Hz, JAX ) 10.0 Hz, JBX ) 6.0
Hz, 1Heq + 1Hax), 3.48 (quint, J ) 5.6 Hz, 1H), 4.04 (m, 1H),
4.23 (q, J ) 7.2 Hz, 2H), 4.33 (s, 1H), 4.93 (d, J ) 6.2 Hz, 1H),
5.35 (s, 1H), 6.77 (s, 1H). ESI-MS (m/z) 504 (M + H+, 20), 448
(M + H+ - C4H8, 90), 404 (M + H+ - C4H8 - CO2, 100). Anal.
Calcd for C20H32F3NO8S: C, 47.71; H, 6.41; N, 2.78; S, 6.37; F,
11.32. Found: C, 47.69; H, 6.43; N, 2.81; S, 6.32; F, 11.45.
(3R,4R,5S)-4-Azido-5-tert-butoxycarbonylamino-3-(1-ethyl-
propoxy)-cyclohex-1-enecarboxylic Acid Ethyl Ester (20). To a
stirred suspension of the triflate 18 (10.1 g, 20 mmol) in 90%
acetone-water (50 mL) was added NaN3 (1.43 g, 22 mmol), and
the reaction mixture was stirred at room temperature for 15 h. The
dinone 13 (25.4 g, 80% over two steps), mp 180-181 °C. [R]20
D
) +31.2 (c 1.0; CHCl3). IR (nujol) ν 3423, 3307, 1750, 1711, 1462,
1
1224 cm-1. H NMR (CDCl3, 400 MHz) δ 0.94 and 0.95 (t, J )
7.6 Hz, 3H each), 1.29 (t, J ) 6.8 Hz, 3H), 1.50-1.68 (m, 4H),
2.04-2.22 (m, 2H), 2.28-2.37 (m, 1H), 2.75 (s, 1H), 3.47 (quint,
4900 J. Org. Chem. Vol. 73, No. 13, 2008

New, Efficient Synthesis of OseltamiVir Phosphate
yellowish clear solution was concentrated, and the oily residue was
dissolved in EtOAc (50 mL) and washed with 5% brine (2 × 25
mL). The aqueous layers were extracted with EtOAc (25 mL), and
the combined organic layers were dried (Na2SO4). After evaporation
of solvent, the yellow, oily residue (8.00 g) was dissolved in hot
hexane (80 mL) at 55 °C, filtered, and crystallized at -20 °C.
Filtration and washing with cold hexane gave after drying the white,
crystalline azide 20 (15.0 g, 78%), mp 92-93 °C. [R]20D ) -61.2
C, 46.83; H, 7.61; N, 6.83; P, 7.55. Found: C, 46.61; H, 7.74; N,
6.78; P, 7.58.
Boc-Protection of Oseltamivir Phosphate 1 for Determina-
tion of Optical Purity. (3R,4R,5S)-4-Acetylamino-5-tert-butoxy-
carbonylamino-3-(1-ethylpropoxy)-cyclohex-1-enecarboxylic Acid
Ethyl Ester (21). A solution of oseltamivir phosphate 1 (ca. 100
mg, 0.25 mmol), di-tert-butyl dicarbonate (65 mg, 0.3 mmol), and
triethylamine (200 µL, 1.5 mmol) in dichlormethane (4 mL) was
stirred at room temperature for 30 min. The reaction mixture was
washed with 1 M HCl (2 mL) and 10% brine (2 × 2 mL), and the
organic layer was evaporated. The semicrystalline residue was
dissolved in hot hexane (4 mL, ca. 60 °C), and the solvent was
evaporated, yielding white, crystalline 21 (ca. 100 mg). The optical
purity of 21 was determined by HPLC on a Chiralpak AD column
(250 mm × 4.6 mm, Daicel) with the eluent EtOH/Et2NH/heptane
) 20:0.4:1000 (220 nm; tR ) 10.9 min ent-21, 15.1 min 21).
Enantiomeric excess: >99.9% ee. For spectral data, see procedure
for the synthesis of 1.
(c 1.0; CHCl3). IR (nujol) ν 3336, 2113, 1714, 1688, 1533 cm-1
.
1H NMR (CDCl3, 400 MHz) δ 0.92 and 0.94 (t, J ) 7.2 Hz, 3H
each), 1.29 (t, J ) 7.2 Hz, 3H), 1.46 (s, 9H), 1.48-1.66 (m, 4H),
2.34 and 2.78 (ABX, JAB ) 18.0 Hz, JAX ) 8.4 Hz, JBX ) 5.6 Hz,
1Heq + 1Hax), 3.46 (quint, J ) 5.6 Hz, 1H), 3.55 (dd, J ) 9.2, 7.2
Hz, 1H), 3.82 (br s, 1H), 4.01 (m, 1H), 4.21 (q, J ) 7.2 Hz, 2H),
4.90 (br s, 1H), 6.77 (s, 1H). ESI-MS (m/z) 397 (M + H+, 10),
297 (M + H+ - C4H8 - CO 2, 100). Anal. Calcd for C19H32N4O5:
C, 57.56; H, 8.14; N, 14.13. Found: C, 57.43; H, 8.02; N, 13.84.
(3R,4R,5S)-4-Acetylamino-5-amino-3-(1-ethylpropoxy)-cyclo-
hex-1-enecarboxylic Acid Ethyl Ester Phosphoric Acid Salt
(1:1) (Oseltamivir Phosphate, 1). (a) Hydrogenolysis. To a
solution of the azide 20 (3.96 g, 10 mmol) in EtOAc (50 mL) was
added Raney-cobalt catalyst (2.0 g water wet catalyst, washed with
EtOH and EtOAc), and the suspension was stirred at room
temperature for 20 h under 1 bar H2 at 500 rpm. Due to the
formation of N2 during the hydrogenation, the reaction flask was
evacuated and refilled with H2 three times. The catalyst was
removed by filtration and a sample (ca. 100 µL) was evaporated
All-cis-(1S,3R,4R,5R,6S)-5-(1-ethylpropoxy)-4,6-dimethoxycy-
clohexane-1,3-dicarboxylic Acid 1-Ethyl Ester (ent-8a). To a
vigorously stirred suspension of the all-cis-diethyl ester 7a (74.9
g, 0.20 mol) in cyclohexane (240 mL) were added 0.1 M glucose
(1.1 L) and 0.1 M sodium phosphate buffer pH 7 (60 mL). Lipase
from Aspergillus oryzae (0.56 g; Fluka 62285) was added at 35
°C, and the pH was maintained at 7.0 by controlled addition of 1.0
M NaOH (pH-stat). After 20 h and a total consumption of 187.5
mL of 1.0 M NaOH (187.5 mol), the reaction mixture was acidified
with 1 M HCl (ca. 200 mL) to pH 2.0 and extracted with
dichloromethane (1.5 L). The whole emulsion was filtered through
a bed of dicalite (150 g), and the aqueous layer was extracted with
dichloromethane (2 × 1.5 L). The combined organic layers were
dried (Na2SO4), and the solvent was evaporated affording 69.4 g
(100%) of white, crystalline monoacid ent-8a, mp 147-148 °C.
Enantiomeric excess: >99.9% ee, determined by chiral GC of the
methyl ester derivative (CH2N2) with a BGB-172 column (30 m ×
0.25 mm). [R]20D ) +7.4 (c 1.0; CHCl3). IR (nujol) ν 3400-2450
1
for analysis. H NMR (CDCl3, 250 MHz) δ 0.93 (t, J ) 7.5 Hz,
6H), 1.29 (t, J ) 7.2 Hz, 3H), 1.45 (s, 9H), 1.48-1.69 (m, 4H),
2.22 and 2.81 (ABX, JAB ) 18 Hz, JAX ) 9 Hz, JBX ) 6 Hz, 1Heq
+ 1Hax), 2.87 (dd, J ) 10, 7 Hz, 1H), 3.41 (quint, J ) 5.6 Hz,
1H), 3.71 (br s, 1H), 3.83 (m, 1H), 4.21 (q, J ) 7.2 Hz, 2H), 5.02
(br s, 1H), 6.82 (s, 1H). (b) Acetylation. To the stirred filtrate were
added at room temperature triethylamine (1.11 g, 11 mmol) and
then acetic anhydride (1.07 g, 10.5 mmol) in one portion. The
colorless solution was stirred at room temperature for 1 h, and a
sample was worked up for analysis of 21 (ca. 100 µL in 2 mL of
EtOAc was washed with 2 mL of 0.5 M HCl and 2 mL of 10%
1
(br), 1735, 1707, 1463, 1376, 1280 cm-1. H NMR (CDCl3, 400
MHz) δ 0.92 and 0.93(t, J ) 7.6 Hz, 3H each), 1.27 (t, J ) 6.8
Hz, 3H), 1.52-1.68 (m, 4H), 1.93-2.02 (m, 1H), 2.20-2.46 (m,
3H), 3.28 (t, J ) 2.8 Hz, 1H), 3.42 (quint, J ) 5.6 Hz, 1H), 3.54
and 3.60 (s, 3H each), 4.03 (m, 2H), 4.10-4.27 (m, 2H), 11.10 (br
s, 1H). ESI-MS (m/z) 345 (M - H-, 100). Anal. Calcd for
C17H30O7: C, 58.94; H, 8.73. Found: C, 58.93; H, 8.60.
brine. The organic layer was evaporated). [R]20 ) -90.1 (c 1.0;
D
1
CHCl3). H NMR (CDCl3, 250 MHz) δ 0.88 and 0.90 (t, J ) 7.2
Hz, 3H each), 1.29 (t, J ) 7.1 Hz, 3H), 1.42 (s, 9H), 1.45-1.60
(m, 4H), 1.98 (s, 3H), 2.30 and 2.75 (ABX, JAB ) 18 Hz, JAX
)
10 Hz, JBX ) 5 Hz, 1Heq + 1Hax), 3.37 (quint, J ) 5.6 Hz, 1H),
3.70-3.90 (m, 1H), 3.90-4.12 (m, 2H), 4.21 (q, J ) 7.1 Hz, 2H),
5.12 (d, J ) 10 Hz, 1H), 5.82 (d, J ) 10 Hz, 1H), 6.79 (s, 1H).
Anal. Calcd for C21H36N2O6: C, 61.14; H, 8.80; N, 6.79. Found:
C, 61.23; H, 8.82; N, 6.80. (c) Deprotection. 5.7 M HBr-AcOH
(5.26 mL, 30 mmol HBr) was added to the clear reaction mixture,
and stirring at room temperature was continued for 20 h. The
resulting suspension was washed with 2 M NaOH (55 mL, pH =
9.5) and 20% brine (2 × 30 mL). All three aqueous layers were
extracted with EtOAc (2 × 30 mL), and the combined organic layers
were dried (Na2SO4), filtered, and evaporated. (d) Salt formation.
The resulting yellow, viscous free base 1a (3.47 g) was dissolved
in EtOH (20 mL) and added under stirring to a warm solution (50
°C) of orthophosphoric acid (0.98 g, 10 mmol) in EtOH (40 mL)
over 30 min. After seeding with pure 1, the white suspension was
cooled and stirred at 0 °C for 3 h. The suspension was filtered,
washed with acetone, and dried, affording 3.41 g (83%) of white,
crystalline oseltamivir phosphate 1, mp ca. 199-200 °C (dec).
[R]20D ) -31.7 (c 1.0; H2O). IR (nujol) ν 3352, 3300-2400 (br),
All-cis-(1S,3R,4R,5R,6S)-5-(1-ethylpropoxy)-4,6-dihydroxycy-
clohexane-1,3-dicarboxylic Acid 1-Ethyl Ester (ent-8b). To NaI
(30.0 g, 200 mmol) in acetonitrile (100 mL) was added trimeth-
ylchlorosilane (21.7 g, 200 mmol) in one portion, and the suspension
was stirred at room temperature for 30 min. After the addition of
the dimethoxy acid ent-8a (17.3 g, 50 mmol), the reaction mixture
was stirred at room temperature for 12 h. The orange suspension
was diluted with dichloromethane (250 mL) and washed with an
aqueous Na2S2O3 solution (0.3 g in 250 mL) and with 10% brine
(2 × 100 mL). The aqueous layers were extracted with dichlo-
romethane (100 mL), and the combined organic layers dried
(Na2SO4), and the solvent was evaporated producing 15.8 g (99.4%)
of crude dihydroxy acid ent-8b as a colorless gum which was used
without purification in the next step. [R]20D ) -7.2 (c 1.0; CHCl3).
The following spectral data are identical with those for the
enantiomer 8b. IR (film) ν 3600-2450 (br), 1729, 1270, 1195, 1114
cm-1. 1H NMR (DMSO-d6, 400 MHz) δ 0.89 (t, J ) 7.2 Hz, 6H),
1.19 (t, J ) 6.8 Hz, 6H), 1.40-1.56 (m, 4H), 1.67 and 2.00 (ABX2,
JAB ) 14 Hz, JAX ) 2 Hz, JBX ) 13.2 Hz, 1Heq + 1Hax), 2.38-2.58
(m, 2H), 3.28 (t, J ) 2.0 Hz, 1H), 3.34 (quint, J ) 6.0 Hz, 1H),
4.08 (m, 2H), 4.24 (br d, 2H), 5.14 (br s, 2H), 12.0 (br s, 1H).
ESI-MS (m/z) 317 (M - H-, 100), 271 (M - H- - EtOH, 50).
Anal. Calcd for C15H26O7: C, 56.59; H, 8.23. Found: C, 56.31; H,
8.05.
1
1724, 1663, 1551, 1463, 1377, 1263 cm-1. H NMR (DMSO-d6,
400 MHz) δ 0.79 and 0.84 (t, J ) 7.2 Hz, 3H each), 1.23 (t, J )
7.2 Hz, 3H), 1.30-1.54 (m, 4H), 1.88 (s, 3H), 2.22 and 2.74 (ABX,
JAB ) 18 Hz, JAX ) 12 Hz, JBX ) 5 Hz, 1Heq + 1Hax), 3.18 (m,
1H), 3.36 (quint, J ) 5.6 Hz, 1H), 3.69 (“q”, J = 10 Hz, 1H), 4.15
(m, 3H), 6.65 (s, 1H), 8.15 (br s, ∼5H), 8.32 (d, J ) 9.2 Hz, 1H).
ESI-MS (m/z) 313 (M + H+, 100). Anal. Calcd for C16H31N2O8P:
All-cis-(1S,3R,4R,5R,6S)-7-(1-ethylpropoxy)-6-hydroxy-2-oxo-
octahydrobenzooxazole-5-carboxylic Acid Ethyl Ester (ent-13).
J. Org. Chem. Vol. 73, No. 13, 2008 4901

Zutter et al.
Synthesized from ent-8b according to the preparation of its
Acknowledgment. The authors thank Karl Bolliger, Jens
Gallert, Christof Sparr, and Patrick Stocker for their skillful
experimental work and Sophie Brogly and Willy Walther for
providing analytical support. We are grateful to Michelangelo
Scalone and Josef Stadelmann for the use of their autoclaves
and for their support received during the carbonylation experi-
ments. We also thank the members of the Analytical Services
of F. Hoffmann-La Roche Ltd., Basel, for providing and
interpreting the physical data of all compounds described. The
careful reading of the manuscript by Rudolf Schmid and Jean-
Michel Adam is gratefully acknowledged.
enantiomer 13 in 80% yield. [R]20 ) -31.1 (c 1.0; CHCl3). For
D
spectral data, see enantiomer 13.
(3S,4R,5R)-5-tert-Butoxycarbonylamino-3-(1-ethylpropoxy)-
4-trifluoromethanesulfonyloxy-cyclohex-1-enecarboxylic Acid
Ethyl Ester (ent-18). Synthesized from 13 according to the
preparation of its enantiomer 18 in 82% yield. [R]20 ) +78.3 (c
D
1.0; CHCl3). For spectral data, see enantiomer 18.
(3S,4S,5R)-4-Azido-5-tert-butoxycarbonylamino-3-(1-ethyl-
propoxy)-cyclohex-1-enecarboxylic Acid Ethyl Ester (ent-20).
Synthesized from triflate ent-18 according to the preparation of its
enantiomer 20 in 77% yield. [R]20 ) +60.1 (c 1.0; CHCl3). For
D
Supporting Information Available: General remarks and
spectral data, see enantiomer 20.
1
copies of H NMR spectra for compounds 11, 12, 6a, 7a, 7b,
(3S,4S,5R)-4-Acetylamino-5-amino-3-(1-ethylpropoxy)-cyclo-
hex-1-enecarboxylic Acid Ethyl Ester Phosphoric Acid Salt
(1:1) (ent-1). Synthesized from azide ent-20 according to the
preparation of oseltamivir phosphate 1 in 80% yield. [R]20D ) +31.3
(c 1.0; CHCl3). For spectral data, see oseltamivir phosphate 1.
8b, 13, 14, 17, 18, 20, 21, 1, ent-8a, ent-8b, and 19 and the
13C NMR spectrum for compound 19. This material is available
free of charge via Internet at http://pubs.acs.org.
JO800264D
4902 J. Org. Chem. Vol. 73, No. 13, 2008