A novel azide-free asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from Roche's epoxide

Article abstract of DOI:10.1016/j.tetasy.2013.04.016

A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu) starting from Roche's epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF₃· OEt₂-catalyzed epoxide-opening with acetonitrile as a nucleophile. Compound 3 was then transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in 91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield. In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucleophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82% yield.

Full text of DOI:10.1016/j.tetasy.2013.04.016

Tetrahedron: Asymmetry 24 (2013) 638–642
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel azide-free asymmetric synthesis of oseltamivir phosphate (Tamiflu)
starting from Roche’s epoxide
⇑
Liang-Deng Nie, Fei-Feng Wang, Wei Ding, Xiao-Xin Shi , Xia Lu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (TamifluÒ) starting from Roche’s
epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a
Article history:
Received 12 March 2013
Accepted 22 April 2013
BF3ꢀOEt2-catalyzed epoxide-opening with acetonitrile as
a nucleophile. Compound 3 was then
transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in
91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and
b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford
compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield.
In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucle-
ophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82%
yield.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
tert-butylamine8d instead of sodium azide as a nucleophile in the
epoxide-opening. However, both of Roche’s azide-free synthetic
Recently, the synthesis of oseltamivir phosphate 1 (TamifluÒ)
has attracted great interest from organic and medicinal chemists
around the world, because it is an active prodrug of a potent neur-
aminidase inhibitor,1,2 and has been widely used not only as a
front-line therapy for H5N1 influenza3–5 and H1N1 influenza6 but
also as a preventive agent against an unpredictable outbreak of
pandemic influenza.
routes8c,d are quite long, and the total yields remain to be
increased.
We have recently been involved in the synthesis of oseltamivir
phosphate 1 in order to develop more efficient and practical syn-
thetic processes.9a–d Herein we report a novel azide-free asymmet-
ric synthesis of oseltamivir phosphate 1 (Tamiflu) starting from
Roche’s epoxide 2, which could be obtained in a sequence of five
steps in 63–65% yield from the naturally abundant (ꢁ)-shikimic
acid22 according to Roche’s procedure.8b,23
Due to the extreme importance of Tamiflu for human health,
many synthetic routes towards oseltamivir phosphate 1 have been
studied and reported up to data.7–21 Some synthetic routes have
started from natural chiral materials such as (ꢁ)-quinic acid,1,2,8
2. Results and discussion
(ꢁ)-shikimic acid,2,8,9
L
-serine,10
D
-xylose,11
D
-glucose,12
D
-manni-
tol,13
L
-methionine,14
D
-tartrate,15and -ribose.16 Other miscella-
D
As shown in Scheme 1, Roche’s epoxide 2 was first treated with
1.5 equiv of BF3ꢀOEt2 in acetonitrile at 0 °C to room temperature
and then subjected to hydrolysis under basic conditions. This led
to a highly regio- and stereoselective ring-opening process which
afforded N-acetyl aminoalcohol 3 in 95% yield. Acetonitrile acted
both as the solvent and a weak nucleophile in this BF3ꢀOEt2-cata-
lyzed epoxide-opening.24
A possible mechanism and conformational analysis for the
MeCN-mediated BF3ꢀOEt2-catalyzed regio- and stereoselective
ring-opening of Roche’s epoxide 2 is shown in Figure 1. Compound
2 most likely adopted a boat conformation, which first coordinated
with BF3ꢀOEt2 to form chelate complex I-1. Intermediate I-1 might
follow path a or path b to form other chelate complexes I-2 and I-3
via epoxide-opening by nucleophilic attack of MeCN at C-5 or C-4.
Since the fused bicyclic chelate complex I-2 is much more stable
neous synthetic routes have started from unnatural materials
such as Diels–Alder cycloaddition products,17 Michael addition
products,18 cyclohexene derivatives,19 benzene derivatives20 and
pyridine.21 However, among all of the aforementioned syntheses,
only Roche’s synthesis starting from (ꢁ)-shikimic acid or
(ꢁ)-quinic acid seems to have been developed as an industrial pro-
cess for the manufacture of Tamiflu. Several synthetic routes have
been disclosed by Roche.8 Hazardous sodium azide and potentially
explosive azide intermediates were involved in Roche’s early
synthesis.8a Later, Roche chemists also developed an azide-free
synthesis8c,d of oseltamivir phosphate 1 by using allylamine8c or
⇑
Corresponding author. Tel.: +86 2164252052.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.016

L.-D. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 638–642
639
2
3
1
O
CO2Et
O
CO2Et
O
CO2Et
c
a
b
4
5
5
98%
91% for
95%
HO
MsO
6
5% for
O
NHAc
NHAc
2
3
Roche epoxide
4
O
CO2Et
ref.8d
88%
d
AcHN
93%
N
O
CO2Et
O
AcHN
CO2Et
7
AcN
5 (major)
NH2·H3PO4
Oseltamivir phosphate 1
O
CO2Et
CCl3
e
f
O
CO2Et
94%
82%
AcHN
HN
NHAc
(minor)
O
6
8
Scheme 1. A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 starting from Roche’s epoxide 2. Reagents and conditions: (a) 1.5 equiv of BF3ꢀOEt2, 0 °C in
CH3CN for 1 h; then water at rt in aqueous acetonitrile (CH3CN/H2O = 10:1) for 4 h, and then 8.0 equiv of powdered K2CO3 at rt for 36 h; (b) 1.5 equiv of MsCl, 1.5 equiv of
Et3N, 0.1 equiv of DMAP, 0 °C in CH2Cl2 for 1 h; (c) 2.0 equiv of NaH, rt in CH2Cl2/DMSO (30:1) for 8 h; (d) (allyl)2NH, reflux (112 °C) for 6 h; (e) 1.5 equiv of isopropyl 2,2,2-
trichloroacetimidate, 2.0 equiv of BF3ꢀOEt2, ꢁ15 °C in CH2Cl2 for 20 min; (f) 2.5 equiv of Cs2CO3, 80 °C in DMSO for 15 min, then AcOH/H2O (1:1), 80 °C in DMSO for 20 min;
1.1 equiv of H3PO4, 50 °C in EtOAc/EtOH (1:1) for 2 h.
MeCN
than the bridged bicyclic chelate complex I-3, the nucleophilic at-
H
H
EtO2C
tack of MeCN at C-5 (path a) is favorable, whereas the nucleophilic
attack of MeCN at C-4 (path b) is unfavorable. Intermediate I-2
then underwent hydrolysis to afford a twist chair conformer A of
compound 3, and this less stable conformer rapidly flipped to be-
come a more stable twist chair conformer B of compound 3, where
both the NHAc and OH groups were located on equatorial posi-
tions. Furthermore, during the above BF3ꢀOEt2-catalyzed epoxide-
opening, the nucleophile MeCN would attack C-5 on the opposite
side of the epoxide moiety, and thus the (S) absolute configuration
of C-5 was inverted to (R).
Compound 3 was treated with 1.5 equiv of methanesulfonyl
chloride in the presence of 1.5 equiv of triethylamine and 0.1 equiv
of 4-N,N-dimethylaminopyridine (DMAP) to afford mesylate 4 in
98% yield. When compound 4 was treated with a base, the desired
aziridine 5 was obtained via intramolecular SN2-type nucleophilic
substitution, while the undesired 1,3-diene 6 was also formed as a
by-product via b-elimination. In order to obtain the best yield of
the desired product 5, optimization of the reaction conditions for
conversion of compound 4 to aziridine 5 was carried out. Various
bases such as sodium bicarbonate, sodium carbonate, potassium
carbonate, potassium tert-butoxide, sodium ethoxide and sodium
hydride were tested for the reaction. Various solvents such as
ethanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene,
dichloromethane, chloroform, 1,2-dimethoxyethane, N,N-dimeth-
ylformamide and dimethyl sulfoxide were also tested. We found
that when the reaction was performed in a mixed solvent of
dichloromethane and dimethyl sulfoxide (CH2Cl2/DMSO = 30:1)
at room temperature with 2.0 equiv of sodium hydride as the base,
the desired aziridine 5 was obtained in 91% yield, and only a small
amount of the undesired b-elimination by-product 6 was formed.
Compound 5 could be converted to oseltamivir phosphate 1 via
both path a and path b. In path a, a solution of compound 5 in
EtO2C
H
H
5
5
.
BF3 OEt2
H
H
3
3
O
O
H
4
H
4
O
O
BF3
I-1
path b
attack at C-4
(unfavorable)
2
path a
attack at C-5
(favorable)
N
5
CMe
EtO2C
H
H
H
H
3
MeC
EtO2C
N
H
4
5
O
O
H
3
4
O
BF3
H
H
O
BF3
I-2
H2O
NHAc
I-3
H
5
4
H
H
H
O
CO2Et
CO2Et
NHAc
HO
H
O
4
5
OH
H
conformer A of 3
(less stable)
conformer B of 3
(more stable)
Figure 1. Mechanism and conformational analysis of the BF3ꢀOEt2-catalyzed highly
regioselective epoxide-opening of Roche’s epoxide 2 with MeCN as a nucleophile.

640
L.-D. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 638–642
diallylamine was allowed to reflux for 6 h; the aziridine-opening
took place smoothly to afford compound 7 in 93% yield. Compound
7 was then converted into oseltamivir phosphate 1 in 88% yield
after palladium-catalyzed deallylation and ammonium salt forma-
tion was carried out according to the literature.8d In path b, com-
pound 5 was first treated with 1.5 equiv of isopropyl 2,2,2-
trichloroacetimidate and 2.0 equiv of BF3ꢀOEt2 in dichloromethane
at ꢁ15 °C. The aziridine-opening took place very rapidly to afford
the desired product 8 in 94% yield. Compound 8 was then treated
with 2.5 equiv of cesium carbonate at 80 °C in DMSO;25 removal of
the trichloroacetyl group occurred rapidly to give the base of osel-
tamivir, which was used as such to react with 1.1 equiv of phos-
phoric acid in a mixed solvent of ethyl acetate and ethanol
(EtOAc/EtOH = 1:1) to furnish oseltamivir phosphate 1 in 82% yield.
The conversion of aziridine 5 into oseltamivir phosphate 1 via path
a gave a better yield over 2 steps, but the conversion via path b
avoided the use of a poisonous transition metal palladium cata-
lyst,8d which might be significant in drug synthesis.
BF3ꢀOEt2 (8.360 g, 58.90 mmol) was added dropwise over
10 min to the above solution, after which the reaction solution
was stirred for 1 h at 0 °C. Water (15 mL) was then added, the
ice bath was removed, and the mixture was stirred for 4 h.
Powdered potassium carbonate (43.48 g, 314.6 mmol) was then
added in portions, and the suspension was stirred at room tem-
perature for approximately 36 h. The suspension was filtered by
suction, and the cake was washed twice with acetonitrile
(2 ꢂ 50 mL). The filtrates were combined, and acetonitrile was
removed by vacuum distillation. The residue was then parti-
tioned between ethyl acetate (200 mL) and water (50 mL). The
two phases were separated, and the aqueous phase was ex-
tracted twice with ethyl acetate (2 ꢂ 40 mL). The extracts were
combined, washed with brine (50 mL), and dried over anhy-
drous MgSO4. The organic solvents were removed by vacuum
distillation to give an oily residue, which was purified by flash
chromatography (eluent: EtOAc/hexane = 1:4) to afford com-
pound 3 (11.71 g, 37.36 mmol) in 95% yield. Mp 98.1–98.6 °C.
It should be noted that because of the bulkiness of the
3-pentoxy group at the C-3 position, both nitrogen-nucleophiles
(diallylamine and isopropyl 2,2,2-trichloroacetimidate) would
favorably attack the much less-hindered C-5 position of aziridine
5 in an opposite direction with high regio- and stereoselectivities;
the (R)-absolute configuration of C-5 was inverted to an (S)-config-
uration during the above aziridine-opening.
½
a 2D0
ꢃ
¼ ꢁ171 (c 2.00, CHCl3). 1H NMR (CDCl3)
d 0.86 (t,
J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 0.92 (t, J = 7.4 Hz, 3H, CH3
in 3-pentoxyl), 1.26 (t, J = 7.1 Hz, 3H, CH3 in COOEt), 1.43–
1.60 (m, 4H, both CH2 in 3-pentoxyl), 2.00 (s, 3H, CH3 in Ac),
2.04 (dd, J1 = 18.0 Hz; J2 = 9.4 Hz, 1H, H-6), 2.73 (br s, 1H, OH),
3.01 (dd, J1 = 18.0 Hz; J2 = 5.4 Hz, 1H, H-60), 3.43–3.48 (m, 1H,
OCH in 3-pentoxyl), 3.58–3.64 (m, 1H, H-5), 4.04 (dd,
J1 = 4.4 Hz, J2 = 4.6 Hz, 1H, H-4), 4.14–4.26 (m, 3H, H-3 and
OCH2 in COOEt), 5.91 (d, J = 6.4 Hz, 1H, H-2), 6.86 (br s, 1H,
3. Conclusion
NHAc). 13C NMR (CDCl3)
d 171.26, 166.19, 135.18, 131.10,
82.16, 71.30, 71.07, 60.93, 47.41, 30.21, 26.54, 26.15, 23.27,
14.15, 9.72, 9.42. HRMS (EI) calcd for (C16H27NO5)+: 313.1889;
found: 313.1884. IR (KBr film) 3448, 3285, 2961, 1718, 1621,
In conclusion, a novel azide-free asymmetric synthesis of osel-
tamivir phosphate 1 starting from Roche’s epoxide 2 is described.
Roche’s epoxide 2 was converted into the key intermediate aziri-
dine 5 in 85% yield over 3 steps. Aziridine 5 was then converted
into compound 1 in 82% yield over 2 steps via path a, or in 77%
yield over 2 steps via path b. The key step of the above azide-free
synthesis is the BF3ꢀOEt2-catalyzed highly regio- and stereoselec-
tive epoxide-opening of Roche epoxide 2 with CH3CN as the nucle-
ophile. Compared with the two previous Roche azide-free
syntheses,8c,d the present synthesis of oseltamivir phosphate 1
from Roche’s epoxide 2 has been shortened from 8 steps8d (or 9
steps8c) to 6 steps, and the overall yield from Roche’s epoxide 2
to oseltamivir phosphate 1 has been increased from 35–38%8c or
61%8d to 69% (path a) or 65% (path b).
1546, 1369, 1251, 1094 cmꢁ1
.
4.3. (3R,4S,5R)-Ethyl 5-acetylamido-4-methanesulfonyloxy-3-
(pentan-3-yloxy)cyclohex-1-ene carboxylate 4
A
solution of compound 3 (5.000 g, 15.95 mmol), Et3N
(2.420 g, 23.92 mmol) and DMAP (190.0 mg, 1.555 mmol) in
ethyl acetate (100 mL) was cooled to 0 °C with an ice bath.
Methanesulfonyl chloride (2.740 g, 23.92 mmol) was added
dropwise, and the resulting solution was then stirred at 0 °C
for 1 h. An aqueous solution of HCl (1 mol Lꢁ1, 50 mL) was
added, and the mixture was stirred vigorously for 5 min. The
two phases were separated, and the aqueous solution was ex-
tracted twice with ethyl acetate (2 ꢂ 50 mL). The extracts were
combined, washed with an aqueous solution of ammonia (10%
w/w, 30 mL), and dried over anhydrous MgSO4. The solvent
was removed by vacuum distillation to give the crude product
as a pale yellow oil, which could be used as such for the next
step or was purified by flash chromatography (eluent: EtOAc/
hexane = 1:3) to afford compound 4 (6.118 g, 15.63 mmol) in
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were obtained on a Bruker
AM-500 spectrometer at 300 K, and chemical shifts are given on
the delta scale as parts per million (ppm) with tetramethylsilane
(TMS) as the internal standard. Infrared (IR) spectra were recorded
on a Nicolet 6700 instrument. MS spectra were recorded on a Shi-
madzu GC–MS 2010 or a LC/MSD TOF HR-MS equipment. Melting
points were determined on a Mel-TEMP II apparatus. Optical
rotations of chiral compounds were measured on WZZ-1S auto-
matic polarimeter at room temperature. Column chromatography
was performed on silica gel. All chemicals were analytically pure.
Epoxide 2 was prepared in five steps according to the Roche
report.8b,23
98% yield. ½a 2D0
ꢃ
¼ ꢁ118 (c 1.30, CHCl3). 1H NMR (acetone-d6) d
0.90 (t, J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 0.94 (t, J = 7.4 Hz,
3H, CH3 in 3-pentoxyl), 1.27 (t, J = 7.1 Hz, 3H, CH3 in COOEt),
1.54–1.62 (m, 4H, both CH2 in 3-pentoxyl), 1.91 (s, 3H, CH3
in Ac), 2.42 (dd, J1 = 18.0 Hz, J2 = 6.9 Hz, 1H, H-6), 2.79 (dd,
J1 = 18.0 Hz, J2 = 5.9 Hz, 1H, H-60), 3.16 (s, 3H, CH3 in Ms),
3.51–3.58 (m, 1H, OCH in 3-pentoxyl), 4.19 (q, J = 7.1 Hz, 2H,
OCH2 in COOEt), 4.39–4.44 (m, 1H, H-5), 4.48–4.56 (m, 1H, H-
4), 4.93 (dd, J1 = 7.6 Hz; J2 = 4.7 Hz, 1H, H-3), 6.82 (br s, 1H,
NHAc), 7.24 (d, J = 7.6 Hz, 1H, H-2). 13C NMR (acetone-d6) d
169.73, 165.49, 134.95, 130.21, 82.09, 78.81, 70.44, 60.53,
44.78, 37.69, 29.21, 25.97, 25.88, 22.33, 13.65, 9.16, 8.73. HRMS
(ESI) calcd for (C17H29NO7S+Na)+: 414.1562; found: 414.1562. IR
(neat) 3274, 2968, 2936, 1716, 1656, 1550, 1463, 1359, 1246,
4.2. (3R,4S,5R)-Ethyl 5-acetylamido-4-hydroxy-3-(pentan-3-
yloxy)cyclohex-1-ene carboxylate 3
A solution of Roche’s epoxide 2 (10.00 g, 39.32 mmol) in
CH3CN (150 mL) was cooled to 0 °C with an ice bath. Next,
1176, 1058, 966, 862, 528 cmꢁ1
.

L.-D. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 638–642
641
4.4. (3R,4R,5R)-Ethyl 4,5-acetylimino-3-(pentan-3-yloxy)-
cyclohex-1-ene carboxylate 5
2H, two inner sp2-H in allyl), 6.73 (br s, 1H, NHAc). 13C NMR
(CDCl3) d 170.43, 170.01, 138.52, 137.31, 129.93, 116.92, 82.38,
77.72, 61.10, 56.50, 53.52, 52.49, 26.31, 25.82, 23.92, 23.69,
14.50, 9.84, 9.52. HRMS (ESI) calcd for (C22H36N2O4+H)+:
393.2753; found: 393.2752. IR (KBr film) 3269, 2962, 1710, 1652,
To a solution of compound 4 (2.000 g, 5.109 mmol) in a mixed
solvent of dichloromethane and dimethyl sulfoxide (60 mL,
CH2Cl2/DMSO = 30:1), was added NaH (490.0 mg, 50% in mineral
oil, 10.21 mmol) in portions. The suspension was then stirred at
room temperature for 8 h, and the reaction was monitored by
TLC. The mixture was cooled to 0 °C, and water (30 mL) was slowly
added to quench the reaction. The two phases were separated, and
the aqueous solution was extracted twice with dichloromethane
(2 ꢂ 30 mL). The extracts were combined and dried over anhy-
drous MgSO4. The organic solution was concentrated by vacuum
distillation to give the crude product as a pale yellow oil, which
was purified by flash chromatography (eluent: EtOAc/hex-
ane = 1:4) to afford compound 5 (1.375 g, 4.655 mmol) in 91% yield
as well as compound 6 (75.0 mg, 0.254 mmol) in 5% yield.
1563, 1369, 1237, 1122, 912 cmꢁ1
4.6. Isopropyl 2,2,2-trichloroacetimidate
solution of 1,8-diazabicyclo[5,4,0]undec-7-ene (1.523 g,
.
A
10.00 mmol) and isopropanol (3.000 g, 49.92 mmol) in dichloro-
methane (30 mL) was cooled to 0 °C with an ice bath. Trichloroace-
tonitrile (1.160 g, 8.034 mmol) was then added dropwise. After the
addition was complete, the mixture was stirred at 0 °C for 1 h. The
ice bath was then removed, and stirring was continued at room
temperature for 4 h. The reaction solution was concentrated under
vacuum to give a brown oily residue, which was purified by flash
chromatography (eluent: EtOAc/hexane = 1:8) to furnish isopropyl
2,2,2-trichloroacetimidate (1.183 g, 5.785 mmol) as a colorless oil
in 72% yield. 1H NMR (CDCl3) d 1.37 (d, J = 6.2 Hz, 6H, two CH3 in
iospropyl), 5.10–5.18 (m, 1H, OCH in isopropyl), 8.23 (br s, 1H,
NH). 13C NMR (CDCl3) d 162.16, 91.98, 72.88, 21.08. HRMS (EI)
calcd for (C5H8Cl3NO)+: 202.9671; found: 202.9674. IR (neat)
3347, 2983, 1661, 1359, 1294, 1112, 1081, 976, 859, 797,
Characterization data for compound 5: ½a D20
¼ ꢁ46 (c 0.60,
ꢃ
CHCl3). 1H NMR (CDCl3) d 0.91 (t, J = 7.4 Hz, 3H, CH3 in 3-pentoxyl),
0.96 (t, J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 1.29 (t, J = 7.1 Hz, 3H, CH3
in COOEt), 1.48–1.62 (m, 4H, both CH2 in 3-pentoxyl), 2.14 (s, 3H,
CH3 in Ac), 2.65 (dd, J1 = 18.0 Hz, J2 = 4.8 Hz, 1H, H-6), 2.87–3.01
(m, 3H, H-4, H-5 and H-60), 3.41–3.49 (m, 1H, OCH in 3-pentoxyl),
4.21 (q, J = 7.1 Hz, 2H, OCH2 in COOEt), 4.36–4.41 (m, 1H, H-3), 6.83
(d, J = 4.2 Hz, 1H, H-2). 13C NMR (CDCl3) d 182.55, 166.46, 133.04,
127.72, 82.41, 68.50, 60.87, 37.11, 34.76, 26.62, 26.56, 23.78,
23.44, 14.15, 9.89, 9.44. HRMS (EI) calcd for (C16H25NO4)+:
295.1784; found: 295.1786. IR (neat) 2969, 2875, 1710, 1426,
650 cmꢁ1
.
4.7. (3R,4R,5S)-Ethyl 4-acetylamido-3-(pentan-3-yloxy)-5-
(2,2,2-trichloro-acetimido)cyclohex-1-ene carboxylate 8
1368, 1248, 1063, 743 cmꢁ1
.
Characterization data for (5R)-ethyl 5-acetylamido-3-(pentan-
3-yloxy)cyclohexa-1,3-diene carboxylate 6: Mp 108.5–109.1 °C.
A solution of aziridine 5 (590.0 mg, 1.997 mmol) and isopropyl
2,2,2-trichloroacetimidate (610.0 mg, 2.983 mmol) in dichloro-
methane (15 mL) was cooled to ꢁ15 °C with a salt-ice bath. Next,
BF3ꢀOEt2 (570.0 mg, 4.012 mmol) was dropwise added over
2 min. After the addition was complete, the mixture was stirred
at ꢁ15 °C for 20 min. The reaction was immediately quenched by
adding water (10 mL). After the mixture was vigorously stirred
for 10 min, the two phases were separated, and the aqueous phase
was extracted twice with dichloromethane (2 ꢂ 15 mL). The organ-
ic extracts were combined and dried over anhydrous MgSO4. Evap-
oration of the solvent under vacuum gave a solid residue, which
was purified by flash chromatography (eluent: EtOAc/hex-
ane = 1:5) to afford compound 8 (860.0 mg, 1.879 mmol) as off-
½
a 2D0
ꢃ
¼ þ118 (c 1.10, CHCl3). 1H NMR (acetone-d6) d 0.90 (t,
J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 0.92 (t, J = 7.4 Hz, 3H, CH3 in 3-
pentoxyl), 1.29 (t, J = 7.1 Hz, 3H, CH3 in COOEt), 1.56–1.66 (m,
4H, both CH2 in 3-pentoxyl), 1.83 (s, 3H, CH3 in Ac), 2.55 (dd,
J1 = 18.0 Hz; J2 = 8.0 Hz, 1H, H-6), 2.68 (dd, J1 = 18.0 Hz;
J2 = 4.9 Hz, 1H, H-60), 3.94–4.00 (m, 1H, OCH in 3-pentoxyl), 4.20
(q, J = 7.1 Hz, 2H, OCH2 in COOEt), 4.70–4.76 (m, 1H, H-5), 5.08
(d, J = 5. 6 Hz, 1H, H-4), 6.79 (s, 1H, H-2), 7.32 (br s, 1H, NHAc).
13C NMR (acetone-d6) d 168.22, 165.74, 152.27, 131.89, 129.32,
99.54, 78.46, 60.25, 42.37, 29.03, 25.23, 25.12, 22.05, 13.65, 8.88,
8.85. HRMS (EI) calcd for (C16H25NO4)+: 295.1784; found:
295.1785. IR (KBr film) 3350, 2969, 1674, 1650, 1596, 1522,
white crystals in 94% yield. Mp 193.9–195.2 °C, ½a D20
¼ ꢁ45 (c 1.0,
ꢃ
1278, 1270, 1212, 1200, 1067, 985, 835, 585 cmꢁ1
.
CHCl3). 1H NMR (CDCl3) d 0.90 (t, J = 7.4 Hz, 6H, both CH3 in 3-pent-
oxyl), 1.31 (t, J = 7.1 Hz, 3H, CH3 in COOEt), 1.46–1.58 (m, 4H, two
CH2 in 3-pentoxyl), 2.00 (s, 3H, CH3 in Ac), 2.51 (dd, J1 = 18.1 Hz;
J2 = 8.3 Hz, 1H, H-6), 2.83 (dd, J1 = 18.1 Hz; J2 = 5.1 Hz, 1H, H-60),
3.36–3.44 (m, 1H, OCH in 3-pentoxyl), 4.03–4.16 (m, 2H, H-4 and
H-5), 4.19–4.30 (m, 3H, H-3 and OCH2 in COOEt), 5.98 (d,
J = 8.0 Hz, 1H, H-2), 6.85 (br s, 1H, NHAc), 8.07 (br s, 1H, NHCOCl3).
13C NMR (CDCl3) d 171.43, 165.86, 162.69, 137.11, 128.83, 92.46,
82.43, 74.87, 61.07, 52.97, 50.61, 29.34, 26.22, 25.72, 23.22,
14.17, 9.55, 9.23. HRMS (EI) calcd for (C18H27Cl3N2O5)+:
456.0986; found: 456.0989. IR (KBr film) 3345, 3181, 2972, 1714,
4.5. (3R,4R,5S)-Ethyl 4-acetylamido-5-diallylamino-3-(pentan-
3-yloxy)cyclohex-1-ene carboxylate 7
Aziridine 5 (2.000 g, 6.771 mmol) was dissolved in diallylamine
(10 mL), and the solution was then heated at reflux (112 °C) for
approximately 6 h under an argon atmosphere. When TLC showed
the reaction was complete, diallylamine was removed by vacuum
distillation to give a crude oil, which was purified by flash chroma-
tography (eluent: EtOAc/hexane = 1:5) to afford compound
7
(2.472 g, 6.298 mmol) in 93% yield. ½a D20
ꢃ
¼ ꢁ30 (c 1.0, CHCl3). 1H
1666, 1546, 1245, 1059, 831, 669 cmꢁ1
.
NMR (CDCl3) d 0.87 (t, J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 0.90 (t,
J = 7.4 Hz, 3H, CH3 in 3-pentoxyl), 1.30 (t, J = 7.1 Hz, 3H, CH3 in
COOEt), 1.46–1.55 (m, 4H, both CH2 in 3-pentoxyl), 2.00 (s, 3H,
CH3 in Ac), 2.19 (dd, J1 = 17.6 Hz; J2 = 7.6 Hz, 1H, H-6), 2.58 (dd,
J1 = 17.6 Hz; J2 = 4.1 Hz, 1H, H-60), 2.92 (dd, J1 = 14.2 Hz;
J2 = 7.8 Hz, 2H, two sp3-H in allyl), 3.00–3.09 (m, 1H, H-5),
3.24–3.37 (m, 3H, the other two sp3-H in allyl, and OCH in pent-
oxyl), 3.89–3.98 (m, 1H, H-4), 4.06 (dd, J1 = 8.2 Hz, J2 = 7.3 Hz, 1H,
H-3), 4.21 (q, J = 7.1 Hz, 2H, CH2 in COOEt), 5.08 (d, J = 10.1 Hz,
2H, two terminal sp2-H in allyl), 5.16 (d, J = 17.1 Hz, 2H, the other
two terminal sp2-H in allyl), 5.61 (d, J = 8.2 Hz, H-2), 5.65–5.78 (m,
4.8. Oseltamivir phosphate 1
A solution of compound 8 (460.0 mg, 1.005 mmol) in DMSO
(8 mL) was heated to 80 °C. Fine powdered Cs2CO3 (815.0 mg,
2.501 mmol) was added quickly, and the mixture was stirred at
80 °C for 15 min. An aqueous solution of acetic acid (50% w/w,
3 mL) was added, and stirring was continued at 80 °C for 20 min.
After the mixture was cooled down to room temperature, ethyl
acetate (30 mL) and an aqueous solution of K2CO3 (20% w/w,
15 mL) were added. After the mixture was vigorously stirred for

642
L.-D. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 638–642
11. Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tasi, 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.
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Eur. J. 2010, 16, 4533.
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Org. Chem. 2010, 75, 7006.
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10 min, the two phases were separated, and the aqueous phase
was extracted twice with ethyl acetate (2 ꢂ 20 mL). The organic
extracts were combined and dried over anhydrous MgSO4. Evapo-
ration of the solvent under vacuum gave a pale yellow oily residue,
which was dissolved in a mixed solvent of ethyl acetate (4 mL) and
ethanol (4 mL). Phosphoric acid (85%, 130.0 mg, 1.128 mmol) was
then added, and the resulting suspension was heated and stirred
at 50 °C for 2 h. The suspension was cooled down to room temper-
ature, and then allowed to stand overnight. White crystals were
collected on a Buchner funnel by suction and washed twice with
ethyl acetate (2 ꢂ 1 mL). After being dried overnight in warm air,
oseltamivir phosphate 1 (0.340 g, 0.828 mmol) was obtained in
82% yield. The characterization data of compound 1 were identical
with those of the sample obtained in our previous report.9a–d
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Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20972048) for the financial support of this work.
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