A novel and high-yielding asymmetric synthesis of oseltamivir phosphate (Tamiflu) starting from (-)-shikimic acid

Article abstract of DOI:10.1016/j.tetasy.2012.05.014

A novel and high-yielding asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu) is described. The target compound 1 was obtained in 55% overall yield via an 11-step asymmetric synthesis starting from the naturally abundant (-)-shikimic acid. The present synthesis is characterized by some advantages such as the easy separation of intermediate 6 from triphenylphosphine oxide by using its large water-solubility, the use of inexpensive reagents throughout the synthesis, the lack of toxic heavy metals, mild reaction conditions and high yields for all steps. The stereochemical structure of the key intermediate 6 was unequivocally confirmed by X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tetasy.2012.05.014

Tetrahedron: Asymmetry 23 (2012) 742–747
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel and high-yielding asymmetric synthesis of oseltamivir phosphate
(Tamiflu) starting from (ꢀ)-shikimic acid
⇑
Liang-Deng Nie, Wei Ding, Xiao-Xin Shi , Na Quan, 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 and high-yielding asymmetric synthesis of oseltamivir phosphate 1 (TamifluÒ) is described. The
target compound 1 was obtained in 55% overall yield via an 11-step asymmetric synthesis starting from
the naturally abundant (ꢀ)-shikimic acid. The present synthesis is characterized by some advantages
such as the easy separation of intermediate 6 from triphenylphosphine oxide by using its large water-sol-
ubility, the use of inexpensive reagents throughout the synthesis, the lack of toxic heavy metals, mild
reaction conditions and high yields for all steps. The stereochemical structure of the key intermediate
6 was unequivocally confirmed by X-ray crystallographic analysis.
Article history:
Received 13 April 2012
Accepted 9 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
by our previously reported procedure in 98% yield from ethyl
shikimate 2.21 Compound 3 was then treated with 1.5 equiv of
H5N1 and H1N1 influenzas are both fatal diseases for human
beings and if left unchecked could rapidly spread. Oseltamivir
phosphate 1 (TamifluÒ) is an active prodrug of the potent neur-
aminidase inhibitor,1,2 and has been widely used not only as a
frontline therapy for H5N1 influenza3–5 and H1N1 influenza,6 but
also as a preventive agent against an unpredictable outbreak of
pandemic influenza; as a result, there is a tremendous worldwide
requirement for this important drug. In order to protect people
from an attack of both H5N1 and H1N1 influenza viruses, organic
and medicinal chemists have paid great attention to the synthesis
of oseltamivir phosphate 1 over the last decade, and thus it has
become a very active field of scientific research. To date, extensive
efforts have been made by many synthetic chemists7–62 to tackle
the difficult problems associated with the synthesis of oseltamivir
phosphate in order to develop more efficient and useful synthetic
routes. Recently, we have been engaged in the synthesis of
this important compound aiming at practical and industrial
processes;21,37,38 herein we report a novel and high-yielding asym-
metric synthesis of oseltamivir phosphate (Tamiflu) starting from
(ꢀ)-shikimic acid, which is abundant in plant sources.63–67
methanesulfonyl chloride in the presence of 1.2 equiv of triethyl-
amine and a catalytic amount of 4-dimethylaminopyridine (DMAP)
in ethyl acetate, and O-mesylate cyclic sulfite 4 was obtained in
96% yield. Subsequent treatment of compound 4 with 1.6 equiv
of sodium azide and 2.0 equiv of ammonium chloride at room tem-
perature in aqueous N,N-dimethylformamide (DMF/H2O = 5:1) led
to regio- and stereospecific ring opening at the allylic position,
affording azide 5 in 95% yield. The presence of ammonium chloride
was necessary to allow the reaction to proceed under almost neu-
tral conditions, otherwise the yield of the desired compound 5
would be lowered due to b-elimination. Both cyclic sulfites 3 and
4 were obtained as an epimeric mixture of two epimers with oppo-
site configurations of the sulfur atoms; however separation of the
two epimers was unnecessary, because nucleophilic substitution of
the two epimers of compound 4 with sodium azide gave the same
ring-opening product 5 after removal of the epimeric sulfinyl
groups in the next step.
Conversion of azide 5 into aziridine 6 was performed in one step
via tandem reactions. Successive treatment of compound 5 succes-
sively with 1.0 equiv of triphenylphosphine, 1.0 equiv of powdered
potassium carbonate, and a small amount of water in ethanol
(H2O/EtOH = 1:100 v/v) furnished the desired aziridine 6. During
the conversion, triphenylphosphine oxide was obtained as a by-
product along with the Staudinger reduction and aziridination.
Aziridine 6 has considerable water-solubility, and so can be easily
separated from the undesired triphenylphosphine oxide by the fol-
lowing procedure: aziridine 6 was allowed to dissolve in water,
and the undissolved amorphous solid triphenylphosphine oxide
was thus removed by simple filtration. The aqueous solution of
compound 6 was then used as such in the next step. According
2. Results and discussion
As shown in Scheme 1, our synthetic efforts began with ethyl
shikimate 2, which could be obtained from (ꢀ)-shikimic acid
according to a known procedure.61 Cyclic sulfite 3 was prepared
⇑
Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.014

L.-D. Nie et al. / Tetrahedron: Asymmetry 23 (2012) 742–747
743
HO
HO
CO2Et
O
O
CO2Et
O
O
CO2Et
O
O
Ref.[61]
97%
Ref.[21]
98%
a
S
(
–
)-shikimic
S
acid
96%
OH
OH
OMs
2
3
4
CO2Et
N3
CO2Et
CO2Et
3
c
d
e
93%
b
AcN
HN
5
4
90%
95%
HO
4
(2 steps
OH
7
OMs
OH
6
from 5)
5
O
CO2Et
O
CO2Et
O
CO2Et
f
96%
g
h
4
95%
5
92%
AcHN
AcHN
AcN
10
OH
OMs
8
9
O
CO2Et
O
CO2Et
Ref.[21]
91%
AcHN
AcHN
NH2 . H3PO4
oseltamivir phosphate 1
N3
11
Scheme 1. Synthesis of oseltamivir phosphate 1. Reagents and conditions: (a) 1.5 equiv of MsCl, 1.2 equiv of Et3N, 0.1 equiv of DMAP, 0 °C for 1 h in EtOAc; (b) 1.6 equiv of
NaN3, 2.0 equiv of NH4Cl, rt for 9 h in DMF/H2O (5:1); (c) 1.0 equiv of Ph3P, 1.0 equiv of K2CO3, rt for 3 h in EtOH, and then 5.0 equiv of H2O, reflux for 3 h in EtOH; (d) 1.5 equiv
of Ac2O, 2.0 equiv of Et3N, 0 °C for 0.5 h in CH2Cl2/H2O (1:1); (e) 0.2 equiv of BF3ꢁOEt2, ꢀ8 °C for 1 h in 3-pentanol; (f) 1.5 equiv of MsCl, 2.0 equiv of Et3N, 0.1 equiv of DMAP,
0 °C for 1 h in EtOAc; (g) 4.0 equiv of NaH, rt for 1 h in THF; (h) 4.2 equiv of LiCl, 4.0 equiv of NaN3, 80 °C for 3 h in DMF.
to a similar procedure,21 N-acetylation of compound 6 with
1.5 equiv of acetic anhydride and 2.0 equiv of triethylamine in a
two-phase reaction system (CH2Cl2/H2O = 1:1) at 0 °C afforded
compound 7 in 90% yield (over 2 steps from compound 5), while
leaving the hydroxyl group (at the C-5 position) intact.
N
CO2Et
Ph3P
N
CO2Et
Ph3P
PPh3
-N2
5
HO
HO
OMs
I-A
OMs
I-B
A plausible mechanism for the conversion of compound 5 to
compound 6 is proposed in Scheme 2. The following cascade reac-
tions were involved in the conversion: Staudinger reduction of
compound 5 produced an intermediate aza-ylid I-A (or I-B), which
readily changed to another aza-ylid I-C via epoxide-formation un-
der basic conditions. An intramolecular SN2-type reaction via
nucleophilic attack of the nitrogen anion on the vicinal epoxide
moiety furnished a complex aziridine I-D in the presence of water.
Decomposition of the intermediate I-D afforded compound 6,
while releasing triphenylphosphine oxide as a by-product. Both
configurations of the two stereogenic centers at the C(3) and
C(4)-positions were inverted during the conversion of compound
5 to compound 6, which was unequivocally confirmed by X-ray
crystallographic analysis of the single crystal of compound 6 as
shown in Figure 1.
CO2Et
Ph3P
N
CO2Et
HN
H2O
K2CO3
-MsOH
O
O
Ph3P
OH
I-D
I-C
CO2Et
-Ph3PO
HN
OH
Subsequently, the mild BF3ꢁOEt2-catalyzed regioselective and
stereospecific ring-opening reaction of N-Ac-aziridine 7 produced
compound 8 in 93% yield. A similar procedure could be followed
for this transformation;21 herein the reaction was performed in
3-pentanol at ꢀ8 °C with 0.2 equiv of BF3ꢁOEt2 as the catalyst. Since
the allylic C(3)-position is much more active than the C(4)-posi-
tion, so 3-pentanol attacked the allylic C(3)-position with very high
regioselectivity during the aziridine ring-opening. Following a sim-
ilar procedure,37 compound 8 was then exposed to 1.5 equiv of
methanesulfonyl chloride and 2.0 equiv of triethylamine in ethyl
acetate in the presence of a catalytic amount of DMAP (0.1 equiv),
6
Scheme 2. Possible mechanism for the conversion of compound 5 to compound 6.
and methanesulfonate 9 was thus obtained in 96% yield. Next, N-
acetylaziridine 10 was formed in 95% yield by an SN2 type intramo-
lecular reaction of mesylate 9 with 4.0 equiv of sodium hydride
(60% in mineral oil) in dry tetrahydrofuran. Treatment of com-
pound 10 with 4.2 equiv of lithium chloride and 4.0 equiv of so-
dium azide in N,N-dimethylformamide (DMF) at 80 °C caused the

744
L.-D. Nie et al. / Tetrahedron: Asymmetry 23 (2012) 742–747
are quite clean, and the yields for every step are greater than 90%,
meaning that the crude products of these transformations can be
used directly for the next steps without purification. Some advan-
tages such as the easy separation of intermediate 6 from triphenyl-
phosphine oxide based on its high water-solubility, the use of
inexpensive reagents throughout the synthesis, lack of toxic heavy
metals, mild reaction conditions, and high yields for all steps,
would make the above described synthesis more practical and easy
to scale up.
4. Experimental
4.1. General
Melting points were determined on a Mel-TEMP II apparatus. 1H
NMR and 13C NMR spectra were acquired on a Bruker AM-500
spectrometer at 300 K. Chemical shifts were 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 Shimadzu
GC–MS 2010 or a LC/MSD TOF HR-MS equipment. Column chroma-
tography was performed on silica gel. Optical rotations of chiral
compounds were measured on a WZZ-1S automatic polarimeter
at room temperature. All chemicals were analytically pure. (ꢀ)-
Ethyl shikimate 2 was prepared in 97% yield according to a known
procedure.61 Cyclic sulfite 3 was prepared in 98% yield according to
a previously reported method.21
Figure 1. ORTEP drawing of compound 6.
ring-opening reaction of compound 10 to give an azido compound
11 in 92% yield. Finally, compound 11 was transformed into osel-
tamivir phosphate 1 in 91% yield according to our previously re-
ported procedure,21 and the characterization data of compound 1
obtained from the above synthesis were identical to those of the
sample previously obtained.37,38
The regioselectivity of the ring opening of compound 10 was
found to be very high, with almost no C(4)-attacked by-product
being detected. Conformational analysis as portrayed in Figure 2
might explain the above high regioselectivity: compound 10 would
most likely adopt a boat conformation (conformer A), since the
nucleophilic attack of the azide anion ðNꢀ3 Þ at the C(4)-position of
conformer A could be exclusively blocked by the neighboring bulky
3-pentoxy group, hence the nucleophile ðNꢀ3 Þ would favorably at-
tack the much less hindered C(5)-position of conformer A, and ax-
ial attack at C(5) would first produce an unstable twist chair
conformer B, which would then flip to a stable twist chair con-
former C of compound 11.
4.2. Ethyl (3R,4S,5R)-3,4-O-thionyl-5-O-methanesulfonyl-shiki-
mate 4
Methanesulfonyl chloride (6.920 g, 60.41 mmol) and DMAP
(0.490 g, 4.011 mmol) were added to a solution of cyclic sulfite 3
(10.00 g, 40.28 mmol) in ethyl acetate (200 mL) at 0 °C. Triethyl-
amine (4.890 g, 48.32 mmol) was then added dropwise over
0.5 h. After the addition was finished, the reaction mixture was
stirred at 0 °C for another 0.5 h. The reaction was quenched by add-
ing a dilute HCl aqueous solution (1 M, 100 mL), and then the or-
ganic phase was separated and washed with dilute potassium
carbonate aqueous solution until pH 8–9. The organic solution
was dried over anhydrous MgSO4, and then concentrated under
vacuum to afford a pale yellow oil that could be used directly for
the next step or purified by flash chromatography to furnish com-
Ac
N
NHAc
EtO2C
4
5 H
Nu
H
CO2Et
H
Nu = N3
H
3
H
H
4
O
5
O
N3
Nu
pound 4 (12.62 g, 38.67 mmol) in 96% yield. ½a D20
ꢂ
¼ þ19 (c 1.5,
EtOAc). 1H NMR (CDCl3) for major diastereomer:
d
1.33 (t,
conformer B
conformer A
J = 7.1 Hz, 3H), 2.54–2.64 (m, 1H), 3.09–3.18 (m, 1H), 3.14 (s, 3H),
4.27 (q, J = 7.1 Hz, 2H), 4.72–4.81 (m, 1H), 5.01 (dd, J1 = 8.2 Hz;
J2 = 5.7 Hz, 1H), 5.65 (dd, J1 = 5.7 Hz, J2 = 4.8 Hz, 1H), 6.96–7.01
(m, 1H). 13C NMR (CDCl3) for major diastereomer: d 164.23,
132.79, 128.87, 78.12, 76.27, 75.58, 61.91, 38.80, 28.97, 14.13. 1H
NMR (CDCl3) for minor diastereomer: d 1.33 (t, J = 7.1 Hz, 3H),
2.58–2.66 (m, 1H), 3.14 (s, 3H), 3.18–3.27 (m, 1H), 4.27 (q,
J = 7.1 Hz, 2H), 4.81–4.86 (m, 1H), 5.19–5.27 (m, 1H), 5.28–5.35
(m, 1H), 7.01–7.06 (m, 1H). 13C NMR (CDCl3) for minor diastereo-
mer: d 164.49, 131.53, 130.37, 79.43, 79.24, 77.53, 61.82, 38.20,
29.12, 14.13. HRMS (ESI) calcd for (C10H14O8S2+K)+: 364.9767;
found: 364.9769. IR (KBr film) 2983, 1716, 1662, 1367, 1257,
H
5
H
O
N
3 CO2Et
NHAc
4
H
conformer C
Figure 2. Conformational analysis for the highly regioselective aziridine-opening of
compound 10 by favorable N3ꢀ-attack at the C(5)-position.
1174, 1100, 1005, 830, 526 cmꢀ1
.
3. Conclusion
4.3. Ethyl (3S,4R,5R)-3-azido-4-hydroxy-5-methanesulfonyloxy-
cyclohex-1-ene-1-carboxylate 5
In conclusion, compound 1 was obtained in 55% overall yield via
an 11 step synthesis starting from the naturally abundant (ꢀ)-shi-
kimic acid. The total yield (55%) of the present synthesis is obvi-
ously higher than the best overall yield (47%)38 of three previous
syntheses.21,37,38 All of the transformations in the present synthesis
Ammonium chloride (3.280 g, 61.32 mmol) and sodium azide
(3.230 g, 49.68 mmol) were added to a solution of compound 4
(10.00 g, 30.64 mmol) in aqueous N,N-dimethylformamide

L.-D. Nie et al. / Tetrahedron: Asymmetry 23 (2012) 742–747
745
(80 mL, DMF/H2O = 5:1). The mixture was stirred at room temper-
ature for 9 h, and then diluted with ethyl acetate (250 mL) and
water (200 mL). The organic phase was separated, and then
washed with water (50 mL) and brine (50 mL). The organic solu-
tion was dried over anhydrous MgSO4. The solvent was then re-
moved by distillation under vacuum to give the crude product as
yellow crystals. The crystals were collected on a Buchner funnel
and rinsed with aqueous methanol (CH3OH/H2O = 6:4) to afford
phy to furnish compound 7 (1.330 g, 5.905 mmol) in 90% yield over
2-steps (compound 5 to compound 7). ½a D20
¼ ꢀ105 (c 0.8, CHCl3).
ꢂ
1H NMR (CDCl3) d 1.30 (t, J = 7.1 Hz, 3H), 2.14 (s, 3H), 2.20–2.31 (m,
1H), 2.64–2.70 (m, 1H), 2.79–2.89 (m, 1H), 3.10–3.18 (m, 2H), 4.20
(q, J = 7.1 Hz, 2H), 4.55–4.59 (m, 1H), 7.18–7.22 (m, 1H). 13C NMR
(CDCl3) d 181.79, 166.37, 132.99, 129.99, 61.92, 61.02, 41.73,
32.56, 29.21, 23.17, 14.15. HRMS (EI) calcd for (C11H15NO4+H)+:
226.1079; found: 226.1075. IR (KBr film) 3412, 2979, 1709, 1368,
compound
5
(8.890 g, 29.12 mmol) in 95% yield. Mp 88.9–
1263, 1199, 1099, 1053, 753 cmꢀ1
.
89.2 °C. ½a 2D0
ꢂ
¼ þ31 (c 2.3, CHCl3). 1H NMR (CDCl3) d 1.31 (t,
J = 7.1 Hz, 3H), 2.51–2.59 (m, 1H), 3.10 (dd, J1 = 17.5 Hz;
J2 = 5.9 Hz, 1H), 3.16 (s, 3H), 3.88 (dd, J1 = 9.0 Hz, J2 = 9.1 Hz, 1H),
3.97 (br s, 1H), 4.18–4.29 (m, 3H), 4.70–4.79 (m, 1H), 6.64–6.68
(m, 1H). 13C NMR (CDCl3) d 165.54, 134.57, 129.96, 79.52, 73.44,
63.72, 62.17, 39.24, 31.41, 14.72. HRMS (ESI) calcd for
(C10H15N3O6S+NH4)+: 323.1025; found: 323.1026. IR (KBr film)
4.6. Ethyl (3R,4R,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-hydro-
xy-cyclohex-1-ene-1-carboxylate 8
A procedure similar to a previous article21 was followed herein.
Compound 7 (1.000 g, 4.440 mmol) was dissolved in 3-pentanol
(5 mL), and the resulting solution was cooled to ꢀ8 °C by a salt-
ice bath. A fresh solution of boron trifluoride-diethyl etherate
(0.120 g, 0.846 mmol) solution in 3-pentanol (5 mL) was then
added over 30 min. After the addition was finished, the reaction
mixture was stirred for a further 1 h at ꢀ8 °C. The reaction was
quenched by adding an aqueous solution of potassium carbonate
(15% w/v, 20 mL), then the aqueous solution was extracted twice
with methylene chloride (2 ꢃ 30 mL). The organic extracts were
combined, and dried over anhydrous MgSO4. Evaporation of the
solvents under vacuum gave a yellow solid product, which could
be used directly for the next step or purified by flash chromatogra-
phy to furnish compound 8 (1.300 g, 4.148 mmol) in 93% yield. Mp
3604, 3333, 3031, 2104, 1721, 1663, 1253, 1175, 953 cmꢀ1
.
4.4. Ethyl (3S,4S,5S)-5-hydroxy-3,4-imino-cyclohex-1-ene-1-car-
boxylate 6
A solution of compound 5 (2.000 g, 6.551 mmol) in ethanol
(40 mL) was cooled to 0 °C by an ice bath. Next, triphenylphos-
phine (1.720 g, 6.558 mmol) was added in portions over 5 min.
After the solution was stirred at 0 °C for 15 min, powdered potas-
sium carbonate (0.910 g, 6.584 mmol) was added. The ice bath
was removed, and the mixture was then vigorously stirred for
3 h at room temperature. The resulting suspension was then fil-
tered by suction to remove insoluble inorganic salts, and the cake
was rinsed twice with ethanol (2 ꢃ 10 mL). The filtrates were com-
bined and water (0.6 mL) was added. The reaction solution was
then heated at reflux for 3 h until the reaction was complete. The
solvent was removed by distillation under vacuum to give the
crude product as a viscous yellow oil. Water (30 mL) was added,
and the mixture was stirred vigorously. Triphenylphosphine oxide
gradually precipitated, and was separated from the aqueous solu-
tion of compound 6 by filtration. After the cake of triphenylphos-
phine oxide was washed twice with water (2 ꢃ 5 mL), the
aqueous filtrates were combined and used in the next step without
further purification. For spectroscopic characterization, a sample of
6 was extracted from the aqueous solution, and purified by chro-
104.3–105.4 °C. ½a D20
ꢂ
¼ ꢀ60 (c 2.5, CHCl3). 1H NMR (CDCl3) d 0.91
(t, J = 7.0 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.45–1.58 (m, 4H), 2.04
(s, 3H), 2.32–2.42 (m, 1H), 2.75–2.85 (m, 1H), 3.31–3.42 (m, 1H),
3.75–3.85 (m, 1H), 3.92–4.03 (m, 1H), 4.00–4.18 (m, 2H), 4.22 (q,
J = 7.1 Hz, 2H), 5.96–6.02 (m, 1H), 6.76–6.81 (m, 1H). 13C NMR
(CDCl3) d 172.11, 166.26, 136.91, 129.07, 81.90, 74.97, 67.87,
60.91, 57.35, 32.92, 26.19, 25.64, 23.48, 14.15, 9.52, 9.22. HRMS
(EI) calcd for (C16H27NO5+H)+: 314.1967; found: 314.1955. IR
(KBr film) 3413, 3293, 2973, 2879, 1722, 1642, 1555, 1377, 1248,
1057, 1009 cmꢀ1
.
4.7. Ethyl (3R,4S,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-metha-
nesulfonyloxy-cyclohex-1-ene-1-carboxylate 9
matography. Data for 6: Mp 99.0–99.9 °C. ½a D20
ꢂ
¼ ꢀ296 (c 2.0,
A procedure similar to a previous article37 was followed herein:
To a solution of compound 8 (2.000 g, 6.382 mmol) in ethyl acetate
(40 mL) was added methanesulfonyl chloride (1.100 g,
9.603 mmol) and DMAP (0.078 g, 0.638 mmol) at 0 °C. Triethyl-
amine (1.290 g, 12.75 mmol) was then dropwise added over
30 min. After the addition was finished, the reaction mixture was
stirred at 0 °C for another 0.5 h. The reaction was quenched by add-
ing a dilute HCl aqueous solution (1 M, 100 mL), and then the or-
ganic phase was separated and washed with a dilute potassium
carbonate aqueous solution until pH 8–9. The organic solution
was dried over anhydrous MgSO4, and then concentrated under
vacuum to afford a pale yellow solid product, which could be used
directly for the next step or purified by flash chromatography to
furnish compound 9 (2.400 g, 6.131 mmol) in 96% yield. Mp
CHCl3). 1H NMR (CDCl3) d 1.28 (t, J = 7.0 Hz, 3H), 2.20–2.32 (m,
1H), 2.60–2.68 (m, 1H), 2.72–2.85 (m, 2H), 4.18 (q, J = 7.0 Hz,
2H), 4.45–4.55 (m, 1H), 7.25–7.30 (m, 1H). 13C NMR (acetone-d6)
d 167.12, 138.86, 128.53, 63.85, 60.77, 39.30, 30.76, 28.34, 14.61.
HRMS (EI) calcd for (C9H13NO3+H)+: 184.0974; found: 184.0964.
IR (KBr film) 3290, 2999, 2964, 1691, 1645, 1466, 1409, 1268,
1236, 1096, 777 cmꢀ1
.
4.5. Ethyl (3S,4S,5S)-3,4-acetylimino-5-hydroxy-cyclohex-1-ene-
1-carboxylate 7
A procedure similar to a previous article21 was followed herein.
The above aqueous solution of aziridine 6 was mixed with dichlo-
romethane (40 mL), and the two-phase mixture was cooled to 0 °C
by an ice bath. Triethylamine (1.320 g, 13.04 mmol) was added,
and then acetic anhydride (1.000 g, 9.795 mmol) was added drop-
wise over 15 min. After the addition was finished, the reaction
mixture was further stirred for a further 15 min. Two phases were
separated, and the aqueous layer was salted with potassium car-
bonate (0.500 g) and sodium chloride (15.00 g), and then extracted
twice with dichloromethane (2 ꢃ 30 mL). The organic extracts
were combined, dried over anhydrous MgSO4, and then concen-
trated under vacuum to afford a pale yellow oily product that could
be used directly for the next step or purified by flash chromatogra-
102.7–104.0 °C. ½a D20
ꢂ
¼ ꢀ29 (c 1.0, CHCl3). 1H NMR (CDCl3) d
0.83–0.95 (m, 6H), 1.30 (t, J = 7.1 Hz, 3H), 1.44–1.59 (m, 4H), 2.03
(s, 3H), 2.53–2.63 (m, 1H), 3.05 (s, 3H), 3.07 (dd, J1 = 16.8 Hz;
J2 = 5.6 Hz, 1H), 3.29–3.39 (m, 1H), 3.84–3.92 (m, 1H), 4.22 (q,
J = 7.1 Hz, 2H), 4.36–4.44 (m, 1H), 4.99–5.11 (m, 1H), 6.00–6.05
(m, 1H), 6.78–6.82 (m, 1H). 13C NMR (CDCl3) d 171.14, 165.47,
138.06, 127.21, 82.46, 75.89, 74.42, 61.19, 55.48, 38.58, 31.55,
26.23, 25.66, 23.54, 14.20, 9.55, 9.26. HRMS (EI) calcd for
(C17H29NO7S+H)+: 392.1743; found: 392.1746. IR (KBr film) 3433,
3270, 2972, 2939, 1717, 1647, 1572, 1362, 1258, 1177, 963,
838 cmꢀ1
.

746
L.-D. Nie et al. / Tetrahedron: Asymmetry 23 (2012) 742–747
4.8. Ethyl (3R,4R,5R)-4,5-acetylimino-3-(1-ethyl-propoxy)-
cyclohex-1-ene-1-carboxylate 10
Diffraction intensities were collected on a Bruker APEX2 CCD
diffractometer using graphite monochromated Cu K radiation
a
(k = 1.54178 Å) at 133 K. The absorption was corrected via multi-
scan. The structure was solved by direct methods using SHELXS-
97 and refined on F2 by full-matrix least-squares methods using
SHELXL-97. All non-H atoms were refined anisotropically and H-
atoms isotropically.
Crystallographic data for the structure herein have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 848662. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033, e-mail:
deposit@ccdc.cam.ac.uk, or internet: www.ccdc.cam.ac.uk/da-
ta_request/cif.].
Compound 9 (2.000 g, 5.109 mmol) was dissolved in tetrahy-
drofuran (60 mL), after which sodium hydride (0.820 g, 60%,
20.50 mmol) was added portionwise. The reaction mixture was al-
lowed to stir at room temperature for 1 h, and then was quenched
by adding ethanol (2 mL). The resulting suspension was filtered by
suction to remove insoluble salts, and the filtrate was concentrated
under vacuum to remove tetrahydrofuran. The residue was parti-
tioned between ethyl acetate (40 mL) and water (10 mL). The or-
ganic solution was separated, dried over anhydrous MgSO4, and
then concentrated under vacuum to afford a pale yellow oily prod-
uct, which could be used directly for the next step or purified by
flash chromatography to furnish compound 10 (1.430 g,
4.841 mmol) in 95% yield. ½a D20
ꢂ
¼ ꢀ46 (c 1.6, CHCl3). 1H NMR
Acknowledgments
(CDCl3) d 0.91 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.29 (t,
J = 7.1 Hz, 3H), 1.48–1.64 (m, 4H), 2.14 (s, 3H), 2.58–2.68 (m, 1H),
2.85–3.00 (m, 3H), 3.38–3.48 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H),
4.35–4.40 (m, 1H), 6.81–6.85 (m, 1H). 13C NMR (CDCl3) d 182.54,
166.45, 133.03, 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: 295.1785. IR (KBr film) 2969,
We are grateful to the National Natural Science Foundation of
China (No. 20972048) for the financial support of this work.
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