Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid via cyclic sulfite intermediates

Article abstract of DOI:10.1016/j.tetasy.2011.09.014

A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (-)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively. Copyright

Full text of DOI:10.1016/j.tetasy.2011.09.014

Tetrahedron: Asymmetry 22 (2011) 1692–1699
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu)
from (ꢀ)-shikimic acid via cyclic sulfite intermediates
⇑
Liang-Deng Nie, Xiao-Xin Shi , Na Quan, Fei-Feng Wang, 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
Article history:
A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (ꢀ)-shikimic acid
via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39%
overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio-
and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic
sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was
not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sul-
fites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was
obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively.
Received 20 August 2011
Accepted 22 September 2011
Available online 29 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
readily prepared in excellent yield via esterification of (ꢀ)-shikimic
acid according to a known procedure.55
Oseltamivir phosphate (TamifluÒ) 1 is an active prodrug of a po-
tent neuraminidase inhibitor,1,2 which has been widely used for
the treatment of H5N1 influenza3–5 as well as H1N1 influenza.6
Not only as a reasonable frontline therapy against a possible flu
pandemic but also as a preventive agent, Tamiflu has now been
stockpiled by many nations to be used strategically when a wide-
spread influenza outbreak occur.3,4 In order to meet the worldwide
requirement for Tamiflu, the synthesis of oseltamivir phosphate 1
has gathered the attention of synthetic chemists, and has become a
very active field of research.1,2,7–56
Recently, we have been engaged in the synthesis of oseltamivir
phosphate, and have reported two practical syntheses31,32 from
(ꢀ)-shikimic acid via 3,4-bismesylate31 or 3,4,5-trimesylate32 of
shikimic acid ethyl ester. Based on the high reactivity and regiose-
lectivity of the cyclic sulfite toward nucleophile azide,57,58 and due
to the wide availability of (ꢀ)-shikimic acid,27,31 we have just fin-
ished and herein want to report a novel asymmetric synthesis of
oseltamivir phosphate (Tamiflu) 1 from the naturally abundant
(ꢀ)-shikimic acid, where 3,4-cyclic sulfites derived from ethyl shi-
kimate 2 were used as the key intermediates and were subjected to
a highly regioselective and stereoselective nucleophilic replace-
ment by sodium azide at the more active allylic C-3 position.
Exposure of ethyl shikimate 2 to 2.5 equiv of thionyl chloride
and 2.5 equiv of triethylamine in ethyl acetate at 0 °C to room
temperature efficiently produced 3,4-cyclic sulfite 3 in 98% yield.
Although 3,4-cyclic sulfite 3 actually occurred as an epimeric
mixture of two epimers with different configurations of the sulfur
atoms, separation of the two epimers was unnecessary, because
the two epimers gave the same ring-opening product 4 in the
next step. Treatment of compound 3 with 2.0 equiv of sodium
azide at reflux in absolute ethanol led to regio- and stereospecific
ring opening at the allylic (C-3) position affording azide 4 in 93%
yield, while at the same time the (R)-configuration of C-3 was in-
verted into the (S)-configuration via
a typical Walden-type
inversion.
With dihydroxyl azide 4 in hand, we first attempted to prepare
aziridine 5 directly via a Staudinger59,60 reduction and simulta-
neous cyclization without protecting the hydroxyl groups. Com-
pound 4 was treated with 1.1 equiv of triphenylphosphine and
0.1 equiv of freshly prepared diethylammonium p-toluenesulfo-
nate (Et2NH2+p-TsOꢀ) at 60 °C in toluene to generate aziridine 5
in 62% yield. In this transformation, the reduction of the azido
group and the aziridination via an intramolecular nucleophilic sub-
stitution of the neighboring hydroxyl group at C-4 position took
place simultaneously, while the (R)-configuration at C-4 of com-
pound 4 was inverted into the (S)-configuration at C-6 of com-
pound 5. We also tried this conversion under other conditions,
and the results are summarized in Table 1. An ammonium salt as
a catalyst was necessary for the conversion of compound 4 to com-
pound 5 (entry 1), eight ammonium salts and six solvents were
tested for the reaction; diethylamonium p-toluenesulfonate gave
the best yield at 60 °C in toluene (entry 8).
2. Results and discussion
As shown in the novel synthetic route depicted in Scheme 1, our
new synthetic effort began with ethyl shikimate 2, which could be
⇑
Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.014

L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
1693
2
2
2
HO
HO
1
CO2H
HO
HO
CO2Et
O
O
1
CO2Et
N3
CO2Et
1
O
ref. 55
97%
a
b
3
3
3
S
4
4
4
6
5
6
5
5
98%
93%
HO
OH
(-)-Shikimic Acid
OH
OH
OH
2
3
4
2
3
CO2Et
CO2Et
O
CO2Et
1
6
c
7
HN
d
e
ref. 31
95%
AcN
5
4
95%
93%
62%
AcHN
OH
OH
OH
5
6
7
O
CO2Et
O
CO2Et
O
CO2Et
g
f
92%
91%
AcHN
AcHN
AcHN
NH2 ·H3PO4
OMs
N3
1
Oseltamivir Phosphate
8
9
Scheme 1. Novel asymmetric synthesis of oseltamivir phosphate 1 from (ꢀ)-shikimic acid via a 3,4-cyclic sulfite intermediate. Reagents and conditions: (a) 2.5 equiv of
SOCl2, 2.5 equiv of Et3N, 0–5 °C for 2 h, and then rt for 12 h in EtOAc; (b) 2.0 equiv of NaN3, reflux for 12 h in absolute EtOH; (c) 1.1 equiv of PhP3, 0.1 equiv of diethylamonium
toluenesulfonate (Et2NH–TsOH), rt for 1 h, and then 60 °C for 2 h; (d) 1.2 equiv of Ac2O, 2.0 equiv of Et3N, 0 °C for 0.5 h in CH2Cl2. (e) 1.5 equiv of BF3ꢁOEt2, ꢀ8 °C for 1.5 h in 3-
pentanol; (f) 2.0 equiv of NaN3, 90 °C for 8 h in anhydrous DMF; (g) 1.1 equiv of Ph3P, reflux for 8 h in THF/H2O (10:1); 1.2 equiv of H3PO4, 50 °C for 2 h, then rt for 8 h in
EtOAc/EtOH (2:1).
Table 1
Optimization of the reaction conditions for the conversion of compound 4 to compound 5
Entry
Catalysta
Solvent
Temperature (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
None
Et3N–p-TsOH
Et3N–MsOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
Chloroform
Dichloromethane
THF
60
60
60
60
60
60
60
60
60
45
70
60
60
40e
60
60
3
3
3
2
2
2
2
2
2
4
2
2
2
6
3
3
0
38
40
57
56
54
56
62
60
50
53
55
10
<5
<5
<5
DIPEAc–p-TsOH
DIPEA–MsOH
DIPAd–p-TsOH
DIPA–MsOH
Et2NH–p-TsOH
Et2NH–MsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
Et2NH–p-TsOH
EtOAc
a
b
c
An ammonium salt as catalyst was freshly prepared prior to use, and 0.1 equiv of the ammonium salt were used (entries 2–16).
Isolated yield of compound 5.
Diisopropylethylamine.
Diisopropylamine.
Reflux.
d
e
Aziridine 5 was then exposed to 1.2 equiv of acetic anhydride
C-1 of compound 6 was inverted back into the (R)-configuration
of C-3 of compound 7.
and 2.0 equiv of triethylamine in dichloromethane to form N-acet-
yl aziridine 6 in 95% yield. Herein it is noteworthy that both the
amount of acetic anhydride and the reaction temperature are cru-
cial for the selective acetylation at the N-7 position of the bicyclic
molecule while leaving the hydroxyl group at the C-5 position in-
tact. Subsequently, compound 6 was immediately exposed to
1.5 equiv of borontrifluoride etherate (BF3ꢁOEt2) and a large excess
3-pentanol; ring opening of N-acetyl aziridine 6 in 3-pentanol
solution at ꢀ8 °C thus occurred regio- and stereospecifically to
generate compound 7 in 93% yield, while the (S)-configuration of
Compound 7 was converted to mesylate 8 in 95% yield accord-
ing to the same procedure as described in our previous article.31
Compound 8 was then treated with 2.0 equiv of sodium azide in
anhydrous N,N-dimethylformamide (DMF) to afford azido com-
pound 9 in 92% yield, while the (R)-configuration of C-5 was
inverted into the (S)-configuration via an SN2 mechanism. The
same conversion of compound
8 to compound 9 has been
described twice in our previous articles,31,32 but herein the yield
of compound 9 was increased by using anhydrous DMF as the

1694
L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
N3
CO2Et
O
O
CO2Et
N3
CO2Et
O
O
c
ref. 31
b
a
3
7
S
S
4
4 steps
71%
5
96%
95%
98%
MsO
HO
OBz
12
OBz
10
OBz
11
3,4-Cyclic
Sulfite 3
N3
CO2Et
O
O
CO2Et
N3
CO2Et
c
e
b
d
3
4
95%
87%
98%
5
91%
MsO
HO
OAc
OAc
OAc
15
14
13
CO2Et
CO2Et
O
CO2Et
g
h
f
HN
AcN
7
91%
94%
98%
AcHN
OAc
OAc
17
OAc
18
16
Scheme 2. Improved preparations of compound 7 from 3,4-cyclic sulfite 3. Reagents and conditions: (a) 2.0 equiv of Et3N, 0.1 equiv of 4-dimethylaminopyridine (DMAP),
1.2 equiv of benzoyl chloride, 0 °C to rt for 5 h in CH2Cl2; (b) 2.5 equiv of NaN3, rt for 24 h in DMF/H2O (5:1); (c) 1.5 methanesulfonyl chloride, 1.2 equiv of Et3N, 0.1 equiv of
DMAP, 0 °C for 1 h in EtOAc; (d) 2.0 equiv of Et3N, 0.1 equiv of DMAP, 1.5 equiv of Ac2O, rt for 2 h in CH2Cl2; (e) 1.1 equiv of Ph3P, 3.0 equiv of Et3N (in portions), rt for 10.5 h in
THF/H2O (10:1); (f) 2.0 equiv of Et3N, 1.5 equiv of Ac2O, 0 °C for 0.5 h in EtOAc; (g) 1.5 equiv of BF3ꢁOEt2, ꢀ5–0 °C for 1.5 h in 3-pentanol; (h) 1.1 equiv of K2CO3, rt for 6 h in
absolute EtOH.
solvent instead of aqueous DMF, and a lesser amount of sodium
azide was used. It was found that the anhydrous condition was
obviously better than aqueous conditions31,32 for the conversion,
because hydrolysis of the ester group was diminished as much as
possible in anhydrous DMF.
At the end of the synthesis, azido compound 9 was treated suc-
cessively with 1.1 equiv of triphenylphosphine in aqueous tetrahy-
drofuran (THF/H2O = 10:1) and then with 1.2 equiv of phosphoric
acid in a mixed solvent of ethyl acetate and ethanol (EtOAc/
EtOH = 2:1) to furnish oseltamivir phosphate 1 in 91% yield. In
order to avoid the use of an expensive and poisonous palladium
catalyst (Lindlar’s catalyst), we employed the less expensive tri-
phenylphosphine as the reducing agent to reduce the azido group
instead. Since the process is free of toxic transition metals, it
should be beneficial to the pharmaceutical industry.9
It should be noted that during the four-step conversion from
cyclic sulfite 3 to compound 7 in the synthesis described above,
the direct transformation of dihydroxyl azido compound 4 to aziri-
dine 5 without protecting the hydroxyl groups, only gave a moder-
ate yield (62%). However, our further attempts showed that the
overall yield of the conversion from cyclic sulfite 3 to compound
7 could be greatly increased by protecting the C-5 hydroxyl group
with a benzoyl (Bz) or acetyl (Ac) group and by masking the C-4
hydroxyl group with a methanesulfonyl (Ms) group.
As shown in Scheme 2, treatment of 3,4-cyclic sulfite 3 with
1.2 equiv of benzoyl chloride, 2.0 equiv of triethylamine and
0.1 equiv of 4-dimethylaminopyridine (DMAP) in dichloromethane
generated the Bz-protected 3,4-cyclic sulfite 10 in an almost quan-
titative yield. Compound 10 was then exposed to 2.5 equiv of so-
dium azide in aqueous N,N-dimethylformamide (DMF/H2O = 5:1)
at room temperature to afford the ring-opening product 11 in
95% yield. Reaction of compound 11 with 1.5 equiv of methanesul-
fonyl chloride in the presence of 1.2 equiv of triethylamine and
0.1 equiv of DMAP in ethyl acetate produced the vicinal azido mes-
ylate 12 in 96% yield. Compound 12 could be converted to com-
pound 7 over four steps in 71% overall yield by following the
same sequence as described in our previous article.31
As shown in Scheme 2, treatment of 3,4-cyclic sulfite 3 with
1.5 equiv of acetic anhydride, 2.0 equiv of triethylamine and
0.1 equiv of DMAP in dichloromethane generated the Ac-protected
3,4-cyclic sulfite 13 in an almost quantitative yield. Compound 13
was then exposed to 2.5 equiv of sodium azide in aqueous
N,N-dimethylformamide (DMF/H2O = 5:1) at room temperature to
afford the ring-opening product 14 in 91% yield. The reaction of
compound 14 with 1.5 equiv of methanesulfonyl chloride in the
presence of 1.2 equiv of triethylamine and 0.1 equiv of DMAP in
ethyl acetate produced the vicinal azido mesylate 15 in 95% yield.
A Staudinger reduction of azide 15 with 1.1 equiv of triphenyl-
phosphine and simultaneous cyclization under basic conditions
in aqueous tetrahydrofuran (THF/H2O = 10:1) afforded aziridine
16 in 87% yield. Exposure of aziridine 16 to 1.5 equiv of acetic
anhydride and 2.0 equiv of triethylamine in ethyl acetate formed
N-Ac-aziridine 17 in an excellent yield. N-Acetyl aziridine 17 was
then treated with 1.5 equiv of boron trifluoride etherate in 3-pent-
anol to furnish a ring-opening product 18 in 91% yield. Alcoholysis
of compound 18 in absolute ethanol in the presence of 1.1 equiv of
potassium carbonate gave the desired compound 7 in 94% yield.
Both the Bz and Ac-protected 3,4-cyclic sulfites 10 and 13 oc-
curred as epimeric mixtures with different configurations at the
sulfur atoms, but these epimeric mixtures do not need separation
and could be used as such in the next step similar to the unpro-
tected 3,4-cyclic sulfite 3, since the epimeric sulfinyl groups are
lost during the subsequent ring-opening reactions, and diastereo-
merically pure compounds 11 and 14 are obtained in high yields.
3. Conclusion
In conclusion, we have successfully developed a novel asym-
metric synthesis of oseltamivir phosphate 1 from the naturally
abundant (ꢀ)-shikimic acid via 3,4-cyclic sulfite 3 (Scheme 1). A
total of nine steps are involved in the synthesis, and the overall
yield of the whole synthesis from (ꢀ)-shikimic acid to the target
compound 1 is 39%. The disadvantage of this synthesis is the low

L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
1695
yield of compound 5 in the aziridine-formation step, that is the
conversion of unprotected dihydroxyl azide 4 to aziridine 5. In or-
der to overcome such an obvious drawback, two improved prepa-
rations of compound 7 from 3,4-cyclic sulfite 3 have also been
developed (Scheme 2). In the first improved preparation, Bz was
used as a protecting group for the hydroxyl group at the C-4 posi-
tion of cyclic sulfite 3, and compound 7 was obtained in 7-steps in
64% overall yield. In the second improved preparation, Ac was used
as a protecting group for the hydroxyl group at the C-4 position of
cyclic sulfite 3, and compound 7 was obtained in 7-steps in 62%
overall yield. In both improved preparations, Ms was used to mask
the hydroxyl groups at the C-5 positions of compounds 11 and 14.
and heated at reflux, and then refluxing was continued for around
12 h. After the reaction was complete, ethanol was distilled off un-
der reduced pressure, after which the residue was partitioned be-
tween ethyl acetate (200 mL) and water (100 mL). Two layers
were separated, and the aqueous layer was extracted with ethyl
acetate (100 mL) once again. The organic extracts were combined
and dried over anhydrous MgSO4, and then was concentrated un-
der vacuum to afford a yellow oil that could be directly used for
the next step or purified by flash chromatography to furnish com-
pound 4 (8.51 g, 37.45 mmol) in 93% yield. ½a D20
¼ þ67:7 (c 4.3,
ꢂ
CHCl3). 1H NMR (CDCl3) d 1.31 (t, J = 7.1 Hz, 3H), 2.21–2.33 (m,
1H), 2.92 (dd, J1 = 17.8 Hz; J2 = 4.9 Hz, 1H), 3.56–3.67 (m, 1H),
3.75–3.86 (m, 1H), 3.91 (br s, 1H), 4.07–4.17 (m, 1H), 4.22 (q,
J = 7.1 Hz, 2H), 4.29 (br s, 1H), 6.64 (dd, J1 = 2.5 Hz, J2 = 2.4 Hz,
1H). 13C NMR (CDCl3) d 165.72, 133.95, 130.63, 75.71, 69.53,
63.55, 61.38, 32.13, 14.10. HRMS (EI) calcd for (C9H13N3O4+NH4)+:
245.1250. Found: 245.1253. IR (KBr film) 3427, 2104, 1716, 1657,
4. Experimental
4.1. General methods
Melting points are uncorrected. 1H NMR spectra were acquired
on Bruker AM-500. Chemical shifts were given on the delta scale as
parts per million (ppm) with tetramethylsilane (TMS) as the inter-
nal standard. IR spectra were recorded on Nicolet Magna IR-550.
Mass spectra were recorded on HP5989A. Column chromatography
was performed on silica gel. Optical rotations of chiral compounds
were measured on a WZZ-1S automatic polarimeter at room tem-
perature. All chemicals were analytically pure. (ꢀ)-Ethyl shikimate
2 was prepared according to a known procedure.55
1374, 1252, 1100, 1068, 742 cmꢀ1
.
4.4. Ethyl (1S,5R,6S)-5-hydroxy-7-azabicyclo[4.1.0]hept-2-ene-
3-carboxylate 5
To a vigorously stirred solution of Et2NH (1.46 g, 19.96 mmol) in
ethyl acetate (15 mL), was added dropwise a solution of TsOHꢁH2O
(3.80 g, 19.98 mmol) in ethyl acetate (15 mL) at room temperature.
White crystals formed and precipitated during the addition. After
the addition was finished, stirring was continued for one hour.
Diethylammonium p-toluenesulfonate (4.82 g, 19.65 mmol) was
collected on Büchner funnel by suction, and was then dried under
vacuum for 3 h at 45 °C.
Compound 4 (2.05 g, 9.02 mmol) was dissolved in toluene
(100 mL). Diethylamonium p-toluenesulfonate(223 mg, 0.91 mmol)
was added, and then PPh3 (2.60 g, 9.90 mmol) was slowly added in
portions at room temperature. Upon completion of the addition,
the reaction mixture was further stirred at room temperature for
1 h. Next, the reaction mixture was warmed to 60 °C and stirred
for 2 h. Toluene was removed by vacuum distillation to give a crude
oil, which was then subjected to direct chromatography to give
aziridine 5 (1.03 g, 5.62 mmol) as pale yellow crystals in 62% yield.
4.2. Ethyl (3R,4S,5R)-3,4-cyclic sulfite-shikimate 3
(ꢀ)-Ethyl shikimate 2 (10.00 g, 49.46 mmol) and triethylamine
(12.46 g, 123.13 mmol) were dissolved in ethyl acetate (200 mL)
and cooled to 0 °C with an ice bath. A solution of thionyl chloride
(14.71 g, 123.64 mmol) in dichloromethane (30 mL) was then drop-
wise added over 1 h, and the temperature of the reaction mixture
was kept below 10 °C during the addition. After the dropwise addi-
tion was finished, the ice bath was removed, and the mixture was
warmed to room temperature. The reaction mixture was then fur-
ther stirred at room temperature for 12 h. The reaction was
quenched by adding water (60 mL) and an aqueous solution of
potassium carbonate (20% w/v, 110 mL) until pH 8–9. The organic
phase was separated and dried over anhydrous MgSO4, and then
concentrated under vacuum to afford a pale yellow oil that could
be directly used for the next step or purified by flash chromatogra-
phy to furnish cyclic sulfite 3 (12.05 g, 48.54 mmol) in 98% yield.
Mp 145.0–145.9 °C, ½a D20
ꢂ
¼ ꢀ219:8 (c 1.1, CHCl3). 1H NMR (CDCl3)
d 1.28 (t, J = 7.1 Hz, 3H), 1.98–2.11 (m, 1H), 2.66–2.72 (m, 1H),
2.80–2.86 (m, 1H), 2.88–2.95 (m, 1H), 4.10–4.25 (m, 3H), 7.13 (dd,
J1 = 4.7 Hz; J2 = 3.3 Hz, 1H). 13C NMR (CDCl3) d 165.98, 136.40,
130.13, 66.47, 60.76, 38.27, 29.51, 29.20, 14.21. HRMS (EI) calcd
for (C9H13NO3+H)+: 184.0974. Found: 184.0970. IR (KBr film)
½
a 2D0
ꢂ
¼ þ52:0 (c 1.5, CHCl3). 1H NMR (CDCl3) for major diastereomer
d 1.33 (t, J = 7.1 Hz, 3H), 2.34 (dd, J1 = 18.1 Hz; J2 = 8.5 Hz, 1H), 2.80
(br s, 1H), 2.88 (dd, J1 = 18.0 Hz; J2 = 4.8 Hz, 1H), 3.91–3.99 (m, 1H),
4.26 (q, J = 7.1 Hz, 2H), 4.86 (dd, J1 = 7.9 Hz; J2 = 6.4 Hz, 1H), 5.57
(dd, J1 = 4.9 Hz, J2 = 4.8 Hz, 1H), 6.90–6.94 (m, 1H). 13C NMR (CDCl3)
for major diastereomer d 165.26, 133.40, 129.09, 81.31, 75.79, 67.25,
61.64, 29.67, 14.11. 1H NMR (CDCl3) for minor diastereomer d 1.32 (t,
J = 7.1 Hz, 3H), 2.38 (dd, J1 = 18.2 Hz; J2 = 8.1 Hz, 1H), 2.80 (br s, 1H),
2.93 (dd, J1 = 17.8 Hz; J2 = 4.7 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.43–
4.52 (m, 1H), 4.65 (dd, J1 = 7.6 Hz; J2 = 6.9 Hz, 1H), 5.27 (dd,
J1 = 5.1 Hz, J2 = 5.0 Hz, 1H), 6.98–7.03 (m, 1H). 13C NMR (CDCl3) for
minor diastereomer d 165.54, 132.09, 130.70, 83.35, 79.14, 68.20,
61.56, 29.75, 14.11. HRMS (EI) calcd for (C9H12O6S+H)+: 249.0433.
Found: 249.0438. IR (KBr film) 3490, 2981, 1758, 1719, 1257,
3281, 3190, 1700, 1375, 1322, 1257, 1047, 852, 731 cmꢀ1
.
4.5. Ethyl (1S,5R,6S)-7-acetyl-5-hydroxy-7-azabicyclo[4.1.0]-
hept-2-ene-3-carboxylate 6
Compound 5 (0.80 g, 4.37 mmol) and triethylamine (0.88 g,
8.70 mmol) were dissolved in methylene chloride (16 mL), and
the resulting solution was cooled to 0 °C. Acetic anhydride
(0.54 g, 5.29 mmol) was then added dropwise over 15 min. After
the addition was finished, the reaction mixture was further stirred
at 0 °C for 15 min. The reaction was then immediately quenched by
adding an aqueous solution of potassium carbonate (15% w/v,
10 mL). After the organic and aqueous phases were separated,
the aqueous layer and brine (10 mL) were mixed and extracted
twice with methylene chloride (2 ꢃ 15 mL). The organic extracts
were combined and dried over anhydrous MgSO4, and then
concentrated under vacuum to give a yellow oil that could be di-
rectly used for the next step or purified by flash chromatography
1210, 1100, 984, 854, 768 cmꢀ1
.
4.3. Ethyl (3S,4R,5R)-3-azido-4,5-dihydroxycyclohex-1-ene-1-
carboxylate 4
The cyclic sulfite 3 (10.00 g, 40.28 mmol) was dissolved in abso-
lute ethanol (100 mL) at room temperature, after which sodium
azide (5.24 g, 80.60 mmol) was added. The mixture was stirred
to furnish compound
6 (0.94 g, 4.17 mmol) in 95% yield.
½
a 2D0
ꢂ
¼ ꢀ90:7 (c 1.0, CHCl3). 1H NMR (CDCl3) d 1.30 (t, J = 7.1 Hz,
3H), 2.06–2.16 (m, 1H), 2.21 (s, 3H), 2.94 (dd, J1 = 16.5 Hz;

1696
L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
J2 = 6.6 Hz, 1H), 3.17–3.24 (m, 2H), 3.92 (br s, 1H), 4.03–4.12 (m,
1H), 4.20 (q, J = 7.1 Hz, 2H), 7.04–7.14 (m, 1H). 13C NMR (CDCl3) d
182.82, 165.73, 132.60, 132.45, 65.54, 61.03, 42.96, 35.06, 29.41,
23.42, 14.15. HRMS (EI) calcd for (C11H15NO4+K)+: 264.0638.
Found: 264.0641. IR (KBr film) 3406, 2981, 1705, 1369, 1252,
4.9. Ethyl (3R,4S,5R)-5-O-benzoyl-3, 4 -cyclic sulfite-shikimate
10
To a solution of cyclic sulfite 3 (5.00 g, 20.14 mmol) in dichlo-
romethane (50 mL), triethylamine (4.08 g, 40.32 mmol), and
DMAP (0.25 g, 2.05 mmol) were added, and the resulting solution
was then cooled to 0 °C with an ice bath. Benzoyl chloride (3.40 g,
24.19 mmol) was added dropwise over 10 min. The ice bath was
removed, and the mixture was then further stirred for 5 h until
the reaction was complete (TLC). The reaction solution was con-
centrated under vacuum to remove dichloromethane, after which
the residue was dissolved in ethyl acetate (100 mL), and the or-
ganic solution was washed successively with a dilute hydrochlo-
ric aqueous solution (2 M, 25 mL), potassium carbonate aqueous
solution (10% w/v, 15 mL), and brine (15 mL). The organic solu-
tion was dried over anhydrous MgSO4 and evaporated to give a
crude oil, which could be used directly for the next step or puri-
fied by flash chromatography to furnish compound 10 (6.95 g,
1200, 1099, 1054, 741 cmꢀ1
.
4.6. Ethyl (3R,4R,5R)-4-acetamido-3-(1-ethyl-propoxy)-5-
hydroxy-cyclohex-1-ene-1-carboxylate 7
Compound 6 (0.90 g, 4.00 mmol) was dissolved in 3-pentanol
(4.5 mL), and the resulting solution was cooled to ꢀ8 °C with a
salt-ice bath. Then a solution of boron trifluoride diethyl etherate
(0.85 g, 5.99 mmol) in 3-pentanol (4.5 mL) was added dropwise
over 30 min. After the addition was finished, the reaction mixture
was further stirred at ꢀ8 °C for 1 h. The mixture was diluted with
methylene chloride (20 mL), and the reaction was quenched by
adding an aqueous solution of potassium carbonate (15% w/v,
20 mL). The two phases were separated, and the aqueous phase
was extracted twice with methylene chloride (2 ꢃ 10 mL). The or-
ganic extracts were combined and dried over anhydrous MgSO4.
The organic solution was concentrated under vacuum to give a res-
idue as yellow crystals that could be directly used for the next step
or purified by flash chromatography to furnish compound 7
(1.17 g, 3.73 mmol) in 93% yield. The characterization data of com-
pound 7 were identical with those obtained in our previous
article.31
19.72 mmol) in 98% yield. ½a D20
ꢂ
¼ þ17:2 (c 9.7, CHCl3). 1H NMR
(CDCl3) for major diastereomer d 1.25 (t, J = 7.1 Hz, 3H), 2.38–
2.52 (m, 1H), 2.98 (dd, J1 = 18.1 Hz; J2 = 4.9 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 5.07 (dd, J1 = 7.5 Hz; J2 = 6.4 Hz, 1H), 5.26–5.38
(m, 1H), 5.52–5.61 (m, 1H), 6.91 (dd, J1 = J2 = 1.8 Hz, 1H), 7.31–
7.45 (m, 2H), 7.47–7.57 (m, 1H), 7.95 (d, J = 7.4 Hz, 2H). 13C
NMR (CDCl3) for major diastereomer d 165.47, 164.81, 133.64,
132.82, 129.80, 129.75, 129.19, 128.56, 77.61, 75.70, 69.03,
61.70, 27.28, 14.14. 1H NMR (CDCl3) for minor diastereomer d
1.24 (t, J = 7.1 Hz, 3H), 2.66 (dd, J1 = 18.3 Hz; J2 = 4.7 Hz, 1H),
2.89–2.94 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.78 (dd,
J1 = J2 = 6.0 Hz, 1H), 5.26–5.38 (m, 1H), 5.73–5.80 (m, 1H), 6.97–
7.03 (m, 1H), 7.31–7.45 (m, 2H), 7.47–7.57 (m, 1H), 7.91 (d,
4.7. Ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethyl-propoxy)-
cyclohex-1-ene-1-carboxylate 9
To a solution of compound 8 (1.20 g, 3.06 mmol) in anhy-
drous N,N-dimethylformamide (8 mL), was added sodium azide
(0.40 g, 6.15 mmol). The mixture was heated to 90 °C for 8 h
and monitored by TLC. After the reaction was complete, the mix-
ture was cooled down to room temperature. The mixture was
then partitioned between ethyl acetate (80 mL) and water
(45 mL). The organic phase was separated and washed with
brine (20 mL). The organic solution was dried over anhydrous
Na2SO4, and then concentrated under vacuum to produce a
crude oil which was purified by chromatography to give com-
pound 9 (0.955 g, 2.82 mmol) in 92% yield. The characterization
data of compound 9 were identical with those obtained in our
previous articles.31,32
J = 7.4 Hz, 2H). 13C NMR (CDCl3) for minor diastereomer
d
165.32, 165.18, 133.64, 131.13, 130.42, 129.80, 129.75, 128.56,
78.89, 77.52, 69.45, 61.51, 25.76, 14.14. HRMS (EI) calcd for
(C16H16O7S+Na)+: 375.0514. Found: 375.0512. IR (KBr film)
2981, 1721, 1453, 1253, 1100, 989, 710 cmꢀ1
.
4.10. Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-hydroxy-cyclo-
hex-1-ene-1-carboxylate 11
Compound 10 (5.00 g, 14.19 mmol) was dissolved in aqueous
N,N-dimethylformamide (50 mL, DMF/H2O = 5:1) at room temper-
ature, after which sodium azide (2.31 g, 35.53 mmol) was added.
The mixture was stirred at room temperature for 24 h. Toluene
(100 mL) and water (100 mL) were added, and the mixture was
vigorously stirred for 15 min. The organic phase was separated,
and then washed with water (30 mL) and brine (20 mL). The
organic solution was dried over anhydrous MgSO4. The solvent
was then removed off by vacuum distillation to give the crude
product as yellow crystals. The crystals were collected on a Buch-
ner funnel by suction and rinsed with hexane/ethyl acetate = 10:1
to afford compound 11 (4.47 g, 13.49 mmol) in 95% yield. Mp
4.8. Oseltamivir phosphate 1
Compound 9 (0.90 g, 2.66 mmol) was dissolved in aqueous
tetrahydrofuran (20 mL, THF/H2O = 10:1). Triphenylphosphine
(0.77 g, 2.94 mmol) was added in portions at room temperature.
After the mixture was heated at reflux and stirring was continued
for 8 h. Solvents were removed by vacuum distillation, and the res-
idue was cooled down to room temperature. The residue was then
dissolved in a mixed solvent of ethyl acetate (3.5 mL) and ethanol
(1.5 mL). After aqueous phosphoric acid (368 mg, 85% w/w,
3.19 mmol) was added, the mixture was warmed to 50 °C, and stir-
ring was continued for 2 h at 50 °C. The reaction mixture was
cooled down to room temperature and stirred for a further 8 h.
White crystals were formed and precipitated. After suction and
twice rinsing with ethyl acetate, the white crystals were dried
under vacuum at 50 °C overnight to furnish the title compound
oseltamivir phosphate 1 (997 mg, 2.43 mmol) in 91% yield. The
characterization data of compound 1 were identical with those of
the sample obtained in our previous articles.31,32
78.5–78.9 °C, ½a D20
ꢂ
¼ ꢀ4:7 (c 3.0, CHCl3). 1H NMR (CDCl3) d 1.29
(t, J = 7.1 Hz, 3H), 2.40–2.47 (m, 1H), 3.09 (dd, J1 = 17.7 Hz;
J2 = 5.8 Hz, 1H), 3.21 (br s, 1H), 4.00 (dd, J1 = J2 = 9.0 Hz, 1H), 4.21
(q, J = 7.1 Hz, 2H), 4.18–4.32 (m, 1H), 5.15–5.30 (m, 1H),
6.63–6.74 (m, 1H), 7.44 (dd, J1 = J2 = 7.7 Hz, 2H), 7.58 (dd,
J1 = J2 = 7.4 Hz, 1H), 8.04 (d, J1 = J2 = 7.5 Hz, 2H). 13C NMR (CDCl3)
d 166.95, 165.82, 134.54, 134.08, 130.60, 130.37, 130.08, 129.10,
74.09, 72.09, 72.53, 63.91, 61.96, 30.32, 14.57. MS m/z (%) 331
(M+, 0.1%), 274 (2), 257 (2), 198 (2), 154 (11), 135 (4), 124 (8),
105 (100), 77 (26). HRMS (EI) calcd for (C16H17N3O5+NH4)+:
349.1512. Found: 349.1523. IR (KBr film) 3542, 2114, 1726, 1702,
1304, 1268, 1089, 1026, 710 cmꢀ1
.

L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
1697
4.11. Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-methanesulfo-
nyloxy-cyclohex-1-ene-1-carboxylate 12
ic solution was dried over anhydrous MgSO4. The solvent was then
removed by vacuum distillation to give a crude oil, which could be
directly used for the next step or purified by flash chromatography
to furnish compound 14 (4.22 g, 15.67 mmol) in 91% yield.
To a solution of compound 11 (5.00 g, 15.09 mmol) in ethyl ace-
tate (100 mL) was added methanesulfonyl chloride (2.59 g,
22.61 mmol). The resulting solution was cooled to 0 °C by an ice
bath, and DMAP (0.18 g, 1.47 mmol) was added. Triethylamine
(1.83 g, 18.08 mmol) was then dropwise added over 15 min. After
the addition was finished, the reaction mixture was stirred at
0 °C for a further 1 h to allow the reaction to complete. The reaction
was quenched by adding water (20 mL). The organic phase was
separated and washed successively with potassium carbonate
aqueous solution (10% w/v, 20 mL) and brine (20 mL). The organic
solution was dried over anhydrous MgSO4, and then concentrated
under vacuum to give a pale yellow oily residue that gradually be-
came solid upon standing at room temperature. The crude solid
product was then triturated with hexane to give compound 12 as
pale yellow crystals (5.93 g, 14.48 mmol) in 96% yield. The charac-
terization data of compound 12 were identical with those we ob-
tained in our previous article.31
½
a 2D0
ꢂ
¼ þ24:2 (c 1.2, EtOAc). 1H NMR (CDCl3) d 1.30 (t, J = 7.1 Hz,
3H), 2.14 (s, 3H), 2.24–2.38 (m, 1H), 2.98 (dd, J1 = 17.7 Hz;
J2 = 5.8 Hz, 1H), 3.19 (br s, 1H), 3.85 (dd, J1 = J2 = 9.0 Hz, 1H), 4.20
(q, J = 7.1 Hz, 2H), 4.14–4.28 (m, 1H), 4.93–5.04 (m, 1H), 6.59–
6.71 (m, 1H). 13C NMR (CDCl3) d 171.50, 165.81, 134.29, 130.62,
73.62, 71.80, 63.64, 61.91, 30.00, 21.59, 14.69. HRMS m/z calcd
for (C11H15N3O5+Na)+: 292.0909. Found: 292.0908. IR (KBr film)
3479, 2979, 1753, 1720, 1447, 1368, 1256, 1092, 1041 cmꢀ1
.
4.14. Ethyl (3S,4R,5R)-3-azido-5-acetoxy-4-methanesulfo-
nyloxy-cyclohex-1-ene-1-carboxylate 15
To a solution of compound 14 (4.00 g, 14.86 mmol) in ethyl ace-
tate (80 mL) was added methanesulfonyl chloride (2.55 g,
22.26 mmol). The resulting solution was cooled to 0 °C in an ice
bath, and DMAP (0.18 g, 1.47 mmol) was added. Triethylamine
(1.80 g, 17.79 mmol) was then dropwise added over 15 min. After
the addition was finished, the reaction mixture was further stirred
at 0 °C for 1 h to allow the reaction to complete (TLC). The reaction
was quenched by adding water (20 mL). The organic phase was
separated and washed successively with potassium carbonate
aqueous solution (10% w/v, 20 mL) and brine (20 mL). The organic
solution was dried over anhydrous MgSO4, and then concentrated
under vacuum to give a pale yellow oily residue, which could be di-
rectly used for the next step or purified by flash chromatography to
furnish compound 15 (4.90 g, 14.11 mmol) in 95% yield.
4.12. Ethyl (3R,4S,5R)-5-O-acetyl-3,4-cyclic sulfite-shikimate 13
To a solution of cyclic sulfite 3 (5.00 g, 20.14 mmol) in dichloro-
methane (50 mL), triethylamine (4.08 g, 40.32 mmol) and DMAP
(0.25 mg, 2.05 mmol) were added at room temperature. Acetic
anhydride (3.08 g, 30.17 mmol) was dropwise added over 10 min.
The mixture was then stirred for 2 h until the reaction was com-
plete (TLC). The reaction solution was concentrated under vacuum
to remove dichloromethane. The residue was dissolved in ethyl
acetate (100 mL), and the resulting solution was washed succes-
sively with dilute hydrochloric aqueous solution (2 M, 20 mL),
potassium carbonate aqueous solution (15% w/v, 30 mL), and brine
(10 mL). The organic solution was dried over anhydrous MgSO4
and evaporated under vacuum to give a crude oil, which could be
directly used for the next step or purified by flash chromatography
to furnish compound 13 (5.73 g, 19.74 mmol) in 98% yield.
½
a 2D0
ꢂ
¼ þ51:5 (c 4.3, EtOAc). 1H NMR (CDCl3) d 1.32 (t, J = 7.1 Hz,
3H), 2.14 (s, 3H), 2.39–2.52 (m, 1H), 3.02 (dd, J1 = 18.0 Hz;
J2 = 6.0 Hz, 1H), 3.17 (s, 3H), 4.24 (q, J = 7.1 Hz, 2H), 4.28–4.40 (m,
1H), 4.78 (dd, J1 = J2 = 8.9 Hz, 1H), 5.20 (dd, J1 = 9.4 Hz; J2 = 6.3 Hz,
1H), 6.69–6.80 (m, 1H). 13C NMR (CDCl3) d 171.60, 165.10,
134.45, 131.49, 80.37, 67.88, 62.12, 61.64, 39.69, 30.14, 21.47,
14.69. HRMS m/z calcd for (C12H17N3O7S+Na)+: 370.0685. Found:
370.0687. IR (KBr film) 2983, 2919, 2104, 1757, 1716, 1358,
½
a 2D0
ꢂ
¼ þ62:9 (c 2.6, CHCl3). 1H NMR (CDCl3) for major diastereo-
mer d 1.32 (t, J = 7.1 Hz, 3H), 2.12 (s, 3H), 2.33–2.42 (m, 1H), 2.92
(dd, J1 = 18.0 Hz; J2 = 4.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.92–
5.01 (m, 1H), 5.03–5.16 (m, 1H), 5.57 (dd, J1 = J2 = 5.8 Hz, 1H),
6.93 (dd, J1 = J2 = 1.6 Hz, 1H). 13C NMR (CDCl3) for major diastereo-
mer d 169.90, 164.77, 132.81, 129.08, 77.63, 75.57, 68.42, 61.65,
27.17, 20.93, 14.12. 1H NMR (CDCl3) for minor diastereomer d
1.32 (t, J = 7.1 Hz, 3H), 2.09 (s, 3H), 2.57 (dd, J1 = 18.2 Hz;
J2 = 4.7 Hz, 1H), 2.86–2.97 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.69
(dd, J1 = J2 = 6.1 Hz, 1H), 5.27–5.35 (m, 1H), 5.58 (dd,
J1 = J2 = 5.0 Hz, 1H), 6.97–7.04 (m, 1H). 13C NMR (CDCl3) for minor
diastereomer d 169.64, 165.29, 131.03, 130.42, 78.90, 77.49, 69.01,
61.46, 25.70, 20.93, 14.12. MS m/z (%) 245 (17), 184 (12), 166 (67),
155 (12), 138 (100), 110 (56), 43 (29). HRMS (EI) calcd for
(C11H14O7S+Na)+: 313.0358. Found: 313.0355. IR (KBr film) 2987,
1232, 1179, 1043, 967, 841 cmꢀ1
.
4.15. Ethyl (1S,5R,6S)-5-acetoxy-7-azabicyclo[4,1,0]hept-2-ene-
3-carboxylate 16
A solution of compound 15 (2.00 g, 5.76 mmol) in THF (50 mL)
was cooled to 0 °C in an ice bath. Triphenylphosphine (1.66 g,
6.33 mmol) was then added in portions. After stirring was contin-
ued at 0 °C for 0.5 h, the ice bath was removed, and the reaction
mixture was allowed to warm to room temperature. Triethylamine
(0.58 g, 5.73 mmol) and water (5 mL) were then added. After stir-
ring was continued at room temperature for 0.5 h, more triethyl-
amine (1.16 g, 11.46 mmol) was added in four portions over 2 h.
The resulting mixture was stirred at room temperature for a fur-
ther 8 h. The reaction solution was concentrated below 40 °C under
vacuum to remove the THF, and the residue was partitioned be-
tween ethyl acetate (60 mL) and water (30 mL). The organic phase
was separated and dried over anhydrous MgSO4. After removal of
the solvent, the crude product was purified by flash chromatogra-
phy to give compound 16 (1.13 g, 5.02 mmol) as a pale yellow oil in
1748, 1717, 1374, 1256, 1230, 1047, 991, 839, 772 cmꢀ1
.
4.13. Ethyl (3S,4R,5R)-3-azido-5-acetoxy-cyclohex-1-ene-
1-carboxylate 14
Compound 13 (5.00 g, 17.22 mmol) was dissolved in aqueous
N,N-dimethylformamide (50 mL, DMF/H2O = 5:1) at room temper-
ature, after which sodium azide (2.80 g, 43.07 mmol) was added.
The mixture was stirred at room temperature for 24 h. Toluene
(100 mL) and water (100 mL) were added, and the mixture was
vigorously stirred for 15 min. The organic phase was separated,
and then washed with water (30 mL) and brine (20 mL). The organ-
87% yield. ½a 2D0
ꢂ
¼ ꢀ139:7 (c 1.4, EtOAc). 1H NMR (acetone-d6) d
1.26 (t, J = 7.1 Hz, 3H), 2.01–2.09 (m, 1H), 2.07 (s, 3H), 2.09–2.17
(m, 1H), 2.59–2.82 (m, 2H), 3.12 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H),
4.90–5.30 (m, 1H), 7.09–7.21 (m, 1H). 13C NMR (CDCl3) d 170.69,
165.25, 136.52, 129.45, 69.82, 60.75, 35.12, 31.53, 28.08, 21.21,
14.17. HRMS m/z calcd for
C11H15NO4: 225.1001. Found:

1698
L.-D. Nie et al. / Tetrahedron: Asymmetry 22 (2011) 1692–1699
225.1002. IR (KBr film) 3479, 3296, 2979, 1742, 1642, 1553, 1442,
1367, 1258, 1100, 1032, 742 cmꢀ1
crude product as off-white crystals, which were collected on a
Büchner funnel and rinsed with a mixed solvent of ethyl acetate
and hexane (4:1) to furnish compound 7 (1.66 g, 5.30 mmol) in
94% yield. The characterization data of compound 7 were identical
with those obtained in our previous article.31
.
4.16. Ethyl (1S,5R,6S)-5-acetoxy-7-acetyl-7-azabicyclo[4,1,0]-
hept-2-ene-3-carboxylate 17
To a solution of compound 16 (2.00 g, 8.88 mmol) in ethyl ace-
tate (40 mL) was added triethylamine (1.80 g, 17.79 mmol), after
which the solution was cooled to 0 °C in an ice bath. Acetic anhy-
dride (1.36 g, 13.32 mmol) was added, and stirring was continued
at 0 °C for 30 min., after which TLC showed that the reaction was
complete. The reaction was immediately quenched by adding an
aqueous solution of potassium carbonate (15% w/v, 20 mL). The or-
ganic phase was separated and washed with brine (5 mL). After the
organic solution was dried over anhydrous MgSO4, the solvent was
evaporated under vacuum to give a crude oil, which could be di-
rectly used for the next step or purified by flash chromatography
to furnish compound 17 (2.32 g, 8.68 mmol) in 98% yield.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 20972048) and Shanghai Educational Development Founda-
tion (The Dawn Program: No. 03SG27) for the financial support
of this work.
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a 2D0
ꢂ
¼ ꢀ36:5 (c 1.9, EtOAc). 1H NMR (CDCl3) d 1.30 (t, J = 7.1 Hz,
3H), 1.90–2.34 (m, 7H), 2.89–3.08 (m, 1H), 3.15–3.32 (m, 2H),
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4.17. Ethyl (3R,4R,5R)-4-acetamido-5-acetoxy-3-(1-ethyl-
propoxy)-cyclohex-1-ene-1-carboxylate 18
A solution of compound 17 (2.00 g, 7.48 mmol) in 3-pentanol
(10 mL) was cooled to ꢀ5 °C in a salt-ice bath. A freshly prepared
solution of boron trifluoride etherate (1.59 g, 11.20 mmol) in 3-
pentanol (10 mL) was added dropwise over 10 min, and stirring
was further continued at ꢀ5–0 °C for around 1.5 h. The reaction
mixture was diluted with ethyl acetate (50 mL), and an aqueous
solution of potassium carbonate (15% w/v, 12 mL) was added to
adjust the pH to 9–10. The organic phase was separated and
washed with brine (10 mL). The aqueous solution was extracted
once more with ethyl acetate (20 mL). The extracts were combined
and dried over anhydrous MgSO4. The organic solution was evapo-
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rectly used for the next step or purified by flash chromatography to
furnish compound 18 (2.42 g, 6.81 mmol) in 91% yield.
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½
a 2D0
ꢂ
¼ ꢀ76:4 (c 2.0, EtOAc). 1H NMR (CDCl3) d 0.85–1.00 (m, 6H),
1.30 (t, J = 7.1 Hz, 3H), 1.45–1.62 (m, 4H), 2.00 (s, 3H), 2.06 (s,
3H), 2.43 (dd, J1 = 18.9 Hz; J2 = 6.5 Hz, 1H), 2.79 (dd, J1 = 18.9 Hz;
J2 = 5.0 Hz, 1H), 3.41–3.49 (m, 1H), 4.00–4.09 (m, 1H), 4.22 (q,
J = 7.1 Hz, 2H), 4.31–4.43 (m, 1H), 5.24–5.36 (m, 1H), 5.51–5.36
(m, 1H), 6.79–6.81 (m, 1H). 13C NMR (CDCl3) d 170.29, 170.16,
166.01, 135.96, 129.17, 82.03, 73.02, 68.85, 61.03, 50.16, 27.71,
26.23, 26.16, 23.32, 21.13, 14.15, 9.63, 9.27. HRMS (EI) calcd for
C
18H29NO6: 355.1995. Found: 355.1993. IR (KBr film) 3042, 2973,
2875, 1742, 1719, 1653, 1543, 1376, 1239, 1099, 1053 cmꢀ1
.
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4.18. Ethyl (3R,4R,5R)-4-acetamido-3-(1-ethyl-propoxy)-
5-hydroxy-cyclohex-1-ene-1-carboxylate 7
To a solution of compound 18 (2.00 g, 5.63 mmol) in absolute
ethanol (30 mL) was added powdered potassium carbonate
(0.86 g, 6.23 mmol). The mixture was then stirred at room temper-
ature for around 6 h. After TLC showed that the reaction was com-
plete, ethanol was removed by distillation under vacuum. The
residue was then partitioned between ethyl acetate (100 mL) and
water (30 mL). The organic phase was separated and washed with
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MgSO4. Removal of the solvent by vacuum distillation gave the
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