A short and practical synthesis of oseltamivir phosphate (tamiflu) from (-)-shikimic acid

Article abstract of DOI:10.1021/jo900218k

(Chemical Equation Presented) Oseltamivir phosphate (1) was synthesized from (-)-shikimic acid through a short and practical synthetic route via eight steps in 47% overall yield. In addition, the highly regioselective and stereoselective nucleophilic replacement of OMs by the N₃ group in the third and seventh steps has been studied in detail, and the reaction conditions were optimized.

Full text of DOI:10.1021/jo900218k

A Short and Practical Synthesis of Oseltamivir
Phosphate (Tamiflu) from (-)-Shikimic Acid
in order to develop an efficient and useful synthetic route that
is anticipated to be suitable as an industrial process. The
chemists at Gilead Sciences, Inc. and F. Hoffman-La Roche
†
6
a,c
Ltd. have developed a practical synthesis
that is currently
Liang-Deng Nie, Xiao-Xin Shi,* Kwang Hyok Ko, and
Wei-Dong Lu
used for the manufacture of oseltamivir phosphate. Among all
the reported synthetic methods, La Roche’s method seems to
have been the best one for industrial large-scale preparation of
Tamiflu until now. However, there are still some drawbacks
associated with this method, for example, the long synthetic
route and the relatively low total yield. Therefore, a better
industrial synthetic method remains highly desirable.
Department of Pharmaceutical Engineering, School of
Pharmacy, East China UniVersity of Science and
Technology, P.O. Box 363, 130 Mei-Long Road, Shanghai
2
00237, People’s Republic of China
xxshi@ecust.edu.cn
Recently, we were engaged in the synthesis of oseltamivir
phosphate and have just disclosed a novel 13-step synthesis
ReceiVed February 01, 2009
7
starting from (-)-shikimic acid. Although this synthesis has
some merits such as the high overall yield, inexpensive reagents,
mildness of the reaction conditions, and ease of manipulation
of every step, the long synthetic route will significantly retard
its use in the large-scale preparation of oseltamivir phosphate.
After an extensive study, we have exploited a much short and
practical synthesis of oseltamivir phosphate from (-)-shikimic
acid. Herein, we would like to report the details.
As depicted in Scheme 2, our synthesis started from (-)-
shikimic acid, which can be obtained by extraction from Illicium
8
Verum (also referred to as Chinese star anise) or other natural
Oseltamivir phosphate (1) was synthesized from (-)-shikimic
acid through a short and practical synthetic route via eight
steps in 47% overall yield. In addition, the highly regiose-
lective and stereoselective nucleophilic replacement of OMs
9
resources, or by fermentation using genetically modified
10
Escherichia coli. To our delight, (-)-shikimic acid is abundant
(6) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
by the N
3
group in the third and seventh steps has been
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.;
Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681. (b) Rohloff,
J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.;
Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.;
Zhang, L. J. Org. Chem. 1998, 63, 4545. (c) Federspiel, M.; Fisher, R.; Henning,
M.; Mair, H. J.; Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann,
H.; Gandert, C.; Gockel, V.; Gotzo, S.; Hoffmann, U.; Huber, G.; Janatsch, G.;
Lauper, S.; Rockel-Stabler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res.
DeV. 1999, 3, 266. (d) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.
studied in detail, and the reaction conditions were optimized.
Oseltamivir phosphate (Tamiflu, 1 in Scheme 1) has recently
attracted considerable attention because it was approved as the
only orally available drug for both prophylaxis and treatment
of human influenza and H5N1 avian flu. The historic record
showed that the human influenza and the H5N1 avian flu have
(
e) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process
Res. DeV. 2004, 8, 86. (f) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365.
g) 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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Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett.
008, 10, 815. (j) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew.
1
2
(
3
killed numerous people in many countries, and they will surely
(
continue to threaten human health in the future. To protect
people from the attack of pandemic human influenza or H5N1
avian flu, it is recommended that oseltamivir phosphate (Tamiflu,
2
Chem., Int. Ed. 2007, 46, 5734. (k) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403. (l) Mita, T.; Fukuda, N.;
Roca, F. X.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259. (m) Fukuta, Y.;
Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
1) should be manufactured and stocked in every country all over
4
,3a
the world.
6
312. (n) Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N.
5
,6
Extensive efforts have been made by synthetic chemists
to tackle the problems in the synthesis of oseltamivir phosphate
Chem. Commun. 2007, 3183. (o) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J.
Org. Chem. 2008, 73, 4895. (p) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew.
Chem., Int. Ed. 2008, 47, 5788. (q) Matveenko, M.; Willis, A. C.; Banwell,
M. G. Tetrahedron Lett. 2008, 49, 7018. (r) Trost, B. M.; Zhang, T. Angew.
Chem., Int. Ed. 2008, 47, 3759. (s) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew.
Chem., Int. Ed. 2009, 48, 1304. (t) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura,
Y.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1070.
(7) Nie, L.-D.; Shi, X.-X. Tetrahedron: Asymmetry 2009, 20, 124.
(8) He, X.-H.; Liu, L.; Liu, X.-G.; Liu, Z.-P.; Zhao, G.-M.; Li, H.-Y. Nat.
Prod. Res. DeV. (in Chinese) 2008, 20, 914.
(9) (a) Enrich, L. B.; Scheuermann, M. L.; Mohadjer, A.; Matthias, K. R.;
Eller, C. F.; Newman, M. S.; Fujinaka, M.; Poon, T. Tetrahedron Lett. 2008,
49, 2503. (b) Sui, R. Chem. Eng. Technol. 2008, 31, 469.
(10) (a) Draths, K. M.; Knop, D. R.; Frost, J. W. J. Am. Chem. Soc. 1999,
121, 1603. (b) Knop, D. R.; Draths, K. M.; Chandran, S. S.; Barker, J. L.; von
Daeniken, R.; Weber, W.; Frost, J. W. J. Am. Chem. Soc. 2001, 123, 10173. (c)
Chandran, S. S.; Yi, J.; von Daeniken, R.; Weber, W.; Frost, J. W. Biotechnol.
Prog. 2003, 19, 808. (d) Pittard, A. J. In Escherichia coli and Salmonella:
Cellular and Molecular Biology; Neidhardt, F. C., Ed.; ASM Press: Washington,
DC, 1996; Chapter 28.
†
Dedicated to Professor Li-Xin Dai (Shanghai Institute of Organic Chemistry)
on the occasion of his 85th birthday.
(
1) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen,
X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem.
998, 41, 2451. (b) Schmidt, A. C. Drugs 2004, 64, 2031.
1
(
2) (a) Moscona, A. New Engl. J. Med. 2005, 353, 1363. (b) Russell, R. J.;
Haire, L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay,
A. J.; Gamblin, S. J.; Skehel, J. J. Nature (London) 2006, 443, 45.
(
3) (a) Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330. (b)
Taubenberger, J. K.; Reid, A. H.; Fanning, T. G. Virology 2000, 274, 241.
(
(
4) Laver, G.; Garman, E. Science 2001, 293, 1776.
5) For reviews, please see:(a) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem.
2
008, 1839. (b) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.;
Wirz, B.; Zutter, U. Chimia 2004, 58, 621. (c) Abrecht, S.; Federspiel, M. C.;
Estermann, H.; Fisher, R.; Karpf, M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.;
Trussardi, R.; Zutter, U. Chimia 2007, 61, 93.
3
970 J. Org. Chem. 2009, 74, 3970–3973
10.1021/jo900218k CCC: $40.75  2009 American Chemical Society
Published on Web 04/14/2009

SCHEME 1
with 4 equiv of sodium azide in aqueous ethanol (EtOH/H
2
O
)
5:1) under refluxing (around 75 °C) for 8 h to afford
compound 9 in 88% yield, and the (R)-cofiguration of C-5 is
reversed to the (S)-configuration.
In the sequence outlined in Scheme 2, nucleophilic replace-
ment of OMs by the N group was used twice in the third and
3
seventh steps. To optimize the reaction conditions for the
nucleophilic substitutions of methanesulfonates 3 and 8 by
sodium azide, we examined the nucleophilic substitutions of
compounds 3 and 8 in aqueous acetone (Me
aqueous N,N-dimethylformamide (DMF/ H O ) 5:1), aqueous
dimethyl sulfoxide (DMSO/H O ) 5:1), aqueous tetrahydro-
furan (THF/H O ) 5:1), and aqueous ethanol (EtOH/H O )
:1). It was found that the substitution of compound 3 by sodium
azide in aqueous acetone and that for compound 8 in aqueous
2 2
CO/H O ) 5:1),
2
2
2
2
5
in the Chinese star anise [1.1 kg of (-)-shikimic acid from 30
kg of the dried plant] and commercially available in large
quantities in China.
1
1,12
ethanol gave the best yield, respectively.
Notably, the
reaction temperatures for the substitutions of compounds 3 and
8 differed dramatically. This is likely due to the fact that the
(
-)-Shikimic acid was first converted to ethyl shikimate 2
6c
-
in high yield according to a known procedure. Compound 2
attack of the nucleophile (N ) on the allylic position of
3
was then exposed to 4.5 equiv of methanesulfonyl chloride and
compound 3 is much easier than that on the nonallylic position
of compound 8 and thus requires a much lower temperature.
Several other nitrogen-containing nucleophiles were also
tested to replace the sodium azide in the nucleophilic substitu-
tions of compounds 3 and 8, considering hazardousness and
potential explosiveness of sodium azide. The nitrogen-containing
nucleophiles that have been tried include ammonia, benzylamine,
allylamine, and tert-butylamine. Unfortunately, none of them
led to the formation of the desired products, and compounds
10 and 11 (see also Scheme 1) were obtained instead.
5
equiv of triethylamine in ethyl acetate in the presence of a
catalytic amount of DMAP, thus trimesylate 3 was obtained in
3% yield. When compound 3 was treated with 4 equiv of
9
sodium azide in aqueous acetone (acetone/water ) 5:1) at 0 °C
for 4 h, a highly stereoselective nucleophilic substitution of the
OMs group at the allylic C-3 position by an azido group
occurred to afford azide compound 4 in 92% yield, and the (R)-
configuration of C-3 is reversed to the (S)-configuration. The
substitution occurred with very high regioselectivity, also, two
OMs groups at C-4 and C-5 remained intact. In this step, a
relatively lower temperature was crucial, otherwise compound
Finally, azide 9 was transformed into the title compound 1
7
according to our reported procedure in 91% yield. The sample
5
(Scheme 1) would be formed from the desired product 4 via
elimination and aromatization. For example, when compound
was treated with 4 equiv of sodium azide in aqueous acetone
of final product oseltamivir phosphate obtained from the
synthesis described herein was found to be identical with the
sample we obtained in the previous synthesis by comparing the
3
7
,6b
at room temperature for 3 h or at 50 °C for 2 h, aromatic
compound 5 was obtained in 16% and 81% yields, respectively.
Compound 4 was successively treated with 1.1 equiv of
triphenylphosphine, 3 equiv of triethylamine, and a large excess
of water at room temperature to afford aziridine 6 in 84% yield.
It was found that the aziridine 6 was hard to separate by
chromatography from the triphenylphosphine oxide, which was
formed during the reaction from the oxidation of triphenylphos-
phine. Fortunately, compound 6 could be easily purified by first
washing it into aqueous solution with an acid and then extracting
it from the aqueous solution after neutralization. Sodium
hydrogen sulfate was found to be the best acid for this purpose.
Compound 6 was then immediately exposed to 2 equiv of acetic
anhydride and 3 equiv of triethylamine in ethyl acetate to
produce N-acetyl aziridine 7 in a nearly quantitative yield.
N-acetyl aziridine 7 was then treated with 1.5 equiv of boron
trifluoride etherate in 3-pentanol to furnish a ring-opening
product 8 in 86% yield. The reaction temperature should be
kept below 0 °C (-8 to 0 °C) with a salt-ice bath to obtain the
best yield. The stereoselectivity of this ring-opening reaction is
excellent, and the (S)-configuration of C-1 in compound 7 is
inversed to the (R)-configuration of C-3 in compound 8
according to the Walden-type inversion. The regioselectivity
of the ring-opening reaction is also excellent because the allylic
position (C-1 of compound 7) is much more reactive than the
analytical data.
In conclusion, a short and practical synthesis of the title
compound 1 has been developed. As compared with our reported
7
synthesis, the total yield starting from (-)-shikimic acid
increased from 40% to 47%, and the synthetic route was
shortened from 13 steps to 8 steps. Higher overall yield and
fewer synthetic steps, combined with other advantages such as
ready crystallization of trimesylate 3 and easy purification of
aziridine 6 without chromatography, make the synthesis more
suitable as an industrial process. Reaction conditions for the
3
nucleophilic replacement of OMs by the N group both in the
3
rd and 7th steps have been studied in detail and optimized.
Experimental Section
Ethyl (3R,4S,5R)-3,4,5-O-Trimethanesulfonyl Shikimate (3).
To a solution of (-)-ethyl shikimate 2 (11.26 g, 55.68 mmol) in
ethyl acetate (150 mL) was added methanesulfonyl chloride (28.71
g, 250.63 mmol). The resulting solution was cooled to 0 °C by an
ice bath, and 4-dimethylaminopyridine (2.04 g, 16.70 mmol) was
added. Triethylamine (28.18 g, 278.49 mmol) was then added
dropwise over 30 min, while vigorous stirring was continued. After
(11) The substitution of compound 3 with 4 equiv of sodium azide gave
compound 4 in 90% yield in DMF-H
20°C, 1 h), 89% yield in THF-H
(20°C, 24 h).
12) The substitution of compound 8 with 4 equiv of sodium azide gave
compound 9 in 75% yield in Me CO-H O (59°C, 60 h), 84% yield in DMF-
O (90°C, 3 h), 70% yield in DMSO-H O (80°C, 15 h), and 64% yield in
THF-H O (63°C, 6 d).
2
O (0°C, 1 h), 88% yield in DMSO-H
2
O (0°C, 6 h), and 85% yield in EtOH-H
2
O
(
2
O
6
a
C-6 position of compound 7.
With the ring-opening product 8 in hand, the next step that
we wanted to perform was nucleophilic replacement of OMs at
(
2
2
H
2
2
the C-5 position by the N
3
group. Compound 8 was then treated
2
J. Org. Chem. Vol. 74, No. 10, 2009 3971

SCHEME 2
the addition was finished, the reaction mixture was stirred at 0 °C
for another 1 h to allow the reaction to complete. The reaction was
quenched by adding a dilute HCl aqueous solution (1 N, 100 mL),
and the mixture was transferred into a separatory funnel. The
organic phase was separated and washed with dilute potassium
carbonate aqueous solution until pH 8-9. The organic solution was
mixture was stirred at room temperature for 24 h. Toluene (100
mL) was added, and the reaction mixture was transferred into a
separatory funnel. The organic phase was then washed three times
with aqueous sodium hydrogen sulfate (5% w/v, 3 × 80 mL). The
aqueous solutions were combined and neutralized to pH 9-10 by
adding potassium carbonate (16.65 g, 120.47 mmol) powder. The
basic aqueous solution was extracted twice with ethyl acetate (2 ×
100 mL). The organic extracts were combined and dried over
4
dried over anhydrous MgSO , and then was concentrated under
vacuum to give a pale yellow oily residue that solidified on standing
at room temperature. The solid was then triturated with aqueous
methanol (methanol/water ) 8:2) and pale yellow crystals were
collected on a Buchner funnel and rinsed with aqueous methanol
to give compound 3 (22.61 g, 51.80 mmol) in 93% yield, mp
2 4
anhydrous Na SO , and evaporation of the solvent under vacuum
gave a crude oil that was seeded to afford compound 6 (4.62 g,
2
0
17.68 mmol) as pale yellow crystals in 84% yield. [R]
D
-116.5
1
(c 1.0, EtOAc). H NMR (acetone-d
6
) δ 1.24 (t, J ) 7.1 Hz, 3H),
2
5
1
9
1
3
7.8-99.0 °C, [R]
.32 (t, J ) 7.1 Hz, 3H), 2.70 (dd, J
.14 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.22 (dd, J
5.9 Hz, 1H), 4.26 (q, J ) 7.1 Hz, 2H), 4.99 (dd, J
) 4.0 Hz, 1H), 5.09-5.18 (m, 1H), 5.52 (dd, J ) J
D
-119.4 (c 1.0, EtOAc). H NMR (CDCl
) 17.5 Hz; J ) 5.9 Hz, 1H),
) 13.9 Hz; J
) 9.2 Hz;
) 4.2 Hz,
3
) δ
1.87-2.02 (m, 1H), 2.21-2.35 (m, 1H), 2.64-3.02 (m, 3H), 3.20
1
2
(s, 3H), 4.14 (q, J ) 7.1 Hz, 2H), 4.86-5.08 (m, 1H), 7.09-7.16
+
1
2
(m, 1H). MS (m/z, rel intensity) 262 (M + 1, 1), 259 (3), 243 (3),
)
1
184 (57), 166 (4), 155 (5), 138 (12), 111 (8), 105 (100), 77 (13).
+
J
2
1
2
HRMS m/z calcd for (C10
H
15NO
5
S) + 1 262.0749, found
262.0752. IR (KBr film) 3249, 2991, 1704, 1363, 1355, 1265, 1187,
+
1
3
1
1
4
H), 6.80-6.86 (m, 1H). MS (m/z, rel intensity) 436 (M , 0.5),
90 (2), 357 (12), 341 (2), 311 (7), 267 (48), 199 (100), 155 (49),
37 (47), 109 (44), 79 (45). IR (KBr film) 3039, 2937, 1711, 1661,
346, 1179, 889 cm . Anal. Calcd for C12
.62. Found: C, 33.23; H, 4.27.
-
1
1173, 1121, 955, 723, 540 cm . Anal. Calcd for C10
45.97; H, 5.79; N,5.36. Found: C, 45.97; H, 5.60; N, 5.14.
Ethyl (1S,5R,6S)-7-Acetyl-5-methanesulfonyloxy-7-
5
H15NO S: C,
-
1
20 11 3
H O S : C, 33.02; H,
azabicyclo[4.1.0]hept-2 -ene-3-carboxylate (7). Compound 6 (4.44
g, 16.99 mmol) and triethylamine (5.16 g, 50.99 mmol) were
dissolved in ethyl acetate (65 mL). The solution was then cooled
to 0 °C with an ice bath, and acetic anhydride (3.47 g, 33.99 mmol)
was added dropwise over 15 min. After the addition was finished,
the reaction mixture was further stirred for half an hour. The reaction
was quenched by adding an aqueous solution of potassium carbonate
(15% w/v, 35 mL), then the organic phase was separated and
washed successively with water (20 mL) and brine (15 mL). After
Ethyl (3S,4R,5R)-3-Azido-4,5-dimethanesulfonyloxycyclohex-
-ene-1-carboxylate (4). Compound 3 (10.00 g, 22.91 mmol) was
1
dissolved in acetone (80 mL), and the solution was cooled to 0 °C
by an ice bath. A freshly prepared solution of sodium azide (5.96
g, 91.68 mmol) in water (16 mL) was then added in 10 min. The
mixture was stirred at 0 °C for 4 h, and the reaction was traced by
TLC. Toluene (200 mL) and water (50 mL) were added upon the
disappearance of 3, then the organic phase was separated and
washed successively with water (50 mL) and brine (25 mL). The
2 4
the organic phase was dried over anhydrous Na SO , evaporation
organic solution was dried over anhydrous MgSO
were removed by distillation under vacuum. The crude product was
then purified by chromatography to furnish azide compound 4 (8.08
4
, and the solvents
of the solvent under vacuum gave a pale yellow oily product that
could be directly used for the next step or purified by flash
chromatography to furnish compound 7 (5.06 g, 16.68 mmol) in
2
5
1
20
1
g, 21.07 mmol) in 92% yield. [R]
NMR (CDCl ) δ 1.32 (t, J ) 7.1 Hz, 3H), 2.64-2.72 (m, 1H),
.16 (s, 3H), 3.21 (dd, J ) 15.1 Hz; J ) 5.7 Hz, 1H), 3.23 (s,
H), 4.25 (q, J ) 7.1 Hz, 2H), 4.31-4.38 (m, 1H), 4.77 (dd, J
.9 Hz; J ) 8.1 Hz, 1H), 4.86-4.94 (m, 1H), 6.74-6.79 (m, 1H).
+ Na)+ 406.0355, found
06.0354. IR (KBr film) 2979, 2938, 2112, 1716, 1358, 1258, 1178,
D
+45.1 (c 1.9, EtOAc). H
98% yield. [R]
(t, J ) 7.1 Hz, 3H), 2.21 (s, 3H), 2.32-2.46 (m, 1H), 3.04-3.14
(m, 1H), 3.18 (s, 3H), 3.24 (dd, J ) 5.9 Hz; J ) 4.7 Hz, 1H),
3.35-3.41 (m, 1H), 4.22 (q, J ) 7.1 Hz, 2H), 4.96-5.06 (m, 1H),
7.10 (dd, J ) 4.5 Hz; J ) 3.5 Hz, 1H). HRMS m/z calcd for
S 303.0777, found 303.0765. IR (KBr film) 2979, 2937,
D
-22.2 (c 1.1, EtOAc). H NMR (CDCl ) δ 1.30
3
3
3
3
9
1
2
1
2
1
)
2
1
2
HRMS m/z calcd for (C11
H
17
N
3
O
8
S
2
12 6
C H17NO
-
1
4
1
1710, 1421, 1358, 1259, 1174, 947, 831, 545 cm . Anal. Calcd
S: C, 47.52; H, 5.65; N, 4.62. Found: C, 47.77; H,
-
1
016, 820, 521 cm .
for C12H17NO
6
Ethyl (1S,5R,6S)-5-Methanesulfonyloxy-7-azabicyclo[4.1.0]hept-
-ene-3-carboxylate (6). To a solution of compound 4 (8.08 g,
1.07 mmol) in tetrahydrofuran (250 mL) was added triphenylphos-
phine (6.08 g, 23.18 mmol) in portions. After the solution was
stirred at room temperature for half an hour, triethylamine (6.40 g,
5.70; N, 4.60.
2
2
Ethyl (3R,4S,5R)-4-Acetamido-3-(1-ethylpropoxy)-5-methane-
sulfonyloxycyclohex-1-ene-1-carboxylate (8). Compound 7 (5.00
g, 16.48 mmol) was dissolved in 3-pentanol (20 mL), and the
solution was cooled to -8 °C by a salt-ice bath. To this cooled
solution was gradually added a freshly prepared solution of boron
6
3.25 mmol) and water (40 mL) were added, then the resulting
3
972 J. Org. Chem. Vol. 74, No. 10, 2009

trifluoride-diethyl etherate (3.15 mL, 24.86 mmol) in 3-pentanol
15 mL) within a period of 15 min. After addition was finished,
were added. The organic phase was separated and washed with
brine (20 mL). The organic solution was dried over anhydrous
(
the reaction mixture was further stirred for 1 h. The mixture was
diluted with ethyl acetate (100 mL) and an aqueous solution of
potassium carbonate (15% w/v, 30 mL). The organic phase was
separated and washed successively with water (20 mL) and brine
MgSO , and evaporation of the solvent under vacuum produced a
crude oil that was purified by chromatography to afford compound
9 (1.91 g, 5.64 mmol) in 88% yield. The analytical data showed
4
that compound 9 obtained herein was identical with the sample
7
(
20 mL). The organic solution was dried over anhydrous MgSO
4
,
obtained in the previous article.
and evaporation of the solvents under vacuum gave a crude oil
that was purified by chromatography to furnish compound 8 (5.56
g, 14.20 mmol) in 86% yield. The analytical data showed that
compound 8 obtained herein was identical with the sample obtained
Acknowledgement. We are grateful to the Chinese National
Science Foundation (No. A-20172015) and the Shanghai
Educational Development Foundation (The Dawn Program: No.
7
in the previous article.
0
3SG27) for financial support of this work. K.H.K. would like
Ethyl (3R,4R,5S)-4-Acetamido-5-azido-3-(1-ethylpropoxy)cy-
clohex-1-ene-1-carboxylate (9). Compound 8 (2.50 g, 6.39 mmol)
was placed in a round-bottomed flask with a stir bar. Ethanol (25
mL) and water (5 mL) were added. The mixture was stirred, and a
white powder of sodium azide (1.66 g, 25.54 mmol) was added.
The reaction mixture was heated to reflux, and stirring was
continued at reflux for 8 h. The reaction was monitored by TLC.
When TLC showed that the reaction was complete, ethanol was
distilled off under a reduced pressure. The residue was cooled to
room temperature and ethyl acetate (80 mL) and water (30 mL)
to thank Ham Huang University of Pharmacy, Democratic
People’s Republic of Korea.
Supporting Information Available: Characterization data
1
for compounds 1, 5, and 8-11, and copies of H NMR of
compounds 1 and 3-11. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900218K
J. Org. Chem. Vol. 74, No. 10, 2009 3973