A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (-)-shikimic acid

Article abstract of DOI:10.1016/j.tetasy.2008.11.027

Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield. The synthesis described in this article is characterized by two particular steps: the highly regioselective and stereoselective facile nucleophilic replacement of an OMs by an N₃ group at the C-3 position of ethyl (3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylate 8.

Full text of DOI:10.1016/j.tetasy.2008.11.027

Tetrahedron: Asymmetry 20 (2009) 124–129
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu)
from (ꢀ)-shikimic acid
*
Liang-Deng Nie, Xiao-Xin Shi
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, PO Box 363, 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:
Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl
(3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield.
The synthesis described in this article is characterized by two particular steps: the highly regioselective
and stereoselective facile nucleophilic replacement of an OMs by an N3 group at the C-3 position of ethyl
(3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine
with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-
ene-3-carboxylate 8.
Received 26 October 2008
Accepted 28 November 2008
Available online 20 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
COOH
Oseltamivirphosphate1 (TamifluÒ, GS-4104-02, Ro 64-0796/002
in Fig. 1) as the prodrug of an active neuraminidase inhibitor (GS-
4071, Ro 64-0802 in Fig. 1) was discovered by Kim et al. of Gilead Sci-
ences1, and has been licensed to Roche as an orally administered
drug for the treatment and prophylaxis of human influenza A and
B.2,3 Moreover, it is also the mostpromising therapeuticfor thetreat-
ment of the H5N1 avian flu virus.4,5 Until now, Tamiflu has been ap-
proved in many countries worldwide, and according to WHO (World
Health Organization), stockpiling of Tamiflu is currently the only
way to guard against a possible pandemic that could be caused by
a human influenza virus or avian flu virus.6,7
O
COOEt
AcHN
AcHN
NH2
NH2 H3PO4
TM 1
active inhibitor in vivo
GS-4071
Tamiflu
GS-4104-02
Ro 64-0796/002
Ro 64-0802
Figure 1. Oseltamivir phosphate and the active neuraminidase inhibitor.
Among all the above synthetic routes, only the route developed
by Roche11–13 can be used in the current industrial synthesis. The
starting material for Roche’s synthesis is (ꢀ)-shikimic acid, which
can be obtained either by extraction from the Chinese star anise
(1 kg of shikimic acid from 30 kg of the dried plant) or by fermen-
tation using genetically modified Escherichia coli.29,30 Herein, we
report a novel practical synthesis of oseltamivir phosphate 1 also
from (ꢀ)-shikimic acid, which is abundant in China.
Due to the importance of Tamiflu for human health, the synthe-
sis of oseltamivir phosphate has aroused much interest from
synthetic chemists.8–10 Many synthetic routes for oseltamivir phos-
phate have been documented in the literature. In all the reported
synthetic routes, the key point should be the construction of three
stereogenic chiral centers in the cyclohexanoid scaffold. Some
routes are based on the derivation of these three stereogenic cen-
ters from natural starting materials, such as (ꢀ)-quinic acid,1,2,11
(ꢀ)-shikimic acid,2,11–14
L D D
-serine,15 -xylose,16,17 and -glucose.17
Some routes employed asymmetric Diels–Alder cycloadditions18–
22 as the key step followed by succeeding transformations to build
up the cyclohexanoid ring and the corresponding stereogenic cen-
ters. The other miscellaneous routes started from prochiral cyclo-
hexene derivatives23–25 or substituted benzenes,26–28 and used
chiral organometallic catalysts or enzymes to provide an access to
the required chirality.
2. Results and discussion
As depicted in Scheme 1, our synthesis started from acetonide 2,
which can be readily prepared from (ꢀ)-shikimic acid in 92% yield
according to a known procedure.12 Compound 2 was first treated
with 1.3 equiv of benzoyl chloride in the presence of 2 equiv of tri-
ethylamine and a catalytic amount of DMAP in dichloromethane to
produce benzoyl acetonide 3 in 98% yield. Removal of the aceto-
nide moiety of the compound 3 gave a crystalline benzoate 4 in
94% yield by exposing 3 to concentrated hydrochloric acid in a
* Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.027

L.-D. Nie, X.-X. Shi / Tetrahedron: Asymmetry 20 (2009) 124–129
125
2
O
O
COOEt
O
O
COOEt
HO
HO
COOEt
2 steps
92%
b
a
3
1
6
Shikimic Acid
5
94%
98%
4
OBz
OH
OBz
3
4
2
2
5
MsO
COOEt
N3
COOEt
1
COOEt
c
d
e
f
3
5
3
4
HN
7
97%
95%
98%
88%
4
6
MsO
MsO
OBz
OBz
OBz
6
7
5
COOEt
1
O
COOEt
O
COOEt
g
h
i
3
AcN
5
5
92%
90%
95%
6
4
AcHN
AcHN
OBz
8
OBz
9
OH
10
O
COOEt
O
COOEt
O
COOEt
j
k
84%
91%
AcHN
AcHN
AcHN
OMs
11
N3
12
H3PO4
NH2
1
Scheme 1. Synthesis of Oseltamivir phosphate 1 starting from (ꢀ)-shikimic acid. Reagents and reaction conditions: (a) 1.3 equiv of benzoyl chloride, 2 equiv of Et3N, cat.
DMAP, 0 °C to rt for 5 h in CH2Cl2. (b) cat. HCl, rt for 6 h in EtOAc–H2O (4:1). (c) 5 equiv of CH3SO2Cl, 4 equiv of Et3N, cat. DMAP, 0 °C for 1 h in EtOAc. (d) 4 equiv of NaN3, ꢀ5 °C to
0 °C for 1.5 h in DMF–H2O (5:1). (e) 1.1 equiv of Ph3P, rt for 2 h in THF; then 3 equiv of Et3N, rt overnight in THF–H2O (10:1). (f) 2 equiv of Ac2O, 3 equiv of Et3N, 0 °C for 0.5 h in
EtOAc. (g) 1.5 equiv of BF3ꢁEt2O, ꢀ5 °C to 0 °C for 0.5 h in 3-pentanol. (h) 1.1 equiv of K2CO3, rt for 6 h in ethanol. (i) 2 equiv of CH3SO2Cl, 2 equiv of Et3N, 0 °C for 1 h in CH2Cl2. (j)
4 equiv of NaN3, 90 °C for 3 h in DMF–H2O (5:1). (k) Lindlar catalyst, rt for 16 h under 1 atm. of H2 in EtOH; then 1.2 equiv of H3PO4, 50 °C for 0.5 h in EtOAc–EtOH (1:1).
mixed solvent of ethyl acetate and water (4:1). Compound 4 was
then treated with 5 equiv of methanesulfonyl chloride and 4 equiv
of triethylamine in the presence of DMAP as a catalyst in ethyl
acetate to furnish bismethanesulfonate 5 in 97% yield. It was found
that the solvent ethyl acetate was obviously better than dichloro-
methane and chloroform here, and triethylamine worked also
better than pyridine.
With bismethanesulfonate 5 in hand, we tried to replace the
OMs group selectively at the C-3 position by a nitrogen nucleophile
such as sodium azide or potassium azide, while keeping the OMs
group at C-4 position intact. This could be done by exposing
compound 5 to 4 equiv of sodium azide in aqueous N,N-dimethyl-
formamide (DMF/H2O = 5:1) at a lower temperature, and the
monoazido compound 6 was thus obtained in 95% yield. The tem-
perature for the reaction is crucial and should be kept in the range
of ꢀ5 °C to 0 °C by a salt–ice bath. This nucleophilic substitution
was quite clean, and almost no other diastereoisomer was detected
by the careful HPLC analysis. The stereoselectivity and regioselec-
tivity of the reaction are very high, and herein the R configuration
the C-3 position (the allylic position) is much more reactive and
less hindered than the C-4 position (see also Fig. 2).
The compound 6 was successively treated with 1.1 equiv of tri-
phenylphosphine, 3 equiv of triethylamine, and some water in tet-
rahydrofuran to give an aziridine
7 in 88% yield. In this
transformation, reduction of the azido group and formation of the
aziridine via an intramolecular nucleophilic substitution of the
neighboring OMs group at C-4 position took place simultaneously,
and meanwhile the (R)-configuration of C-4 is inversed to the (S)-
configuration. Compound 7 was then immediately exposed to
2 equiv of acetic anhydride and to 3 equiv of triethylamine in ethyl
acetate to form N-acetyl aziridine 8 almost quantitatively.
At this stage, the next step which we wanted to perform was the
selective opening of aziridine 8 with the substitution of 1-ethyl
propoxyl group at the allylic position (C-1 position). Compound 8
was then treated with 1.5 equiv of boron trifluoride etherate using
3-pentanolas solvent to afford a ring-opening product 9 in 92%yield.
The Lewis acid-catalyzed ring-opening of aziridine 8 with 3-penta-
nol was achieved with regio- and stereoselectivity; the substitution
of the 1-ethyl propoxyl group took place only at the C-1 position
rather than at the C-6 position, and the (S)-configuration of C-1 in
8 was inversed to (R)-configuration at C-3 in 9. The reaction temper-
ature is also crucial here, it should be kept in the range of ꢀ5 °C to
0 °C, and the slow addition of boron trifluoride etherate was neces-
sary because the reaction is exothermic. In this aziridine ring-open-
ing reaction, the nucleophile (3-pentanol) approaches the face of the
cyclohexene ring opposite to the benzoyl group at the C-5 position
(see also Fig. 2). The high regioselectivity of this aziridine-opening
reactioncouldbeattributedto thelargedifference betweenthereac-
tivities of both the C-1 and C-6 positions, with regards to the nucle-
ophilic attack of 3-pentanol. The allylic position (C-1) is much more
reactive than the non-allylic position (C-6), so the Lewis acid-cata-
lyzed nucleophilic attack of 3-pentanol at allylic position was
of C-3 is inversed to the S configuration according to the Walden-
ꢀ
type inversion. The highly selective attack of the azide anion (N3
)
at C-3 position is reasonable, and can be easily understood because
Ac
N3
N
6
4
COOEt
OBz
COOEt
OBz
1
MsO
3
OMs
OH
R
8
5
Figure 2. Regiospecific and stereospecific nucleophilic replacement of
aziridine opening of 8.
5 and

126
L.-D. Nie, X.-X. Shi / Tetrahedron: Asymmetry 20 (2009) 124–129
completely regiospecific. Kim et al. also observed exclusive regiose-
lectivity in a similar aziridine-opening reaction.1
(CDCl3) d 1.30 (t, J = 7.1 Hz, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 2.20–
2.28 (m, 1H), 2.80 (dd, J1 = 17.4 Hz; J2 = 4.6 Hz, 1H), 3.84–3.93
(m, 1H), 4.10 (dd, J1 = 7.1 Hz; J2 = 6.8 Hz, 1H), 4.22 (q, J = 7.1 Hz,
2H), 4.73–4.78 (m, 1H), 6.92–6.94 (m, 1H). MS (m/z, relative inten-
sity) 242 (M+, 1), 227 (100), 197 (12), 167 (17), 137 (79), 121 (11),
110 (10), 95 (38), 43 (14). IR (KBr film) 3469, 2986, 2935, 1716,
Alcoholysis of compound 9 in ethanol in the presence of
1.1 equiv of potassium carbonate gave compound 10 in 90% yield.
Compound 10 was then treated with 2 equiv of methanesulfonyl
chloride and with 2 equiv of trimethylamine in dichloromethane
to produce methanesulfonate 11 in 95% yield. Compound 11 was
treated with 4 equiv of sodium azide at an elevated temperature
in aqueous N,N-dimethylformamide (DMF/H2O = 5:1) to furnish
an azide compound 12 in 84% yield. In this SN2-type nucleophilic
substitution, the OMs group at C-5 position of compound 11 was
replaced by an azido group, and meanwhile the (R)-configuration
of the C-5 is inversed to the (S)-configuration. It was found that
the nucleophilic substitution did not work at all at room tempera-
ture, and it should be performed under heating conditions. In order
to obtain a maximum yield, it was better to keep the reaction tem-
perature between 85 °C and 95 °C. Actually, the large difference be-
tween the reaction temperatures of both nucleophilic substitutions
of the OMs group at C-5 of compound 11 and the OMs group at C-3
of compound 5 by sodium azide is good evidence, which accounts
for the exclusive regioselectivity of the nucleophilic substitution in
the transformation of compound 5 to compound 6.
Finally, azide compound 12 was reduced by hydrogenation in
the presence of the Lindlar catalyst under an atmosphere of hydro-
gen gas to form an amine, which was directly exposed to 1.2 equiv
of phosphoric acid in a mixed solvent of ethyl acetate and ethanol
(1:1) to afford title compound 1 in 91% yield. Though the hydroge-
nation of the azido group was slow, it was quite clean. Using
Raney-Ni as a catalyst also worked well here for the hydrogena-
tion. When Pd/C was used as a catalyst, both the double bond
and azido group were hydrogenated. The azido group of 12 can also
be reduced by using triphenylphosphine as the reducing agent, but
the yield was relatively lower.
1655, 1448, 1372, 1244, 1054, 860, 754 cmꢀ1
.
4.3. Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-O-isopropylidene
shikimate 3
Compound
2 (6.40 g, 26.42 mmol), triethylamine (5.35 g,
52.87 mmol), and DMAP (161 mg, 1.32 mmol) were dissolved in
dichloromethane (70 mL), and the solution was cooled to 0 °C by
an ice bath. Benzoyl chloride (4.83 g, 34.36 mmol) was added drop-
wise in 10 min. The ice bath was removed, and mixture was then
stirred and traced by TLC. After stirring was continued around
5 h, the reaction was complete. The solution was transferred into
a separatory funnel and washed successively with dilute hydro-
chloric aqueous solution, potassium carbonate aqueous solution,
and brine. Solvent was evaporated to give a crude oil, which was
purified by chromatography to produce compound 3 (8.97 g,
25.90 mmol) in 98% yield. ½a D25
ꢂ
¼ ꢀ55 (c 3.4, EtOAc). 1H NMR
(CDCl3) d 1.31 (t, J = 7.1 Hz, 3H), 1.41 (s, 3H), 1.44 (s, 3H), 2.51
(dd, J1 = 17.9 Hz; J2 = 6.3 Hz, 1H), 2.90 (dd, J1 = 17.8 Hz;
J2 = 3.5 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 4.39 (dd, J1 = J2 = 6.2 Hz,
1H), 4.77–4.85 (m, 1H), 5.46 (dd, J1 = 11.3 Hz; J2 = 5.8 Hz, 1H),
6.93–6.99 (m, 1H), 7.43 (dd, J1 = J2 = 7.5 Hz, 2H), 7.52–7.59 (m,
1H), 8.02 (d, J = 8.2 Hz, 2H). HRMS (EI) calcd for C19H23O6 (M+1):
347.1495. Found: 347.1483. IR (KBr film) 3042, 2979, 1722, 1633,
1600, 1450, 1260, 1112, 1058, 1032, 858, 716 cmꢀ1
.
4.4. Ethyl (3R,4R,5R)-5-O-benzoyl shikimate 4
To a solution of compound 3 (8.97 g, 25.90 mmol) in ethyl ace-
tate (20 mL) and water (5 mL) was added concentrated hydrochlo-
ric acid (3 mL). The mixture was stirred at room temperature and
analyzed by TLC. After stirring was continued around 6 h, the reac-
tion was complete. Ethyl acetate (80 mL) and water (50 mL) were
added and stirred. The organic phase was separated and washed
with potassium carbonate aqueous solution. Organic solution
was dried over anhydrous MgSO4, and then concentrated to dry-
ness to give crude product as a pale yellow solid, which was col-
3. Conclusion
An efficient and practical synthesis of oseltamivir phosphate 1
starting from a readily available compound 2 has been performed
via 11 steps. The overall yield of the whole synthesis is 44% from
compound 2 or 40% from natural material (ꢀ)-shikimic acid. The
configuration of C-3 of compound 2 remains the same after double
inversion, and the configurations of both C-4 and C-5 of compound
2 are inversed. The stereoselectivities are very high during these
inversions. The inexpensive reagents used in all steps, ease of
manipulation of every step, mildness of the reaction conditions
for each step and high yields, make the synthesis attractive and
potential to be developed as an industrial process in the future.
lected on
a
Buchner funnel and rinsed with hexane.
Recrystallization of the pale yellow solid in the mixed solvent of
ethyl acetate and hexane (1:2) afforded compound 4 (7.46 g,
24.35 mmol) as white crystals in 94% yield, mp 128.8–129.2 °C,
½
a 2D5
ꢂ
¼ ꢀ122 (c 2.7, EtOAc). 1H NMR (CDCl3) d 1.29 (t, J = 7.1 Hz,
3H), 2.50 (dd, J1 = 17.2 Hz; J2 = 6.0 Hz, 1H), 2.98 (dd, J1 = 17.1 Hz;
J2 = 6.3 Hz, 1H), 3.22 (br s, 1H), 3.34 (br s, 1H), 4.04 (dd,
J1 = J2 = 3.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.48–4.52 (m, 1H),
5.46–5.49 (m, 1H), 6.90–6.94 (m, 1H), 7.42 (dd, J1 = J2 = 7.9 Hz,
2H), 7.52–7.58 (m, 1H), 7.95–8.02 (m, 1H). MS (m/z, relative inten-
sity) 306 (M+, 1), 288 (2), 259 (3), 243 (3), 184 (57), 166 (4), 155 (5),
138 (12), 111 (8), 105 (100), 77 (13). IR (KBr film) 3302, 2950,
1725, 1709, 1600, 1450, 1279, 1253, 1132, 1100, 710 cmꢀ1. Anal.
Calcd for C16H18O6: C, 62.74; H, 5.92. Found: C, 62.74; H, 5.68.
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 WZZ-1S automatic polarimeter at room temper-
ature. All chemicals were analytically pure.
4.5. Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-O-bismethanesulfonyl
shikimate 5
Compound 4 (7.80 g, 25.46 mmol) was dissolved in ethyl
acetate (150 mL), and the solution was cooled to 0 °C by an ice
bath. Methanesulfonyl chloride (14.57 g, 127.30 mmol) and DMAP
(156 mg, 1.28 mmol) were added, and then triethylamine (10.31 g,
101.89 mmol) was added dropwise within 10 min. After addition,
4.2. Ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2
Compound 2 was obtained as a colorless oil in 92% yield accord-
ing to a known procedure.12
½
a 2D0
ꢂ
¼ ꢀ31 (c 3.0, EtOAc). 1H NMR

L.-D. Nie, X.-X. Shi / Tetrahedron: Asymmetry 20 (2009) 124–129
127
the stirring was continued for 1 h, TLC showed that the reaction
was complete. Water (100 mL) was added, and the mixture was
then transferred to a separatory funnel. The organic phase was sep-
arated and washed with potassium carbonate aqueous solution to
pH 8. The organic solution was dried over anhydrous MgSO4 and
concentrated to dryness to give a crude oil, which was purified
by chromatography to produce compound 5 (11.42 g, 24.69 mmol)
Found: 287.1165. IR (KBr film) 3302, 2979, 1710, 1650, 1600,
1450, 1326, 1268, 1678, 1110, 1023, 987, 711, 684 cmꢀ1
.
4.8. Ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-aza-bicyclo[4,1,0]-
hept-2-ene-3-carboxylate 8
Compound 7 (1.39 g, 4.84 mmol) and triethylamine (1.47 g,
14.53 mmol) were dissolved in ethyl acetate (60 mL), and the solu-
tion was cooled to 0 °C by an ice bath. Acetic anhydride (0.99 g,
9.70 mmol) was added, and stirring was continued at 0 °C for
30 min. TLC showed that the reaction was complete. Potassium car-
bonate aqueous solution was added to adjust the pH 9–10. The
organic phase was separated and washed with brine. After the
organic solution was dried over anhydrous MgSO4, the solvent was
evaporated under vacuum to give a crude oil, which was purified
by chromatography to afford compound 8 (1.57 g, 4.77 mmol) in
in 97% yield. ½a 2D5
ꢂ
¼ ꢀ135 (c 1.9, EtOAc). 1H NMR (CDCl3) d 1.31 (t,
J = 7.1 Hz, 3H), 2.60 (dd, J1 = 19.0 Hz; J2 = 6.6 Hz, 1H), 3.09 (s, 3H),
3.18 (s, 3H), 3.22 (dd, J1 = 19.1 Hz; J2 = 6.7 Hz, 1H), 4.25 (q,
J = 7.1 Hz, 2H), 5.16 (dd, J1 = 8.9 Hz; J2 = 4.0 Hz, 1H), 5.52–5.72 (m,
2H), 6.83–6.98 (m, 1H), 7.47 (dd, J1 = J2 = 7.7 Hz, 2H), 7.58–7.63
(m, 1H), 8.03 (d, J = 7.5 Hz, 2H). MS (EI) calcd for C18H22O10S2:
462.0654. Found: 462.0654. IR (KBr film) 3031, 2979, 2944, 1722,
1658, 1600, 1453, 1180, 1110, 1032, 1174, 910, 716, 530 cmꢀ1
.
4.6. Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-methanesulfon-
yloxy-cyclohex-1-ene-1-carboxylate 6
98% yield. ½a 2D5
ꢂ
¼ ꢀ41 (c 1.6, EtOAc). 1H NMR (CDCl3) d 1.30
(t, J = 7.1Hz, 3H), 2.17 (s, 3H), 2.32–2.47 (m, 1H), 3.04–3.18 (m,
1H), 3.29 (dd, J1 = 10.7 Hz; J1 = 5.9 Hz, 1H), 3.36 (dd, J1 = 6.1 Hz;
J2 = 4.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 5.29–5.40 (m, 1H), 7.15 (dd,
J1 = J2 = 3.9 Hz, 1H), 7.49 (dd, J1 = J2 = 7.8 Hz, 2H), 7.61 (dd,
J1 = J2 = 7.4 Hz, 1H), 8.11 (d, J = 7.3 Hz, 2H). HRMS (EI) calcd for
C18H20NO5 (M+1): 330.1341. Found: 330.1327. IR (KBr film) 2981,
Compound 5 (11.50 g, 24.86 mmol) was dissolved in DMF
(35 mL), and the solution was cooled to ꢀ5 °C by a salt–ice bath. A
freshly prepared solution of sodium azide (6.60 g, 101.51 mmol) in
a mixed solvent of DMF (40 mL) and water (15 mL) was added drop-
wise within 15 min. After the addition was finished, stirring was
continued at ꢀ5 °C to 0 °C for 1.5 h. TLC showed that the reaction
was complete. The reaction solution was then diluted with toluene
(120 mL) and water (200 mL). The organic phase was separated,
and then washed with water (30 mL) and brine (20 mL). The organic
solution was dried over anhydrous Na2SO4. The solvent was then
removed off by distillation under vacuum to give a crude oil, which
gradually solidified as pale yellow crystals. The crystals were col-
lected on a Buchner funnel and rinsed with aqueous methanol
(methanol/water = 4/1) and hexane to afford compound 6 (9.67 g,
23.62 mmol) in 95% yield with 99.5% purity (HPLC analysis:
20RBAX-C18 column, 4.6 ꢃ 250 mm; mobile phase: acetonitrile/
1721, 1648, 1600, 1452, 1374, 1258, 1202, 1100, 910, 833, 712 cmꢀ1
.
4.9. Ethyl (3R,4R,5R)-4-acetamido-5-benzoyloxy-3-(1-ethyl-
propoxy)-cyclohex-1-ene-1-carboxylate 9
A solution of compound 8 (1.60 g, 4.86 mmol) in 3-pentanol
(10 mL) was cooled to ꢀ5 °C by a salt–ice bath. A freshly prepared
solution of BF3ꢁOEt2 (1.04 g, 7.33 mmol) in 3-pentanol (5 mL) was
added dropwise within 10 min, and stirring was further continued
at ꢀ5 °C to 0 °C for around 0.5 h. The reaction mixture was diluted
with ethyl acetate (50 mL), and potassium carbonate aqueous solu-
tion was added to adjust pH 9–10. The organic phase was separated
and washed with brine. 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 evaporated
undervacuumto givethecrudeproduct, whichwaspurifiedbychro-
matography to furnish compound 9 (1.87 g, 4.48 mmol) in 92% yield.
water = 45/55), mp 90.3–90.7 °C, ½a D25
ꢂ
¼ ꢀ27 (c 2.8, EtOAc). 1H
NMR (CDCl3) d 1.30 (t, J = 7.1 Hz, 3H), 2.48–2.61 (m, 1H), 3.07
(s, 3H), 3.21 (dd, J1 = 18.0 Hz; J2 = 6.0 Hz, 1H), 4.24 (q, J = 7.1 Hz,
2H), 4.36–4.46 (m, 1H), 4.97 (dd, J1 = 10.0 Hz; J2 = 8.1 Hz, 1H),
5.34–5.48 (m, 1H), 6.76–6.81 (m, 1H), 7.46 (dd, J1 = J2 = 7.8 Hz, 2H),
7.54–7.62(m, 1H), 8.11(d, J = 8.3 Hz, 2H). MS(m/z, relativeintensity)
367 (M+ꢀN3, 5), 336 (1), 308 (1), 285 (1), 257 (1), 245(2), 217 (2), 199
(2), 180 (6), 163 (4), 152 (14), 124 (5), 105 (100), 77 (15). IR (KBr film)
2979, 2940, 2133, 1720, 1658, 1600, 1450, 1342, 1263, 1168, 1119,
1011, 969, 711, 513 cmꢀ1. Anal. Calcd for C17H19N3O7S: C, 49.87; H,
4.68; N, 10.26. Found: C, 50.21; H, 4.38; N, 9.98.
½
a 2D5
ꢂ
¼ ꢀ113 (c 1.6, EtOAc). 1H NMR (CDCl3) d 0.86–0.97 (m, 6H), 1.30
(t, J = 7.1 Hz, 3H), 1.48–1.64 (m, 4H), 2.00 (s, 3H), 2.58 (dd,
J1 = 19.0 Hz; J2 = 5.8 Hz, 1H), 2.85–2.98 (m, 1H), 3.41–3.52 (m, 1H),
4.12–4.19 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.43–4.51 (m, 1H), 5.54–
5.67 (m, 2H), 6.90–6.98 (m, 1H), 7.46 (dd, J1 = J2 = .9 Hz, 2H), 7.58
(dd, J1 = J2 = 7.4 Hz, 1H), 7.98 (d, J = 7.1 Hz, 2H). HRMS (EI) calcd for
C23H31NO6: 417.2151. Found: 417.2150. IR (KBr film) 3292, 2973,
4.7. Ethyl (1S,5R,6S)-5-benzoyloxy-7-aza-bicyclo[4,1,0]hept-2-
1721, 1653, 1600, 1550, 1453, 1368, 1268, 1099, 712 cmꢀ1
.
ene-3-carboxylate 7
4.10. Ethyl (3R,4R,5R)-4-acetamido-3-(1-ethyl-propoxy)-5-
To a solution of compound 6 (2.00 g, 4.88 mmol) in THF (50 mL)
was added triphenylphosphine (1.41 g, 5.38 mmol). Stirring was
continued at room temperature for 2 h, and then triethylamine
(1.48 g, 14.63 mmol) and water (5 mL) were added. The resulting
mixture was stirred at room temperature overnight. The reaction
solution was concentrated under vacuum to remove THF, and the
residue was partitioned between ethyl acetate (60 mL) and water
(30 mL). The organic phase was separated and dried over anhy-
drous Na2SO4. After removal of the solvent, the crude product
was purified by chromatography to give compound 7 (1.236 g,
hydroxy-cyclohex-1-ene-1-carboxylate 10
To a solution of compound 9 (1.70 g, 4.07 mmol) in absolute
ethanol (30 mL) was added the powder of potassium carbonate
(0.66 g, 4.78 mmol). The mixture was then well stirred at room
temperature for around 6 h. After TLC showed that the reaction
was complete, ethanol was removed by distillation under vacuum.
The residue was then partitioned between ethyl acetate (50 mL)
and water (30 mL). The organic phase was separated and washed
was brine. The organic solution was dried over anhydrous MgSO4.
Removal of the solvent by rotavaporator gave the crude product as
off-white crystals, which was collected on a Buchner funnel and
rinsed with the mixed solvent of ethyl acetate and hexane (4:1)
to furnish compound 10 (1.15 g, 3.67 mmol) in 90% yield, mp
4.30 mmol) as a pale yellow oil in 88% yield. ½a D25
¼ ꢀ63 (c 0.8,
ꢂ
EtOAc). 1H NMR (CDCl3) d 1.17 (br s, NH, 1H), 1.29 (t, J = 7.1 Hz,
3H), 2.40–2.49 (m,1H), 2.69–2.79 (m, 1H), 2.83–3.12 (m, 2H),
4.20 (q, J = 7.1 Hz, 2H), 5.29–5.38 (m, 1H), 7.15–7.24 (m, 1H),
7.46 (dd, J1 = J2 = 7.8 Hz, 2H), 7.58 (dd, J1 = J2 = 7.4 Hz, 1H), 8.11
(d, J = 7.6 Hz, 2H). HRMS (EI) calcd for C16H17NO4: 287.1158.
131.9–132.2 °C, ½a D25
ꢂ
¼ ꢀ104 (c 3.0, EtOAc). 1H NMR (CDCl3) d
0.91 (t, J = 7.4 Hz, 6H), 1.29 (t, J = 7.1 Hz, 3H), 1.42–1.62 (m, 4H),

128
L.-D. Nie, X.-X. Shi / Tetrahedron: Asymmetry 20 (2009) 124–129
2.02 (s, 3H), 2.43 (dd, J1 = 18.6 Hz; J2 = 5.1 Hz, 1H), 2.53–2.71
(m, 1H), 3.33–3.45 (m, 1H), 3.90–3.98 (m, 1H), 4.06 (br s, NH,
1H), 4.20 (q, J = 7.1 Hz, 2H), 4.23–4.30 (m, 1H), 6.19–6.21
(m, 1H), 6.38 (s, 1H). MS (m/z, relative intensity) 314 (M++1, 7),
313 (M+, 2), 267 (11), 242 (13), 226 (21), 212 (55), 208 (39), 197
(19), 155 (46), 142 (100), 138 (47), 96 (77), 59 (12). IR (KBr film)
3490, 3335, 2969, 2917, 1703, 1642, 1544, 1465, 1374, 1309,
1250, 1105, 950 cmꢀ1. Anal. Calcd for C16H27NO5: C, 61.32; H,
8.68; N, 4.47. Found: C, 61.31; H, 8.70; N, 4.37.
room temperature under an atmosphere of hydrogen gas for
16 h. TLC showed that the reaction was complete. The mixture
was then filtered through a thin layer of Celite to remove the Lind-
lar catalyst. The solvent was concentrated to dryness, and a mixed
solvent of ethyl acetate (5 mL) and ethanol (4 mL) was added. The
solution was well stirred and warmed to 50 °C, and a freshly pre-
pared solution of phosphoric acid (0.36 g, 85%, 1.80 mmol) in eth-
anol (1 mL) was added dropwise. After stirring was continued at
50 °C for 0.5 h, white crystals formed, and the suspension was
cooled to room temperature. Filtration and rinsing with cooled
acetone afforded compound 1 (0.57 g, 1.39 mmol) in 91% yield,
4.11. Ethyl (3R,4S,5R)-4-acetamido-3-(1-ethyl-propoxy)-5-
methanesulfonyloxy -cyclohex-1-ene-1-carboxylate 11
mp 203.3–204.1 °C (lit.11 203–204 °C), ½a 2D0
¼ ꢀ39 (c 1, H2O)
ꢂ
{lit.11
½
a 2D0
ꢂ
¼ ꢀ40 (c 1, H2O)}. 1H NMR (D2O) d 0.84 (t, J = 7.2 Hz,
Compound 10 (0.98 g, 3.13 mmol) and triethylamine (0.64 g,
6.32 mmol) were dissolved in dichloromethane (15 mL), and the
solution was cooled to 0 °C by an ice bath. Methanesulfonyl chlo-
ride (0.72 g, 6.29 mmol) was added, and then the resulting solution
was stirred at 0 °C for 1 h. After TLC showed that the reaction was
complete, more dichloromethane (20 mL) and dilute potassium
carbonate aqueous solution (2 M, 35 mL) were added. The organic
phase was washed with brine and then dried over anhydrous
MgSO4. After the solvent was removed by a rotavaporator, the
crude product was purified by chromatography to give compound
11 (1.17 g, 2.99 mmol) in 95% yield, mp 139.4–139.9 °C,
3H), 0.89 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.40–1.63 (m,
4H), 2.09 (s, 3H), 2.52 (dd, J1 = 15.5 Hz; J2 = 12.2 Hz, 1H), 2.97 (dd,
J1 = 17.1 Hz; J2 = 4.7 Hz, 1H), 3.48–3.66 (m, 2H), 4.06 (dd,
J1 = J2 = 10.1 Hz, 1H), 4.25 (dd, J1 = 13.7 Hz; J2 = 6.7 Hz, 1H), 4.34
(d, J = 8.3 Hz, 1H), 6.86 (s, 1H). MS (m/z, relative intensity) 314
(M+1+H+, 7), 295 (1), 267 (11), 254 (11), 242 (13), 226 (21), 212
(55), 197 (19), 184 (19), 166 (10), 155 (46), 142 (100), 110 (20),
96 (77). HRMS (EI) calcd for C16H29N2O4 (M+H+): 313.2127. Found:
313.2131. IR (KBr, film) 3354, 3249, 2969, 2938, 2875, 1621, 1558,
1547, 1374, 1130, 1067, 942 cmꢀ1. Anal. Calcd for C16H31N2O8P: C,
46.83; H, 7.61; N, 6.83. Found: C, 46.42; H, 7.68; N, 6.63.
½
a 2D5
ꢂ
¼ ꢀ85 (c 0.7, ethyl acetate). 1H NMR (CDCl3)
d 0.91
(t, J = 7.5 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H), 1.43–1.58 (m, 4H), 2.02
(s, 3H), 2.73 (dd, J1 = 19.1 Hz; J2 = 4.4 Hz, 1H), 2.80–2.91 (m, 1H),
3.06 (s, 3H), 3.34–3.44 (m, 1H), 4.08 (d, J = 6.8 Hz, 1H), 4.23
(q, J = 7.1 Hz, 1H), 4.27–4.35 (m, 1H), 5.21 (dd, J1 = 6.8 Hz;
J2 = 4.3 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H). MS (m/z, rela-
tive intensity) 392 (M++1, 6), 345 (9), 320 (8), 304 (23), 222 (89),
212 (43), 208 (38), 166 (24), 152 (46), 142 (100), 136 (31), 110
(24), 96 (49). HRMS (EI) calcd for C17H30NO7S (M+1): 392.1743.
Found: 392.1743. IR (KBr, film) 3306, 2969, 2940, 2875, 1720,
Acknowledgments
We thank the Chinese National Science Foundation (No.
A-20172015) and Shanghai Educational Development Foundation
(The Dawn Program No. 03SG27) for the financial support of this
work.
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½
a 2D0
ꢂ
¼ ꢀ44 (c 1.5, CHCl3). 1H NMR (CDCl3) d 0.83–0.95 (m, 6H),
1.30 (t, J = 7.1 Hz, 3H), 1.42–1.58 (m, 4H), 2.04 (s, 3H), 2.23 (dd,
J1 = 17.5 Hz; J2 = 10.5 Hz, 1H), 2.85 (dd, J1 = 17.6 Hz; J2 = 5.4 Hz,
1H), 3.27–3.40 (m, 1H), 3.46 (dd, J1 = 18.6 Hz; J2 = 8.4 Hz, 1 H),
4.08–4.27 (m, 3H), 4.50 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H),
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To a three-necked flask which was equipped with an inlet and
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(20 mL), and Lindlar catalyst (0.30 g). After the flask was purged
with hydrogen gas several times, the mixture was well stirred at

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129
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