A new and efficient asymmetric synthesis of oseltamivir phosphate (Tamiflu) from D-glucose

Article abstract of DOI:10.1016/j.tet.2015.02.081

Abstract The anti-influenza drug, oseltamivir phosphate (Tamiflu) was synthesized from d-glucose via a novel and efficient synthetic route. A unique feature of the synthesis is that the key intermediate aziridine cyclohexene was synthesized as a mixture of diastereomers, via a metal-mediated domino reaction and ring closing metathesis (RCM). The iodoxylose compound was prepared in 9 steps from d-glucose. Both isomers of aziridine cyclohexene intermediate could be converted into Tamiflu via two pathways. First, both isomers of aziridine cyclohexene underwent aziridine-ring opening yielded diastereomeric of 1,2-amino mesylate cyclohexene esters. The trans-1,2-amino mesylate isomer could be transformed to tamiflu by formation of aziridine then regio- and stereoselective nucleophilic substitution of the azide to afford 1,2-amino azido compound whereas the cis-isomer could be transformed directly by S_N2 substitution of azide to give the same azido product, which then converted into oseltamivir phosphate.

Full text of DOI:10.1016/j.tet.2015.02.081

Tetrahedron 71 (2015) 2393e2399
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new and efficient asymmetric synthesis of oseltamivir phosphate
(Tamiflu) from -glucose
D
*
Boonsong Kongkathip, Sunisa Akkarasamiyo, Ngampong Kongkathip
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The anti-influenza drug, oseltamivir phosphate (Tamiflu) was synthesized from D-glucose via a novel and
Received 22 December 2014
Received in revised form 10 February 2015
Accepted 24 February 2015
Available online 3 March 2015
efficient synthetic route. A unique feature of the synthesis is that the key intermediate aziridine cyclo-
hexene was synthesized as a mixture of diastereomers, via a metal-mediated domino reaction and ring
closing metathesis (RCM). The iodoxylose compound was prepared in 9 steps from D-glucose. Both
isomers of aziridine cyclohexene intermediate could be converted into Tamiflu via two pathways. First,
both isomers of aziridine cyclohexene underwent aziridine-ring opening yielded diastereomeric of 1,2-
amino mesylate cyclohexene esters. The trans-1,2-amino mesylate isomer could be transformed to ta-
miflu by formation of aziridine then regio- and stereoselective nucleophilic substitution of the azide to
afford 1,2-amino azido compound whereas the cis-isomer could be transformed directly by SN2 sub-
stitution of azide to give the same azido product, which then converted into oseltamivir phosphate.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Oseltamivir phosphate
Tamiflu
Anti-influenza
D
-Glucose
Bernet-Vasellar reaction
Ring closing metathesis
1. Introduction
chosen for the synthesis of Tamiflu. The retrosynthetic analysis is
depicted in Fig. 1. We envisioned that the installation of the alkoxy
Influenza remains a major global human health issue due to the
risk of a major pandemic. H5N1 is a particularly virulent subtype of
the influenza A virus, which can cause serious illness in humans.1,2
Therefore, studies of inhibitors or vaccines of H5N1 have attracted
interest and worldwide attention.3
group could be achieved by the opening of the aziridine 8. It was
CO2Et
O
CO2Et
BocN
Oseltamivir phosphate, popularly known as Tamiflu, 1, is one of
the most potent orally active neuraminidase inhibitors used for the
treatment of human influenza and H5N1 avian flu infections.3e7 The
commercial manufacturing process of Tamiflu employs (ꢀ)-shikimic
acid as the raw material, which is not always readily available in
AcHN
OMs
NH2 H3PO4
.
8
1
consistently pure form.8 As
a consequence, many synthetic
groups9,10 have recently focused on developing alternative synthetic
strategies from cheaper, more readily available starting materials.
CO2Et
O
I
O
We have recently reported the synthesis of Tamiflu from D-mannose
BocHN
OH
as more efficient and practical synthetic process.11a,b Herein, we go
further by reporting a novel asymmetric synthesis of Tamiflu using
O
Boc-HN
OH
4
5
D-glucose, which is a very cheap and abundant starting material.
CH2OH
Carbohydrates have for decades served as chiral pool com-
O
pounds for the total synthesis of bioactive natural products. In this
paper -glucose, a commercially available starting material, was
HO
HO
D
OH
OH
D-glucose
* Corresponding author. Tel.: þ662 5625444x2139; fax: þ662 5625444x2119;
Fig. 1. Retrosynthetic analysis of oseltamivir phosphate (1) from D-glucose via azir-
idine intermediate 8.
e-mail address: fscinpk@ku.ac.th (N. Kongkathip).
http://dx.doi.org/10.1016/j.tet.2015.02.081
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

2394
B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
proposed that 8 could be obtained via ring closing olefin metathesis
of a diene 5 generated by metal-mediated reductive elimination of
the 3-[(tert-butoxycarbonyl)amino]-3,5-dideoxy-5-iodo-1,2-O-(1-
shift of H5 at 5.46 as a quintet, which is in agreement with that
reported in the literature,9c whereas for 8b, the chemical shift of
H5 appeared at a higher field (
d
¼5.0) as a doublet of doublet of
methylethylidene)-
a
-D-xylofuranose (4) and in situ alkylation of
doublets. Subsequently, N-Boc aziridine 8a and 8b were imme-
diately exposed to BF3$OEt2 and a large excess 3-pentanol; ring
opening of 8a and 8b occurred regio- and stereospecifically to
provide compound 9a and isomer 9b in 91% and 95%,
respectively.14a,b
an aldehyde intermediate by a metal allyl reagent. The xylofuranose
derivative 4 could be easily prepared from a commercially available
D
-glucose.12
2. Results and discussion
The synthesis began with 3-amino-3-deoxy-1,2-O-(1-methyle-
thylidene)-
a
-D-xylofuranose 2, obtained from D-glucose following
a procedure previously reported.12 Protection of the amino group of
compound 2 as N-Boc was accomplished by its treatment with di-
tert-butyl dicarbonate in methanol to afford compound 3 in 83%
yield. Alcohol 3 was converted to the corresponding iodide 4 in 64%
yield by treatment with I2, PPh3, imidazole and refluxing in a mixed
solvent of tolueneeacetonitrile (2:1) (Scheme 1).
O
Ref. 12
HO
O
Boc2O, MeOH,
rt, 83%
D-glucose
O
H2N
2
O
O
O
HO
BocHN
O
O
I2, PPh3, imidazole,
I
toluene/MeCN, reflux,
64%;
O
BocHN
4
3
Scheme 1. Synthesis of 3-[(tert-butoxycarbonyl)amino]-3,5-dideoxy-5-iodo-1,2-O-(1-
methylethylidene)- -D-xylofuranose (4).
a
Scheme 2. Synthesis of N-Boc aziridine 8a and 8b.
It should be noted that the Bernet-Vasella reaction of 5-
deoxy-5-iodo derivatives of -xylose has been reported to be
Both compounds 9a and 9b could be converted into oseltamivir
phosphate (1). Thus, compound 9a underwent intramolecular SN2
type reaction when treated with 2.0 equiv of NaH in CH2Cl2-DMSO
(30:1) to give N-Boc aziridine 10.9q Treatment of 10 with 4.0 equiv
of sodium azide in DMF at 90 ꢁC caused the aziridine ring opening
reaction to give the azido compound 11 in 77% yield over 2 steps
(Scheme 3). The product 11 was obtained in one step, 68% yield
from the isomer 9b, when treated with 2.0 equiv of sodium azide in
DMF/H2O (Scheme 4).15
D
unsuccessful with activated zinc, irrespective of the reaction
conditions.13a,b Therefore, we examined this reaction with re-
spect to compound 4 and ethyl 2-(bromomethyl)acrylate in THF/
H2O(2:1) and found that it worked very well when 10% AcOH
was added into the reaction mixture, affording the correspond-
ing diene 5a and 5b as a distereomeric mixture in 1:1 ratio in
82% yield (Scheme 2). The ratio of diastereomers was improved
to 1:3 when the reaction was carried out as a two steps se-
quence where zinc performed the reductive fragmentation of
iodide 4 and indium powder promoted the coupling between
the aldehyde intermediate and the bromoacrylate ester. The
diastereomers 5a and 5b were separated by flash column chro-
matography using hexaneeethyl acetate (2:1) as eluent. The
relative stereochemistry of diastereomers 5a and 5b was con-
firmed later when both compounds were transformed to azir-
idine cyclohexene 8a and 8b. Protection of the dihydroxyl group
of 5a and 5b upon treatment with MsCl provided both mesylate
6a and 6b in good yield. When compounds 6a and 6b were
treated with 2.0 equiv of NaH in a mixed solvent of dichloro-
methane and dimethyl sulfoxide (CH2Cl2/DMSO¼30:1) at room
temperature, the desired aziridines 7a and 7b were obtained in
88% and 44% yield, respectively. Next, by heating dienes 7a and
7b to 40 ꢁC in CH2Cl2 with the Hoveyda-Grubbs 2nd generation
catalyst resulted in ring closing metathesis, providing cyclo-
hexene aziridine 8a and 8b in 60% and 49% yield, respectively10
(Scheme 2). The 1H NMR spectrum of 8a showed the chemical
Scheme 3. Synthesis of azido cyclohexene 11 from N-Boc aziridine 8a.

B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
2395
benzophenone under nitrogen atmosphere. Triethylamine, pyri-
dine and dichloromethane were distilled from calcium hydride
under nitrogen atmosphere. Moisture- and air-sensitive reactions
were carried out under an atmosphere of nitrogen. Reaction flasks
were oven dried at 105 ꢁC overnight. Unless otherwise stated,
concentration under reduced pressure refers to a rotary evaporator
at water aspirator pressure. Analytical thin-layer chromatography
(TLC) was conducted using MERCK precoated TLC plates (silica gel
60 F-254). Compounds were visualized by ultraviolet light and/or
by heating the plate after dipping in a 1% solution of vanillin in
0.1 M sulfuric acid in ethanol. Flash chromatography was carried
out using MERCK. silica gel (0.04e0.06 mm particle size). Proton
and carbon nuclear magnetic resonance (NMR) spectra were ob-
tained using either a VARIANunity INOVA 400 MHz spectrometer or
a Brucker ADVANCE 300 MHz spectrometer. Chemical shifts were
Scheme 4. Synthesis of azido cyclohexene 11 from N-Boc aziridine 8b.
At the end of the synthesis, the N-Boc of azido compound 11 was
converted into its NeAc derivative by successive treatment with
TFA and subsequent acetylation with acetic anhydride to yield
NeAc azido 12.14 Azide compound 12 was reduced by hydrogena-
tion using the Lindlar catalyst to give the free amine 13, which was
directly reacted with 1.2 equiv H3PO4 in EtOH to furnish oseltamivir
phosphate (1) in 70% yield (Scheme 5).
recorded as d values in ppm. Spectra were acquired in CDCl3 unless
otherwise stated. The peak due to residual CHCl3 (7.26 ppm for 1H
and 77.23 ppm for 13C) was used as the internal reference. Coupling
constant (J) values were given in Hertz, and multiplicity was de-
fined as follows: br¼broad, s¼singlet, d¼doublet, dd¼double of
doublets, ddd¼doublet of doublet doublets, dt¼doublet of triplets,
t¼triplet, td¼triplet of doublets, q¼quartet, qd¼quartet of doublets
and m¼multiplet. Optical rotation was measured using a JASCO P-
2000 polarimeter. Infrared (IR) spectra were recorded in cmꢀ1 on
a Parkin-Elmer 2000 Fourier transform infrared spectrophotome-
ter at Chemistry Department, Faculty of Science, Kasetsart Uni-
versity. Samples were analyzed as KBr disks. The high resolution
mass spectra (HRMS) were recorded on Q-TOF2 hybrid quadrupole
time-of-flight mass spectrometer. Melting points (mp) were de-
termined on Fisher John apparatus and MEI-TEMP capillary melt-
ing point apparatus at Chemistry Department, Faculty of Science,
Kasetsart University and were reported uncorrected in degrees
Celcius (ꢁC).
4.1.1. 3-Amino-3-deoxy-1,2-O-(1-methylethylidene)-a-D-xylo-fura-
nose (2). To a solution of azido alcohol (967 mg, 4.50 mmol) in
a mixture of THF:water (4:1) (25 mL) was added triphenylphos-
phine (2.36 g, 8.96 mmol) and stirred at room temperature for
15 h. Then, the solvent was removed by evaporation and the res-
idue was purified by flash column chromatography (silica gel,
MeOH:CH2Cl2, 10: 90) to give 2 (841 mg, 99%) as a colourless oil. Rf
Scheme 5. Completion of the synthesis of oseltamivir phosphate 1.
(50% EtOAc/hexane) 0.16; ½a D25
ꢀ2.3 (c 1.99, CHCl3); FTIR (neat),
ꢂ
nmax, cmꢀ1: 3465 (OH), 3373 (NH), 2987, 2937 (CeH), 1217 (CeN),
1071 (CeO); 1H NMR (400 MHz, CDCl3)
d
: 5.89 (d, J¼3.6 Hz, 1H, H-
3. Conclusion
1), 4.36 (d, J¼3.6 Hz, 1H, H-2), 4.20 (dt, J¼5.3, 3.6 Hz, 1H, H-4),
3.91e3.79 (m, 2H, H-5), 3.45 (d, J¼3.6 Hz, 1H, H-3), 1.47 (s, 3H,
CH3), 1.27 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 111.4 (C-1),
In conclusion we have developed an efficient alternative
synthesis of Tamiflu from 3-amino-5-hydroxy-1,2-O-iso-
propylidenexylose 2, which can be prepared from cheap and readily
104.2 (C), 86.5 (C-2), 79.5 (C-4), 59.9 (C-5), 57.3 (C-3), 26.4 (CH3),
26.0 (CH3); HRMS (ESIþ) m/z [MþH]þ calcd for C8H16NO4:190.1079,
found: 190.1081.
available -glucose. The strategy requires nine steps from 4 and
D
gives rise to Tamiflu in 7.2% overall yield. The key steps are three
consecutive organometallic reactions: zinc-mediated fragmenta-
tion of 4, indium-mediated coupling between the aldehyde in-
termediate and ethyl 2-(bromomethyl)acrylate, and ruthenium-
catalyzed ring closing metathesis of 7. The synthesis highlights
the utility of these organometallic reactions in the synthesis of
Tamiflu from carbohydrates.
4.1.2. 3-[(tert-Butoxycarbonyl)amino]-3-deoxy-1,2-O-(1-methyl-eth-
ylidene)-a-D-xylofuranose (3). To a solution of 2 (643 mg,
3.42 mmol) in MeOH (7 mL) was added Boc2O (1.49 mg, 6.84 mmol)
and stirred at room temperature for 3 h. The solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: EtOAc 4:1) to give 3 as
a white amorphous solid (816 mg, 83%): mp 155e157 ꢁC. Rf (50%
4. Experimental
4.1. General
EtOAc/hexane) 0.37; ½a D25
ꢂ
þ5.1 (c 3.41, CHCl3); FTIR (KBr), nmax
,
cmꢀ1: 3429 (OH), 3297 (NH), 2984 (CeH), 1708 (C]O), 1062 (CeO);
1H NMR (400 MHz, CDCl3)
d
: 5.84 (d, J¼3.7 Hz, 1H, H-1), 5.55 (d,
J¼6.4 Hz, 1H, NH), 4.54 (d, J¼3.7 Hz, 1H, H-2), 4.30e4.24 (m, 1H, H-
Starting materials and reagents were obtained from commercial
sources and were used without further purification. Solvents were
dried by distillation from the appropriate drying reagents imme-
diately prior to use. Tetrahydrofuran was distilled from sodium and
3), 4.15e4.09 (m, 1H, H-4), 3.85e3.76 (m, 1H, H-5), 1.49 (s, 3H, CH3),
1.43 (s, 9H, Boc), 1.28 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 156.2
(C]O), 112.0 (C(CH3)2), 104.3 (C-1), 84.7 (C-2), 80.3 (C-3), 78.1
(C(CH3)3), 59.9 (C-5), 57.9 (C-4), 28.3 (C(CH3)3), 26.6 (CH3), 26.2

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B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
(CH3); HRMS (ESIþ) m/z [MþNa]þ, calcd for C13H23NNaO6: 312.1423,
(C(CH3)3), 75.4 (C-5), 71.6 (C-4), 70.6 (C-6), 61.0 (CO2CH2CH3), 54.5,
(C-6), 36.3 (C-3), 28.2 (C(CH3)3), 14.0 (CO2CH2CH3); HRMS (ESIþ) m/
z: [MþNa]þ calcd for C16H27NNaO6 352.1731, found 352.1742.
found: 312.1424.
4.1.3. 3-[(tert-Butoxycarbonyl)amino]-3,5-dideoxy-5-iodo-1,2-O-(1-
methylethylidene)-
a
-
D
-xylofuranose (4). To a solution of 3 (1.98 g,
4.1.5. Ethyl(4R,5R,6S)-6-[(tert-butoxycarbonyl)amino]-2-methyli-
dene-4,5 bis[(methylsulfonyl)-oxy]oct-7-enoate (6b). To a solution of
5b (133 mg, 0.40 mmol) in CH2Cl2 (2 mL) at 0 ꢁC was added and
Et3N (0.17 mL, 1.21 mmol) followed by methanesulfonyl chloride
(0.10 mL, 1.21 mmol). The reaction mixture was stirred at 0 ꢁC for
1 h then water was added to the solution, and the mixture was
extracted with CH2Cl2 (3ꢃ20 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: ethyl acetate, 1:1) to
give 6b 126 mg, 65%) as colourless oil. Rf (30% EtOAc/hexane) 0.29;
6.86 mmol) in toluene (32 mL) and acetonitrile (7 mL) was added
imidazole (1.40 g, 20.6 mmol) and triphenylphosphine (4.42 g,
16.5 mmol) and then iodine (4.18 g, 16.5 mmol). The reaction
mixture was refluxed for 3 h and cooled to room temperature. The
reaction mixture was diluted with ethyl acetate (100 mL) and the
organic layer was washed with 10% sodium thiosulphate solution
(3ꢃ100 mL), water (150 mL) and brine (150 mL). The organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: ethyl acetate, 2:1) to
give 4 (1.48 mg, 64%) as a white amorphous solid, which was
½
a 2D5
ꢂ
ꢀ29.4 (c 0.75, CHCl3); FTIR (neat), nmax, cmꢀ1: 3415, (NeH),
recrystallized from hexane to give
a
colourless needle, mp
ꢀ20.8 (c 2.30, CHCl3);
2981 (CeH), 1709 (C]O), 1358, 1336 1175(SO2); 1H NMR (400 MHz,
114e115 ꢁC; Rf (30% EtOAc/hexane) 0.70; ½a 2D5
ꢂ
CDCl3) d: 6.35 (s, 1H, H-1), 5.93e5.38 (m, 1H, H-7), 5.83 (s, 1H, H-1),
FTIR (KBr), nmax, cmꢀ1: 3432, (NeH), 2983, 2930 (CeH), 1714(C]O);
5.34 (d, J¼16.6 Hz, 1H, H-8), 5.31 (dt, J¼10.3 H, 1H, H-8), 5.12 (td,
J¼6.9, 5.2 Hz, 1H, H-4), 4.99 (d, J¼8.6 Hz, 1H, H-6), 4.74 (d, J¼5.0 Hz,
1H, H-5), 4.20 (q, J¼7.1 Hz, 2H, CO2CH2CH3), 3.12 (s, 3H, SO2CH3),
3.04 (s, 3H, SO2CH3), 2.92 (dd, J¼14.5, 5.2 Hz, 1H, H-3), 2.78 (dd,
J¼14.5, 6.9 Hz, 1H, H-3), 1.43 (s, 9H, C(CH3)3), 1.28 (t, J¼7.1 Hz, 3H,
1H NMR (400 MHz, CDCl3)
d: 5.85 (d, J¼3.6 Hz, 1H, H-1), 4.54 (d,
J¼3.6 Hz, 1H, H-2), 4.44 (br, 1H, H-3), 4.32 (d, J¼9.1 Hz, 1H, H-4),
3.24 (t, J¼9.1 Hz, 1H, H-5), 3.10 (dd, J¼10.1, 8.0 Hz, 1H, H-5), 1.51 (s,
3H, CH3), 1.45 (s, 9H, Boc), 1.28 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3)
d
: 154.8 (C]O), 112.1 (C), 104.5 (C-1), 84.8 (C-4), 80.3 (C-2),
CO2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 166.3 (C]O), 155.0 (C]
79.2 (C(CH3)), 57.4 (C-3), 28.2 (C(CH3)3), 26.5 (CH3), 26.1 (CH3), ꢀ1.8
(C-5); HRMS (ESIþ) m/z [MþNa]þ, calcd for C13H22NNaO5I:
422.0440, found: 422.0443.
O), 134.3 (C-2), 134.1 (C]C), 130.5 (C]C), 118.2 (C]C), 81.2
(C(CH3)3), 80.4 (C-5), 76.8 (C-4), 61.2 (CO2CH2CH3), 52.4 (C-6), 39.1
(SO2CH3), 38.8 (SO2CH3), 34.4 (C-3), 28.2 (C(CH3)3), 14.0
(CO2CH2CH3); HRMS (ESIþ) m/z [MþH]þ, calcd for C18H32NO10S2:
486.1462, found: 486.1461.
4.1.4. Ethyl (4S,5R,6S)-6-[(tert-butoxycarbonyl)amino]-4,5-
dihydroxy-2-methylideneoct-7-enoate (5a) and ethyl (4R,5R,6S)-6-
[(tert-butoxycarbonyl)amino]-4,5-dihydroxy-2-methylideneoct-7-
enoate (5b). To a solution of 4 (738 mg, 1.85 mmol) in 2:1 THF:H2O
(60 mL) was added zinc powder (1.78 mg, 27.8 mmol) and 10%
acetic acid (0.1 mL). The mixture was sonicated at 40 ꢁC for 30 min
and then ethyl 2-(bromomethyl) acrylate (0.52 mL, 3.7 mmol) was
added dropwise to the reaction mixture. The sonication was con-
tinued for an additional 30 min and the reaction mixture was then
filtered. The filtrate was extracted with CH2Cl2 (3ꢃ70 mL). The
combined organic layers were dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, hexane:
ethyl acetate, 2:1) to give diene 5a (238 mg, 39%) and 5b (260 mg,
4.1.6. Ethyl
(4S,5R,6S)-6-[(tert-butoxycarbonyl)amino]-2-methyli-
dene-4,5-bis[(methylsulfonyl) oxy]oct-7-enoate (6a). To a solution of
5a (240 mg, 0.73 mmol) in CH2Cl2 (5 mL) at 0 ꢁC was added and
Et3N (0.30 mL, 2.19 mmol) followed by methanesulfonyl chloride
(0.20 mL, 2.19 mmol). The reaction mixture was stirred at 0 ꢁC for
1 h then water was added to the solution, and the mixture was
extracted with CH2Cl2 (3ꢃ20 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: ethyl acetate, 1:1) to
give 6a (300 mg, 60%) as a colourless oil. Rf (30% EtOAc/hexane)
0.30; ½a 2D5
ꢂ
þ38.2 (c 0.21, CHCl3); FTIR (neat), nmax, cmꢀ1: 3432,
43%) as colourless oil; 5a: Rf (50% EtOAc/hexane) 0.40; ½a D25
ꢂ
þ111 (c
(NeH), 2989 (CeH), 1701, 1646 (C]O), 1355, 1177(SO2); 1H NMR
0.05, CHCl3); FTIR (neat), nmax, cmꢀ1: 3431 br, (NeH, OH), 2981
(400 MHz, CDCl3)
d
: 6.33 (d, J¼0.9 Hz, 1H, H-1), 5.86 (ddd, J¼17.2,
(CeH), 1690 (C]O), 1507 (C]C); 1H NMR (400 MHz, CDCl3)
d
: 6.23
10.4, 6.3 Hz, 1H, H-7), 5.77 (s, 1H, H-1), 5.42 (d, J¼17.2 Hz, 1H, H-8),
5.35 (dt, J¼10.4, 1.1 Hz, 1H, H-8), 5.13 (ddd, J¼9.8, 3.2, 2.5 Hz, 1H, H-
4), 5.01 (d, J¼9.4 Hz, 1H, NH), 4.89 (dd, J¼7.0, 2.2 Hz, 1H, H-6), 4.55
(br, 1H, H-5), 4.17 (qd, J¼7.2, 1.7 Hz, 2H, CO2CH2CH3), 3.13 (s, 3H,
SO2CH3), 2.98 (s, 3H, SO2CH3), 2.87 (dd, J¼14.3, 3.2 Hz, 1H, H-3),
2.71 (dd, J¼14.3, 10.1 Hz, 1H, H-3), 1.43 (s, 9H, C(CH3)3), 1.29 (t,
(d, J¼1.5 Hz, 1H, H-1), 5.85 (ddd, J¼17.4, 10.5, 5.2 Hz, 1H, H-7), 5.74
(s, 1H, H-1), 5.22 (dt, J¼17.4, 1.3 Hz, 1H, H-8), 5.16 (dt, J¼10.5, 1.3 Hz,
1H, H-8), 4.47 (br, 1H, H-6), 4.17 (q, J¼7.1 Hz, 2H, CO2CH2CH3), 3.52
(br, 1H, H-4), 3.35 (dd, J¼8.8, 2.0 Hz, 1H, H-5), 2.74 (dd, J¼14.5,
3.0 Hz, 1H, H-3), 2.45 (dd, J¼14.5, 7.6 Hz, 1H, H-3), 1.39 (s, 9H,
(C(CH3)3), 1.25 (t, J¼7.1 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz,
J¼7.2 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 166.1 (C]
CDCl3)
d
: 168.3 (C]O), 157.0 (C]O), 136.7 (C]C), 136.3 (C-2), 128.2
O), 155.0 (C]O), 134.5 (C-2), 133.0 (C]C), 130.0 (C]C), 119.3 (C]
C), 81.5 (C(CH3)3), 80.2 (C-5), 78.4 (C-4), 61.2 (CO2CH2CH3), 52.4(C-
6), 38.9 (SO2CH3), 38.5 (SO2CH3), 32.6 (C-3), 28.2 (C(CH3)3), 14.1
(CO2CH2CH3); HRMS (ESIþ) m/z [MþNa]þ, calcd for
(C]C), 115.9 (C]C), 79.9 (C(CH3)3), 75.7 (C-5), 69.9 (C-4), 60.9
(CO2CH2CH3), 53.2 (C-6), 35.0 (C-3), 28.1 (C(CH3)3), 13.9
(CO2CH2CH3); HRMS (ESI-TOF) m/z [MþNa]þ calcd for
C
16H27NNaO6: 352.1731, found: 352.1742; 5b: Rf (50% EtOAc/hex-
C18H31NNaO10S2: 508.1282, found: 508.1283.
ane) 0.31; ½a 2D6
ꢂ
þ8.3 (c 0.39, CHCl3); FTIR (neat), nmax, cmꢀ1: 3403
br, (NeH, OH), 2980 (CeH), 1701 (C]O), 1522 (C]C); 1H NMR
4.1.7. tert-Butyl(2S,3S)-2-ethenyl-3-{(1R)-3-(ethoxycarbonyl)-1-
[(methylsulfonyl)oxy]but-3-en1-yl}aziridine-1-carboxylate (7b). To
a solution of 6b (198 mg, 0.41 mmol) in a mixed solvent of CH2Cl2
(40 mL) and DMSO (5.5 mL) was added sodium hydride (60% in oil)
(33 mg, 0.82 mmol). The reaction mixture was stirred at room
temperature for 1 h, then water was added, and the mixture was
extracted with CH2Cl2 (3ꢃ20 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
(400 MHz, CDCl3)
d
: 6.21 (d, J¼1.4 Hz, 1H, H-1), 5.79 (ddd, J¼17.1,
6.5, 5.9 Hz, 1H, H-7), 5.69 (d, J¼0.9 Hz, 1H, H-1), 5.22 (dt, J¼17.1,
1.2 Hz, 1H, H-8), 5.15 (dt, J¼10.4, 1.1H, 1H, H-8), 4.23 (br, 1H, H-6),
4.17 (qd, J¼7.1, 1.1 Hz, 2H, CO2CH2CH3), 3.72 (td, J¼8.6, 4.8 Hz, 1H, H-
4), 3.39 (t, J¼4.8 Hz, 1H, H-5), 2.59 (dd, J¼14.2, 2.6 Hz, 1H, H-3), 2.47
(dd, J¼14.2, 8.6 Hz, 1H, H-3), 1.39 (s, 9H, C(CH3)3), 1.29 (t, J¼7.1 Hz,
3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 167.9 (C]O), 156.1
(C]O), 136.9 (C]C), 136.3(C-2), 128.0 (C]C), 116.2 (C]C), 79.6

B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
2397
column chromatography (silica gel, hexane: ethyl acetate, 4:1) to
7a (127 mg, 0.262 mmol) in dry CH2Cl2 (26 mL) was added
Hoveyda-Grubbs catalyst (second generation) (17 mg, 0.026 mmol).
The reaction mixture was stirred at 40 ꢁC for 16 h, then the mixture
was concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, hexane: ethyl acetate, 4:1) to
give 8a (56 mg, 60%) as a colourless oil: Rf (30% EtOAc/hexane) 0.10;
give 7b (70 mg, 44%) as a colourless oil. ½a D25
þ20.8 (c 0.31, CHCl3).
ꢂ
[lit. ½a 2D0
ꢂ
þ25.1 (c 1.33, CHCl3)15]; FTIR (neat), nmax, cmꢀ1: 3422,
(NeH), 2920 (CeH), 1706 (C]O), 1366, 1175 (SO2); 1H NMR
(400 MHz, CDCl3)
d
: 6.33 (d, J¼1.2 Hz, 1H, H-1), 5.84 (ddd, J¼16.9,
10.4, 5.9 Hz, 1H, H-7), 5.78 (d, J¼0.9 Hz, 1H, H-1), 5.39 (ddd, J¼17.0,
1.5, 1.1 Hz, 1H, H-8), 5.49 (ddd, J¼10.4, 1.5, 0.7 Hz, 1H, H-8), 4.66
(ddd, J¼9.4, 7.9, 3.6 Hz, 1H, H-4), 4.26e4.17 (m, 2H, CO2CH2CH3),
3.14 (tt, J¼5.8, 0.8 Hz, 1H, H-6), 3.04 (ddd, J¼14.7, 3.7, 0.9 Hz, 1H, H-
3), 2.93 (s, 3H, SO2CH3), 2.76 (dd, J¼7.9, 6.0 Hz, 1H, H-5), 2.77 (ddd,
J¼14.7, 9.5, 0.6 Hz, 1H, H-3), 1.47 (s, 9H, C(CH3)3), 1.30 (t, J¼7.1 Hz,
½
a 2D5
ꢂ
þ52.2 (c 0.17, CHCl3); FTIR (neat), nmax, cmꢀ1: 3369, (NeH),
2923 (CeH), 1716 (C]O), 1364, 1176 (SO2); 1H NMR (400 MHz,
CDCl3)
d
: 7.19 (dd, J¼4.7, 3.3 Hz, 1H, H-1), 5.46 (quint, J¼2.4 Hz, 1H,
H-5), 4.19 (dq, J¼7.1, 1.0 Hz, 2H, CO2CH2CH3), 3.28 (dt, J¼5.8, 2.3 Hz,
1H, H-4), 3.10 (dd, J¼5.6, 4.9 Hz,1H, H-3), 3.02 (dt, J¼17.9, 2.1 Hz,1H,
H-6), 3.01 (s, 3H, SO2CH3), 2.39 (ddd, J¼17.9, 4.5, 3.3 Hz, 1H, H-6),
1.43 (s, 9H, C(CH3)3), 1.27 (t, J¼7.1 Hz, 3H, CO2CH2CH3); 13C NMR
3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 166.3 (C]O), 161.2
(C]O), 135.1 (C-2), 131.1 (C]C), 129.2 (C]C), 120.3 (C]C), 81.0
(C(CH3)3), 76.6 (C-4), 61.0 (CO2CH2CH3), 44.6 (C-5), 43.6 (C-6), 38.6
(SO2CH3), 36.8 (C-3), 27.9 (C(CH3)3), 14.2 (CO2CH2CH3); HRMS (ESIþ)
m/z [MþNa]þ, calcd for C17H27NNaO7S: 412.1400, found: 412.1419.
(75 MHz, CDCl3) d: 165.5 (C]O), 160.1 (C]O), 133.4 (C-2), 128.8 (C-
1), 82.7 (C(CH3)3), 72.2 (C-5), 61.1 (CO2CH2CH3), 40.1 (C-4), 38.7
(SO2CH3), 33.3 (C-3), 27.8 (C(CH3)3), 26.9 (C-6), 14.2 (CO2CH2CH3);
HRMS (ESIþ) m/z [MþNa]þ calcd for C15H23NNaO7S: 384.1087,
found: 384.1103.
4.1.8. tert-Butyl
(2S,3R)-2-ethenyl-3-{(1S)-3-(ethoxycarbonyl)-1-
[(methylsulfonyl) oxy]but-3-en-1-yl}aziridine-1-carboxylate (7a). To
a solution of 6a (208 mg, 0.43 mmol) in a mixed solvent of CH2Cl2
(43 mL) and DMSO (5.70 mL) was added sodium hydride (60% in
oil) (35 mg, 0.86 mmol). The reaction mixture was stirred at room
temperature for 1 h then water was added, and the mixture was
extracted with CH2Cl2 (3ꢃ20 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: ethyl acetate, 4:1) to
give 7a (148 mg, 88%) as a colourless oil. Rf (30% EtOAc/hexane)
4.1.11. Ethyl (3R,4R,5R)-4d(tert-butoxycarbonyl)-5d(methane-sul-
fonyloxy)-3-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate (9b). To
a solution of 8b (17 mg, 0.05 mmol) in 3-pentanol (1.2 mL) atꢀ10 ꢁC
was added BF3$OEt2 (9 mL, 0.07 mmol) in 3-pentanol (0.5 mL). The
reaction mixture was stirred for 2 h atꢀ10 ꢁC then the mixture was
diluted with EtOAc (10 mL) and 20% aq K2CO3 (5 mL). The organic
phase was separated and washed with water (5 mL) and brine
(5 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica
gel, hexane: ethyl acetate, 4:1) to give white solid, which was
recrystallized from hexaneedichloromethane to give 9b as a white
0.59; ½a 2D5
ꢂ
þ28.7 (c 1.03, CHCl3); FTIR (neat), nmax, cmꢀ1: 3438,
(NeH), 2980 (CeH), 1720 (C]O), 1366, 1176 (SO2); 1H NMR
(400 MHz, CDCl3)
d: 6.33 (d, J¼1.1 Hz,1H, H-1), 5.75 (d, J¼0.9 Hz,1H,
H-1), 5.69 (ddd, J¼17.0, 10.3, 6.6 Hz, 1H, H-7), 5.50 (dt, J¼17.0,
0.9 Hz, 1H, H-8), 5.37 (d, J¼10.3 Hz, 1H, H-8), 4.52 (td, J¼8.9, 4.5 Hz,
1H, H-4), 4.19 (q, J¼7.1 Hz, 2H, CO2CH2CH3), 3.14e3.11 (m, 1H, H-6),
3.12 (s, 3H, SO2CH3), 2.73 (dd, J¼9.3, 6.6 Hz, 1H, H-5), 2.71 (ddd,
J¼13.8, 4.5, 0.9 Hz, 1H, H-3), 2.60 (dd, J¼14.0, 8.6 Hz, 1H, H-3), 1.43
(s, 9H, C(CH3)3), 1.28 (t, J¼7.1 Hz, 3H, CO2CH2CH3); 13C NMR
solid (20 mg, 95%), mp 160e161 ꢁC (lit. Mp 157e158.5 ꢁC).15
½ ꢂ
a 2D5
ꢀ166.7 (c 0.07, CHCl3). [lit. ½a D19
ꢂ
ꢀ75.4 (c 1.52, CHCl3)15]; FTIR (KBr),
nmax, cmꢀ1: 3364, (NeH), 2929 (CeH), 1721, 1682 (C]O), 1345, 1172
(SO2); 1H NMR (400 MHz, CDCl3)
d
: 6.85 (dt, J¼2.9, 1.5 Hz, 1H, H-2),
5.22 (br s,1H, H-5), 4.76 (d, J¼7.4 Hz, 1H, NH), 4.22 (q, J¼7.1 Hz, 2H,
CO2CH2CH3), 4.05e4.00 (m, 1H, H-4), 4.00e3.94 (m, 1H, H-3), 3.40
(quint, J¼5.8 Hz, 1H, H-7), 3.04 (s, 3H, SO2CH3), 2.86e2.68 (m, 2H,
H-6), 1.59e1.48 (m, 4H, 2ꢃ(CH2CH3)), 1.44 (s, 9H, C(CH3)3), 1.29 (t,
J¼7.1 Hz, 3H, CO2CH2CH3), 0.92 (t, J¼7.2 Hz, 3H, CH2CH3), 0.91 (t,
(75 MHz, CDCl3) d: 166.1 (C]O), 160.9 (C]O), 134.1 (C-2), 130.8
(C]C), 129.9 (C]C), 121.0 (C]C), 82.2 (C(CH3)3), 80.8 (C-4), 60.9
(CO2CH2CH3) 45.1 (C-5), 42.9 (C-6), 39.0 (SO2CH3), 36.1 (C-3), 27.8
(C(CH3)3), 14.1 (CO2CH2CH3); HRMS (ESIþ) m/z [MþNa]þ, calcd for
J¼7.2 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.6 (C]O),
C
17H27NNaO7S: 412.1400, found: 412.1407.
155.4 (C]O),136.5 (C-2),127.8 (C-1), 82.4 (C(CH3)3), 80.2 (C-3), 72.8
(C-5), 61.1 (CO2CH2CH3), 52.8 (C-4), 38.4 (SO2CH3), 29.3 (CH2CH3),
28.3 (CH2CH3), 26.3 (C(CH3)3), 26.0 (C-6), 14.1 (CO2CH2CH3), 9.6
(CH2CH3), 9.3 (CH2CH3); HRMS (ESIþ) m/z [MþNa]þ, calcd for
4.1.9. 7-tert-Butyl 3-ethyl (1S,5R,6S)-5-[(methylsulfonyl)oxy]-7-
azabicyclo[4.1.0] hept-2-ene-3,7-dicarboxylate (8b). To a solution
of 7b (30 mg, 0.06 mmol) in dry CH2Cl2 (6 mL) under nitrogen at-
mosphere was added Hoveyda-Grubbs catalyst (second generation)
(4 mg, 0.006 mmol). The reaction mixture was stirred at 40 ꢁC for
16 h, then the mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, hex-
ane: ethyl acetate, 4:1) to give 8b (11 mg, 49%) as a colourless oil:
C20H35NNaO8S: 472.1976, found: 472.1997.
4.1.12. Ethyl(3R,4S,5S)-4-[(tert-butoxycarbonyl)amino]-5-[(methyl
sulfonyl)oxy]-3-(1-ethylpropoxy)cyclohex-1-ene-1-carboxylate
(9a). To a solution of 8a (45 mg, 0.124 mmol) in 3-pentanol (4 mL)
atꢀ10 ꢁC was added BF3$OEt2 (24
mL, 0.19 mmol) in 3-pentanol
½
a 2D5
ꢂ
ꢀ10.2 (c 0.25, CHCl3). (lit. ½a D22
ꢂ
ꢀ8.29 (c 1.62, CHCl3);15 FTIR
(1.5 mL). The reaction mixture was stirred for 2 h at ꢀ10 ꢁC then
the mixture was diluted with EtOAc (10 mL) and 20% aq K2CO3
(10 mL). The organic phase was separated and washed with water
(5 mL) and brine (5 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash column chro-
matography (silica gel, hexane: ethyl acetate, 4:1) to give 9a (51 mg,
91%) as a white solid mp 117e119 ꢁC, Rf (30% EtOAc/hexane) 0.24;
(neat), nmax, cmꢀ1: 3394, (NeH), 2923 (CeH), 1716 (C]O), 1367,
1175 (SO2); 1H NMR (400 MHz, CDCl3)
d
: 7.10 (dd, J¼4.6, 3.4 Hz, 1H,
H-2), 5.00 (ddd, J¼10.1, 6.6, 2.3 Hz, 1H, H-5), 4.20 (dq, J¼7.1, 0.7 Hz,
2H, CO2CH2CH3), 3.37 (dt, J¼6.6, 2.0 Hz, 1H, H-4), 3.18 (s, 3H,
SO2CH3), 3.11 (dd, J¼6.3, 4.6 Hz, 1H, H-3), 3.05 (ddd, J¼16.4, 6.6,
1.8 Hz, 1H, H-6), 2.40 (ddd, J¼16.4, 10.2, 3.4 Hz, 1H, H-6), 1.46 (s, 9H,
C(CH3)3), 1.29 (t, J¼7.1 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz,
CDCl3)
d: 164.9 (C]O), 160.5 (C]O), 132.6 (C-1), 131.3 (C-2), 82.6
½
a 2D5
ꢂ
þ140.5 (c 0.05, CHCl3); FTIR (KBr), nmax, cmꢀ1: 3344, (NeH),
(C(CH3)3), 75.2 (C-5), 61.2 (CO2CH2CH3), 40.8 (C-4), 39.4 (SO2CH3),
36.1 (C-3), 27.8 (C(CH3)3), 26.6 (C-6),14.2 (CO2CH2CH3); HRMS(ESIþ)
m/z [MþNa]þ calcd for C15H23NNaO7S: 384.1087, found: 384.1087.
2920 (CeH),1719,1683 (C]O),1363,1179 (SO2); 1H NMR (400 MHz,
CDCl3)
d
: 6.75 (t, J¼1.8 Hz, 1H, H-2), 5.07e4.97 (m,1H, NH), 4.93 (d,
J¼7.7 Hz, 1H, H-5), 4.39 (d, J¼7.4 Hz, 1H, H-4), 4.19 (q, J¼7.1 Hz, 2H,
CO2CH2CH3), 3.54e3.24 (m, 1H, H-3), 3.29e3.21 (m, 1H), 3.13e3.04
(m, 1H), 3.03 (s, 3H, SO2CH3), 2.53 (ddt, J¼17.5, 9.8, 3.1 Hz, 2H, H-6),
1.53e1.45 (m, 4H, 2ꢃ(CH2CH3)), 1.41 (s, 9H, C(CH3)3), 1.26 (t,
4.1.10. 7-tert-Butyl 3-ethyl (1S,5S,6S)-5-[(methylsulfonyl)-oxy]-7-
azabicyclo[4.1.0]hept-2-ene-3,7-dicarboxylate (8a). To a solution of

2398
B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
J¼7.1 Hz, 3H, CO2CH2CH3), 0.89 (t, J¼7.3 Hz, 3H, CH2CH3), 0.88 (t,
The organic phase was separated and washed with water (5 mL).
The organic layers was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude product was pu-
rified by flash column chromatography (silica gel, hexane: ethyl
acetate, 8:1) to give 11 (7 mg, 68%) as a white solid.
J¼7.3 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.5 (C]O),
155.4 (C]O), 138.0 (C-2), 127.2 (C-1), 82.6 (C(CH3)3), 76.1 (C-3), 74.0
(C-5), 61.1 (CO2CH2CH3), 56.6 (C-4), 38.3 (SO2CH3), 31.8 (CH2CH3),
28.3 (CH2CH3), 26.3 (C(CH3)3), 25.7 (C-6), 14.2 (CO2CH2CH3), 9.5
(CH2CH3), 9.3 (CH2CH3); HRMS (ESIþ) m/z [MþH]þ, calcd for
C
20H36NO8S: 450.2156, found: 450.2156.
4.1.15. Ethyl (3R,4R,5S)-4-(acetylamino)-5-azido-3-(1-ethylpropoxy)
cyclohex-1-ene-1-carboxylate (12). To a solution of 11 (82 mg,
0.21 mmol) in CH2Cl2 (2 mL) at 0 ꢁC was added trifluoro acetic acid
(0.32 mL, 4.14 mmol). The reaction mixture was warmed to room
temperature and stirred for 4 h. Saturated aq NaHCO3 was added to
neutralize the mixture and then extracted with CH2Cl2 (3ꢃ20 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was
dissolved in pyridine (0.23 mL), acetic anhydride was then added.
The reaction mixture was stirred at room temperature for 1 h and
quenched with MeOH (0.23 mL). The trace Ac2O was removed by
coevaporattion with toluene (10 mL). The crude product was pu-
rified by flash column chromatography (silica gel, hexane:ethyl
acetate, 2:1) to give 12 (55 mg, 78%), which was recrystallized from
4.1.13. 7-tert-Butyl 3-ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-
azabicyclo[4.1.0]hept-3-ene-3,7-dicarboxylate (10). To a solution of
9a (44 mg, 0.098 mmol) in a mixed solvent of CH2Cl2 (6 mL) and
DMSO (0.2 mL) was added sodium hydride (60% in oil) (8 mg,
0.196 mmol). The reaction mixture was stirred at room tempera-
ture for 30 min then water was added, and the mixture was
extracted with CH2Cl2 (3ꢃ10 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexane: ethyl acetate, 8:1) to
give 10 (30 mg, 87%) as a colourless oil. Rf (30% EtOAc/hexane) 0.48;
½
a 2D5
ꢂ
ꢀ28.0 (c 0.43, CHCl3); FTIR (neat), nmax, cmꢀ1: 3375, (NeH),
hexane/CH2Cl2 to give a colourless needle, mp 137e139 ꢁC (lit. Mp
2929 (CeH), 1719 (C]O); 1H NMR (400 MHz, CDCl3)
d: 6.78 (br s,
a 23
a 21
14
138e139 ꢁC); ½ ꢂD ꢀ33.1 (c 0.40, CHCl3) [lit. ½ ꢂD ꢀ44.7 (c 0.83,
1H, H-2), 4.39 (br s,1H, NH), 4.18 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 3.42
(quint, J¼5.9 Hz, 1H, H-7), 2.94 (br d, J¼19.2 Hz, 1H, H-4), 2.88e2.78
(m, 2H, H-6), 2.60 (br d, J¼19.2 Hz, 1H, H-5), 1.61e1.48 (m, 4H,
2ꢃ(CH2CH3)), 1.43 (s, 9H, C(CH3)3), 1.26 (t, J¼7.2 Hz, 3H,
CO2CH2CH3), 0.96 (t, J¼7.2 Hz, 3H, CH2CH3), 0.89 (t, J¼7.2 Hz, 3H,
CHCl3)];15 FTIR (KBr), nmax, cmꢀ1: 3278, (NeH), 2967 (CeH),
2101(N]N]N), 1719, 1656 (C]O); 1H NMR (400 MHz, CDCl3)
d:
6.76 (d, J¼2.3 Hz, 1H, H-2), 6.28 (d, J¼6.9 Hz, 1H, NH), 4.50 (d,
J¼8.8 Hz, 1H, H-4), 4.19 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 4.19e4.13 (m,
1H, H-3), 3.40 (td, J¼10.4, 8.1 Hz, 1H, H-5), 3.31 (quint, J¼5.7 Hz, 1H,
H-7), 2.83 (dd, J¼17.6, 5.7 Hz,1H, H-6), 2.21 (ddt, J¼17.6,10.4, 2.9 Hz,
1H, H-6), 2.01 (s, 3H, C(O)CH3), 1.55e1.43 (m, 4H, CH2CH3), 1.27 (t,
J¼7.2 Hz, 3H, CO2CH2CH3), 0.92e0.84 (m, 6H, 2ꢃ(CH2CH3)); 13C
CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 166.5 (C]O), 161.6 (C]O),
133.1 (C-2), 127.8 (C-1), 82.5 (C(CH3)3), 81.4 (C-7), 68.6 (C-3), 60.8
(CO2CH2CH3), 37.5 (C-4), 35.8 (C-5), 27.8 (2ꢃ(CH2CH3)), 26.6
(C(CH3)3), 23.5 (C-6), 14.2 (CO2CH2CH3), 9.9 (CH2CH3), 9.5 (CH2CH3);
HRMS (ESIþ) m/z [MþNa]þ, calcd for C19H31NNaO5: 376.2094,
found: 376.2100.
NMR (75 MHz, CDCl3) d: 171.2 (C]O), 165.7 (C]O), 138.0 (C-2),
128.0 (C-1), 82.0 (C-7), 73.7 (C-3), 61.0 (CO2CH2CH3), 58.0 (2) (C-4,
C-5), 30.4 (C-6), 26.2 (CH2), 25.5 (CH2), 23.4 (C(O)CH3), 14.1
(CO2CH2CH3), 9.5 (CH3), 9.2 (CH3); HRMS (ESIþ) m/z: [MþNa]þ calcd
for C16H26N4O4Na: 361.1854, found: 361.1858.
4.1.14. Ethyl (3R,4R,5S)-5-azido-4-[(tert-butoxycarbonyl)amino]-3-
(1-ethylpropoxy)cyclohex-1-ene -1-carboxylate (11)
Procedure 1. To a solution of 10 (5 mg, 0.014 mmol) in anhydrous
DMF (2 mL) was added sodium azide (16 mg, 0.21 mmol) and
ammonium chloride (3 mg, 0.05 mmol). The reaction mixture was
heated and stirred at 90 ꢁC for 6 h. Then the reaction was cooled
down to room temperature, EtOAc (10 mL) and water (5 mL) were
added. The organic phase was separated and washed with water
(5 mL). The organic layers was dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (silica gel, hexane:
ethyl acetate, 8:1) to give 11 (5 mg, 89%) as a white solid, mp
4.1.16. Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-
ethylpropoxy) cyclohex-1-ene-1-carboxylate (13). To a solution of
12 (55 mg) in EtOH (10 mL) was treated with Lindlar catalyst
(55 mg) and the resulting suspension was stirred under atmo-
sphere of hydrogen gas for 10 h. The mixture was then filtered and
the solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
CH2Cl2:MeOH, 4:1) to give 13 (45 mg, 88%) as a colourless oil, ½a D23
ꢂ
ꢀ41.7 (c 0.92, CH2Cl2) [lit. ½a D25
ꢂ
ꢀ55.8 (c 2.05, CHCl3)];16 FTIR (neat),
nmax, cmꢀ1: 3412, (NeH), 2966 (CeH), 1714, 1651 (C]O), 1559 (C]
C); 1H NMR (400 MHz, CDCl3) 6.74 (s, 1H, H-2), 6.69 (d, J¼8.4 Hz,1H,
NH), 4.22e4.12 (m, 3H, H-3, CO2CH2CH3), 3.65 (td, J¼10.0, 8.9 Hz,
1H, H-4), 3.39e3.24 (m, 2H, H-5, H-7), 2.78 (dd, J¼18.2, 5.0 Hz, 1H,
H-6), 2.28e2.16 (m, 1H, H-6), 2.01 (s, 3H, Ac),1.53e1.42 (m, 4H,
CH2CH3), 1.26 (t, J¼7.0 Hz, 3H, CO2CH2CH3), 0.87 (t, J¼7.2 Hz, 3H,
127e128 ꢁC; Rf (30% EtOAc/hexane) 0.63; ½a 2D5
ꢀ35.0 (c 0.86,
ꢂ
CHCl3); FTIR (KBr), nmax, cmꢀ1: 3341, (NeH), 2978 (CeH), 2103(N]
N]N), 1719, 1687 (C]O); 1H NMR (400 MHz, CDCl3)
d: 6.77 (d,
J¼2.2 Hz, 1H, H-2), 4.91 (br s,1H, H-3), 4.48 (br s, 1H, H-4), 4.20 (q,
J¼7.1 Hz, 2H, CO2CH2CH3), 3.34 (quint, J¼5.7 Hz, 1H, H-7), 3.12 (br s,
1H, H-5), 2.83 (dd, J¼17.7, 5.7 Hz, 1H, H-6), 2.20 (br s, 1H, H-6),
1.56e1.47 (m, 4H, 2ꢃ(CH2CH3)), 1.45 (s, 9H, C(CH3)3), 1.26 (t,
J¼7.1 Hz, 3H, CO2CH2CH3), 0.91 (t, J¼7.3 Hz, 6H, 2ꢃ(CH2CH3)); 13C
CH3), 0.85 (t, J¼7.3 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 171.8
(C]O), 166.1 (C]O), 138.0 (C-2), 128.8 (C-1), 81.9 (C-7), 74.9 (C-3),
60.9 (CO2CH2CH3), 57.2 (C-4), 49.2 (C-5), 32.4 (C-6), 26.1 (CH2), 25.6
(CH2), 23.6 (C(O)CH3), 14.1 (CO2CH2CH3), 9.5 (CH3), 9.2 (CH3); HRMS
(ESIþ) m/z [MþH]þ calcd for C16H29N2O4: 313.2122, found:
313.2121.
NMR (75 MHz, CDCl3) d: 165.7 (C]O), 155.2 (C]O), 138.1 (C-2),
127.9 (C-1), 82.1 (C-7), 79.6 (C(CH3)3), 73.5 (C-3), 60.8 (CO2CH2CH3),
58.1 (C-5), 57.5 (C-4), 30.6 (C-6), 28.2 (C(CH3)3), 26.1 (CH2CH3), 25.5
(CH2CH3), 14.0 (CO2CH2CH3), 9.5 (CH2CH3), 9.2 (CH2CH3); HRMS
(ESIþ) m/z [MþNa]þ, calcd for C19H32N4O5Na: 419.2265, found:
419.2276.
4.1.17. Oseltamivir phosphate (1). To a solution of 13 (10 mg) in
ethanol (1 mL) and added a hot (60 ꢁC) solution of phosphoric acid
(3 mg) in ethanol (1 mL). The reaction mixture was heated and
stirred at 60 ꢁC for 3 h. After cooling to 0 ꢁC, the precipitates were
collected by filtration and rinsed with cold acetone (2ꢃ1 mL) to
afford oseltamivir phosphate (1) (9 mg, 70%) as a white crystal. Mp
Procedure 2. To a solution of 9b (12 mg, 0.026 mmol) in a mixed
solvent of DMF (2 mL) and water (0.4 mL) was added sodium azide
(14 mg, 0.214 mmol). The reaction mixture was heated and stirred
at 90 ꢁC for 8 h. Then the reaction mixture was cooled down to
room temperature, EtOAc (10 mL) and water (5 mL) were added.
203e204 ꢁC (lit. Mp 202ꢀ203 ꢁC) 15; ½a 2D3
ꢀ31.7 (c 0.22, H2O) [lit.
ꢂ
½
a 2D9
ꢂ
ꢀ30.8 (c 0.7, H2O)];17 FTIR (KBr), nmax, cmꢀ1: 3422, (NeH),

B. Kongkathip et al. / Tetrahedron 71 (2015) 2393e2399
2399
3233 (NHþ3 ) 2874 (CeH), 1719, 1629 (C]O), 1553 (C]C), 1355, 1177;
1H NMR (400 MHz, D2O)
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d: 6.88 (s,1H, H-2), 4.35 (d, J¼8.8 Hz,1H, H-
3), 4.28 (q, J¼7.3 Hz, 2H, OCH2), 4.08 (dd, J¼11.7, 9.2 Hz, 1H, H-4),
3.62 (td, J¼10.5, 5.7 Hz, 1H, H-5), 3.58 (quint, J¼7.5 Hz, 1H, CH), 2.99
(dd, J¼17.5, 5.6 Hz, 1H, H-6), 2.55 (dt, J¼17.5, 10.5 Hz, 1H, H-6), 2.11
(s, 3H, Ac),1.65e1.45 (m, 4H, CH2), 1.31 (t, 3H, J¼7.3 Hz, CH3), 0.91 (t,
3H, J¼7.4 Hz, CH3), 0.87 (t, 3H, J¼7.4 Hz, CH3); 13C NMR (75 MHz,
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Acknowledgements
S.A. is a Ph.D. student under the Royal Golden Jubilee Program,
the Thailand Research Fund (TRF) and PERCH-CIC. We are grateful
for financial support from the TRF and Kasetsart University, through
the Royal Golden Jubilee Program. Financial support from the
Center of Excellence for Innovation in Chemistry (PERCH-CIC),
Commission on Higher Education, Ministry of Education and
Kasetsart University Research and Development Institute (KURDI)
are also gratefully acknowledged.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new and
important known compounds) related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2015.02.081.
10. Wichienukul, P.; Akkarasamiyo, S.; Kongkathip, N.; Kongkathip, B. Tetrahedron
Lett. 2010, 51, 3208e3210.
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2012, 68, 6803e6809.
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