A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from d-mannose

Article abstract of DOI:10.1016/j.tet.2012.06.065

A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive and abundant starting material, d-mannose. This synthetic route featured an intramolecular Horner-Wadsworth-Emmons reaction as the key step to furnish the cyclohexene ring product. The hydroxyl group was converted stereo specifically into an amino group by oxidation to the ketone and reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.

Full text of DOI:10.1016/j.tet.2012.06.065

Tetrahedron 68 (2012) 6803e6809
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A concise and practical synthesis of oseltamivir phosphate(Tamiflu) from
D-mannose
*
Nutthawat Chuanopparat, Ngampong Kongkathip, Boonsong 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:
A short and practical synthesis of oseltamivir phosphate was accomplished in 11 steps from inexpensive
Received 10 February 2012
Received in revised form 25 May 2012
Accepted 18 June 2012
and abundant starting material,
D-mannose. This synthetic route featured an intramolecular Hor-
nereWadswortheEmmons reaction as the key step to furnish the cyclohexene ring product. The hy-
droxyl group was converted stereo specifically into an amino group by oxidation to the ketone and
reductive amination whereas the second amino group was introduced by azide substitution of a hydroxyl
group. This synthesis provided an economical and practical alternative for the synthesis of Tamiflu.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 23 June 2012
Keywords:
Tamiflu
Oseltamivir phosphate
D
-Mannose
HornereWadswortheEmmons reaction
H5N1
1. Introduction
As for the routes from natural chiral sources other than shikimic
and quinic acid. Yao and co-workers reported the synthesis of
Oseltamivir phosphate (Tamiflu, 1) is an approved orally effec-
tive neuraminidase inhibitor used for the treatment of human in-
fluenza1 and H5N1 avian flu.2 The recent spread of the avian virus
H5N1 and the swine flu virus (H1N1 human flu) has prompted
many nations to plan to stockpile Tamiflu in case of a possible in-
fluenza outbreak. However only developing countries can afford to
stockpile this drug due to the high cost of the Tamiflu production
process. Currently, Tamiflu is produced and supplied by Roche us-
ing (ꢀ)shikimic acid as the starting material, which is not always
readily available in consistently pure form.3 The limited availability
of the starting material used in the commercial production of
oseltamivir phosphate, is an issue that still requires attention if
future demands for the drug are to be met.4
The need to improve the synthesis of oseltamivir phosphate has
prompted the chemical community to develop new processes for
the synthesis of this drug. For example, Shibasaki and co-workers
have developed four different approaches based on asymmetric
ring opening of meso-aziridines or DielseAlder reaction.5 Corey and
co-workers prepared oseltamivir phosphate employed an asym-
metric DielseAlder reaction as the initial step to synthesize this
drug in high yield.6
oseltamivir via a ring-closing metathesis protocol starting from
-serine.7 Fang and co-workers explored a new approach to osel-
tamivir using
-xylose as the chiral precursor.8 Mandai’s group
published two synthetic routes starting from
-mannitol9 and
-methionine derivatives.10 Recently our group11a and also the Chen
group11b developed an efficient synthesis of oseltamivir phosphate
with inexpensive -ribose starting material. In this paper we report
a concise and practical synthesis of oseltamivir phosphate starting
L
D
D
L
D
from inexpensive and abundant D-mannose.
2. Results and discussion
Our group is currently involved in developing alternative syn-
thetic methods for Tamiflu. In the recent disclosure by us11a and
other researchers,11b
D-ribose was used to synthesize the title
compound. The synthesis was based on metal mediated domino
reaction and ring-closing metathesis to construct the cyclohexene
ester core structure followed by functional group manipulation to
afford Tamiflu. Although this synthesis has some merits, such as
a novel method for constructing the cyclohexene core of the target
compound, the use of an expensive Ru catalyst will hamper its
utility in the large-scale preparation of oseltamivir phosphate. After
an extensive study, we have exploited a more practical synthesis of
oseltamivir phosphate from
material.
D-mannose, which is a less-expensive
* Corresponding author. Tel.: þ66 25625444/2235; fax: þ66 25793955; e-mail
addresses: fscibsk@ku.ac.th, fscinpk@ku.ac.th (B. Kongkathip).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.065

6804
N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
Our retrosynthetic analysis is shown in Fig. 1. We envisioned the
installation of the cyclohexene ester core of the Tamiflu molecule could
be achieved via an intramolecular HornereWadswortheEmmons re-
action of the phosphoryl ester (10), which would be prepared from the
reaction of functionalized furanoside aldehyde (8) and triethylphos-
phonoacetate. Compound 8 could be derived from selective ketal
O
OH
H
O
OH
O
O
O
3-pentanone,
HO
HO
OH
OH
H
DMF, H2SO4, rt,
overnight
H
O
H
H
deprotection of the diketal 6, which would be prepared from
D-man-
(5)
4
D-Mannose ( )
nose (4), followed by oxidative cleavage of the resulting 1,2-diols 7.
CO2Et
OH
HCl, MeOH,
H2O, 0 oC to rt,
4 h
O
CO2Et
O
CO2Et
H3PO4
O
O
O
O
O
NaH, BnCl,
DMF, rt, 4h
OH
AcHN
OBn
O
NH2
NH2
.
O
TamifluTM (1)
Oseltamivir phosphate
2
3
(6)
O
OH
EtO2C
P(O)(OEt)2
HO
O
NaIO4, EtOH,
O
H
O
O
OHC
OH
OBn
OBn
OBn
H2O, rt, 1 h,
30% for 4 steps
D-Mannose
O
O
O
O
O
O
O
O
4
(8)
7
( )
10
8
Fig. 1. Retrosynthetic analysis of oseltamivir phosphate (1) from D-mannose via 1,2-
amino hydroxy intermediate (2).
(EtO)2(O)P
CO2Et
O
OBn
TiCl4, Et3N, CH2Cl2,
H2, Pd-C, EtOH,
rt, 4 days
The synthesis started from D-mannose with protection of 2,3-
and 4,5-dihydroxy groups as the 3-pentylidene ketal 5 by reacting
with 3-pentanone in DMF and a catalytic amount of H2SO4
(Scheme 1). The anomeric position of 5 was protected as the a-
benzyl derivative 6 since it would be resistant to nucleophilic attack
and could be removed by hydrogenolysis under conditions, which
would not affect the phosphonoacetate ester groups. Mild acid
treatment removed the 5,6-acetal group of 6 to give benzyl 2,3-O-
O
(EtO)2(O)PCH2CO2Et,
0 oC, 2h, 51%
O
(9)
(E:Z ; 3:1)
O
O
EtO
P
CO2Et
OEt
O
EtO
isopentylidene-a-D-mannofuranoside (7) in good yield. Oxidation
NaH, THF,
of this compound with sodium periodate provided the in-
termediate aldehydo-compound 8, which was then condensed
with diethoxyphosphorylacetate in the presence of TiCl4 and Et3N
to give 9 in 51% yield.12 Upon hydrogenation of the double bond, the
benzyl protecting groups of 6 was removed to give the lactol 10,
which was treated with sodium hydride in THF to form shikimic
acid derivative 11 [52% from 9].13 Our strategy for the trans-
formation of 11 into the 1,2-diamino compound was different from
the reports in the literature.3 The secondary hydroxyl group of 11
was converted into an amino group by the following sequence of
reactions: oxidation with TEMPO and TCCA provided the corre-
sponding ketone, oxime formation and then reduction of oxime 12
OH
OH
O
0 oC to rt, 30 min,
52% for 2 steps
O
O
O
10
(
)
11
(
)
CO2Et
1) TEMPO, TCCA
CH2Cl2
NaBH4, MoO3,
MeOH, rt, 45 min
OH
2) NH2OH.HCl
pyridine, EtOH
N
O
92%
O
72 % for 2 steps
(12)
with NaBH4 catalyzed by MoO3 gave 5
a-amino ketal 13a in good
yield.11a
CO2Et
1.Et3SiH, TiCl4, CH2Cl2,
-78 o to -10 oC,16 h
Regioselective reductive ring opening of the 5-amino ketal 13a
was best performed by employing a highly selective protocol
(Et3SiH and TiCl4 in CH2Cl2 at ꢀ78 to ꢀ10 ꢁC) reported by scientists
at Roche in the shikimic acid route.3 However the hydroxyl amino
product was found difficult to separate by column chromatography.
Protection of the amino with Boc makes chromatographic separa-
tion of the Boc product 14b much easier (Scheme 1).11a It is in-
teresting to note that when the amino group of acetal 13a was
protected by an electron-withdrawing group (13b, 13c, 13d),
cleavage of the ketal group by the same reagents and reaction
condition gave either the other regioisomer15b (entry 4) or a mix-
ture of both isomers (14þ15) (Table 1, entries 5, 6), whereas un-
protected amino (13a) or protected with an electron donating
group 13e, only the isomers 14a and 14e were obtained (entries1, 2
and 7).
O
CO2Et
NH2
O
HO
2. Boc2O,MeOH, rt, 2h
66% for 2 steps
O
NHBoc
(14b)
(13a)
Scheme 1. Synthesis of 5
intermediate (14b).
a-amino shikimic acid ester (13a) and 1,2-amino hydroxy
The selectivity of 13a and 13e could be explained by the binding
ability of the amino group and the nearby oxygen of the ketal with
the metal catalyst [see Fig. 2]. In the case of 13b, 13c and 13d, the
amino group carried an electron-withdrawing substituent making
it less basic therefore the binding ability to the metal was reduced
and created steric hindrance to the oxygen atom at the C4 position

N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
6805
Table 1
Reductive cleavage of 3,4-O-pentylidene ketal of cyclohexene carboxylate derivatives
CO2Et
CO2Et
NHR
CO2Et
NHR
Conditions
O
O
HO
see Table 1
O
HO
O
NHR
14
15
13a: R = H
13b
: R =Boc
13c: R = Ts
13d
: R = Ac
13e: R= Bn
Entry
Substrates
Reaction conditions
Products (%)
Acid
Reductant
Solvents
Temp (ꢁC)
3-O-Pentyl ether type (14)
4-O-Pentyl ether type (15)
1
2
3
4
5
6
7
13a
13a
13a
13b
13c
13d
13e
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ34
50
70
d
d
ꢀ78 to ꢀ10
ꢀ78 to ꢀ10
ꢀ34
No reaction
d
50
20
21
d
ꢀ34
30
14
60
ꢀ34
ꢀ34
3. Conclusion
H
CO2Et
O
In conclusion we have accomplished an efficient synthesis of
oseltamivirphosphate in 11 steps with 2.9% overall yield, using cheap
and abundant D-mannose as a starting material. The key features of
the synthesis include formation of the shikimic acid ester by intra-
molecular HornereWadswortheEmmons reaction and introduction
of the pentyl ether by regioselective ring opening of pentylidene
O
NH2
Cl
Ti
Cl
ketal. The synthetic route from D-mannose provided an economical
Fig. 2. Transition state of 5a-NH2 pentylidene cleavage by TiCl4.
and practical alternative for the synthesis of oseltamivir phosphate.
thus preventing binding with the Lewis acid catalyst, which
resulted in poor regioselectivity (entries 5 and 6) or inversed
regioselectivity ring opening of the ketal (entry 4).
4. Experimental
4.1. General
To transform the hydroxy amino compound 14b into the pro-
tected 1,2-diamino carboxylate 17, the hydroxyl group was acti-
vated as a triflate and was used in the next step without purification
due to its instability (Scheme 2). The triflate underwent SN2 dis-
placement with sodium azide in acetone/water (9:1) providing the
azido amine 16 in good yield. The azide group of 16 was trans-
formed directly to acetamide by treatment with thioacetic acid, 2,6-
lutidine in chloroform at reflux to afford 17 (44%, three steps from
14b).14 Finally the Boc protecting group of 17 was removed with TFA
in CH2Cl2 to form an amine, which was directly exposed to 1.2 equiv
of phosphoric acid in EtOH at 55 ꢁC to afford oseltamivir phosphate
1 in 75% yield (two steps).
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 immedi-
ately prior to use. Tetrahydrofuran was distilled from sodium and
benzophenone under nitrogen atmosphere. Triethylamine, pyridine
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, concen-
tration under reduced pressure refers to a rotaryevaporator at water
aspirator pressure. Analytical thin-layer chromatography (TLC) was
conducted using MERCK precoated TLC plates (silica gel 60 F254).
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 obtained using either
a VARIANunity INOVA 400 MHz spectrometer or a Brucker ADVANCE
CO2Et
1. Tf2O, Py,
AcSH,
CH2Cl2, -10 o
C
2,6-lutidine,
(14b)
2. NaN3,
acetone:H2O
(9:1), rt
O
NHBoc
CHCl3, reflux
N3
300 MHz spectrometer. Chemical shifts were recorded as d values in
(16)
parts per million. Spectra were acquired in CDCl3 unless otherwise
stated. The peak due to residual CHCl3 (7.26 ppm for 1H and 77.2 ppm
for 13C) was used as the internal reference. Coupling constant (J)
values were given in hertz, and multiplicity was defined as follows:
br¼broad, s¼singlet, d¼doublet, dd¼double of doublets, dt¼double
of triplet, t¼triplet, q¼quartet, and m¼multiplet. Infrared (IR)
spectra were recorded in cmꢀ1 on a PerkineElmer 2000 Fourier
transform infrared spectrophotometer at Chemistry Department,
Faculty of Science, Kasetsart University. Samples were analyzed as
CO2Et
1. TFA, CH2Cl2, rt
1
O
NHBoc
NHAc
2. H3PO4, EtOH
55 oC
(17)
Scheme 2. Completion of the synthesis of oseltamivir phosphate 1.

6806
N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
KBr disks. The high resolution mass spectra (HRMS) were recorded
on Q-TOF2 hybrid quadrupole time-of-flight mass spectrometer.
Melting points (mp) were determined on Fisher John apparatus and
MEI-TEMP capillary melting point apparatus at Chemistry De-
partment, Facultyof Science, Kasetsart Universityand were reported
uncorrected in degrees Celcius (ꢁC).
purification by flash column chromatography on silica gel (hexane/
ethyl acetate: 80:20) gave a colorless oil (2.16 g, 70%); Rf (30%
EtOAc/hexane) 0.2; FTIR (liquid film), nmax, cmꢀ1: 3417, 3089, 3064,
3031, 2971, 2939, 2881, 1462, 1454; 1H NMR (CDCl3, 400 MHz),
d
0.80, 0.84 (t, J¼7.5 Hz, 2ꢃ 3H, H-10, H-11), 1.51, 1.64 (q, J¼7.5,
15.2 Hz, 2ꢃ 2H, H-8, H-9), 2.09, 2.81 (2ꢃ br s, 2ꢃ 1H, eOH), 3.58
(dd, J¼3.6, 11.4 Hz, 1H, H-6), 3.74 (dd, J¼3.0, 11.4 Hz, 1H, H-6), 3.74
(dd, J¼3.6, 8.1 Hz, 1H, H-4), 3.97e3.99 (m, 1H, H-5), 4.42 (d,
J¼11.9 Hz, 1H, eOCH2Ph), 4.54 (d, J¼11.9 Hz, 1H, eOCH2Ph), 4.58 (d,
J¼6 Hz, 1H, H-2), 4.76 (dd, J¼3.6, 6 Hz, 1H, H-3), 5.05 (s, 1H, H-1),
4.1.1. 2,3:5,6-Di-O-isopentylidene-5-a-D-mannofuranose (5). D-Man-
nose (3.60 g, 20.0 mmol) was dissolved in DMF (30 mL) and then 3-
pentanone (40 mL) was added into the solution. Concd sulfuric acid
(1 mL) was slowly added into the mixture and it was stirred for 5 h
at the room temperature. After that the pH of the solution was
adjusted to be neutral by using 10% aq sodium carbonate (30 mL)
and then extracted with dichloromethane. The organic layer was
collected and the solvent was removed under reduced pressure to
afford crude 5 (4.12 g) as a pale yellow oil, which was used in the
next step without further purification. For analysis data: purifica-
tion by flash column chromatography on silica gel (hexane/ethyl
acetate: 80:20) gave a pale yellow oil (4.11 g, 65%); Rf (20% EtOAc/
7.21e7.29 (m, 5H, eOCH2Ph); 13C NMR (CDCl3, 100 MHz),
d 7.7, 8.7
(C-10, C-11), 28.7, 28.8 (C-8, C-9), 64.4 (C-6), 69.2 (eOCH2Ph), 70.3
(C-5), 79.5 (C-4), 80.4 (C-3), 85.2 (C-2), 105.9 (C-1), 116.9 (Cq1), 27.8,
127.9, 128.0, 128.4, 128.4 (eOCH2Ph), 137.4 (Cq); (ESI-TOF) m/z:
[MþNa]þ calcd for C18H26O6: 361.1627, found: 361.1613.
4.1.4. Benzyl-2,3-O-isopentylidene-5-a-D-aldomannofurano-side
(8). To a solution of sodium periodate (5.13 g, 24.0 mmol) in eth-
anol (10 mL) and water (50 mL) was added a solution of crude 7
(2.22 g) in ethanol (40 mL) at room temperature. The resulting
mixture was stirred for 1 h. The white precipitate was filtered and
then a few drops of ethylene glycol were added into the filtrate. The
white precipitate was filtered again and the filtrate was concen-
trated. Then ethanol was added into the residue and the white
precipitate was filtered and repeated until no precipitation oc-
curred. The combined filtrates were concentrated under reduced
pressure to give a colorless oil. Purification of the residue by flash
column chromatography on silica gel (ethyl acetate/hexane, 5:95)
gave 8 (1.84 g, 30% for four steps) as a colorless oil; Rf (10% EtOAc/
hexane) 0.2; ½a 2D5
ꢂ
þ17.38 (c 0.29, CHCl3); FTIR (liquid film), nmax
,
:
cmꢀ1: 3429, 2973, 2942, 2883, 1463; 1H NMR (CDCl3, 400 MHz),
d
0.78e0.86 (m, 12H, eCH3), 1.49e1.65 (m, 8H, eCH2e), 3.52 (br s, 1H,
eOH), 3.88 (dd, J¼6.1, 8.4 Hz,1H, H-6), 4.03 (dd, J¼6.4, 8.4 Hz,1H, H-
6), 4.08 (dd, J¼3.4, 7.0 Hz,1H, H-4), 4.34 (dd, J¼6.4, 13.1 Hz,1H, H-5),
4.52 (d, J¼5.9 Hz, 1H, H-2), 4.71 (dd, J¼3.4, 5.8 Hz, 1H, H-3), 5.28 (d,
J¼2.4 Hz, 1H, H-1); 13C NMR (CDCl3, 100 MHz),
d: 7.6, 7.7, 7.8, 7.9 (C-
10, C-11, C-15, C-16), 28.6, 28.6, 28.6, 28.6 (C-8, C-9, C-13, C-14), 67.2
(C-6), 72.8 (C-5), 77.3 (C-3), 80.0 (C-4), 85.9 (C-2), 101.4 (C-1), 112.8
(Cq), 116.8 (Cq); (ESI-TOF) m/z: [MþNa]þ calcd for C16H28O6:
339.1784, found: 339.1783.
hexane) 0.5; ½a 2D5
ꢂ
þ47.02 (c 0.14, CH2Cl2); FTIR (liquid film), nmax
,
cmꢀ1: 3089, 3064, 3031, 2972, 2940, 2881, 2733, 2363, 1739, 1462,
4.1.2. Benzyl 2,3:5,6-di-O-isopentylidene-5-
a-D
-mannofurano-side
1455.1H NMR (CDCl3, 400 MHz),
d
0.77, 0.79 (t, J¼7.8 Hz, 2ꢃ 3H, H-
(6). A solution of 5 (4.12 g) in dry DMF (15 mL) was added into
a cooled mixture of 60% sodium hydride (1.20 g, 30.0 mmol), washed
with tetrahydrofuran, in dry DMF (15 mL) under a nitrogen atmo-
sphere. Benzyl chloride (5.50 mL, 48 mmol) was slowly added into
the mixture and the mixture was stirred for 4 h at room tempera-
ture. Then dichloromethane was added into the solution and the
mixture was extracted with water. The organic layer was collected
and concentrated to afford crude 6 (3.76 g) as a pale yellowoil, which
was used in the next step without further purification. For analysis
data: purification by flash column chromatography on silica gel
(hexane/ethyl acetate: 95:5) gave a pale yellow oil (3.70 g, 70%); Rf
10, H-11), 1.51, 1.64 (q, J¼7.8 Hz, 2ꢃ 2H, H-8, H-9), 3.97e3.99 (m, 1H,
H-5), 4.36 (d, J¼4.1 Hz, 1H, H-4), 4.45 (d, J¼11.7 Hz, 1H, eOCH2Ph),
4.62 (d, J¼11.7 Hz, 1H, eOCH2Ph), 4.62 (d, J¼5.9 Hz, 1H, H-2), 5.01
(dd, J¼4.1, 5.8 Hz, 1H, H-3), 5.22 (s, 1H, H-1), 7.21e7.29 (m, 5H,
eOCH2Ph), 9.63 (s, 1H, H-5); 13C NMR (CDCl3, 100 MHz),
d 7.4, 8.3
(C-10, C-11), 28.6, 29.0 (C-8, C-9), 69.3 (-OCH2Ph), 81.2 (C-3), 84.5
(C-4), 85.0 (C-2), 105.8 (C-1), 117.7 (Cq), 128.5, 128.5, 128.5, 128.5,
128.5 (Ph), 136.8 (Cq), 197.5 (C-5); HRMS (ESI-TOF) m/z [MþH]þ
calcd for C17H22O5: 307.1467, found: 307.1545.
4.1.5. Ethyl(benzyl-5,6-dideoxy-6-diethoxyphosphoryl-2,3-O-iso-
pentylidene-a-D-lyxoheptofuranoside) uronate (9). TiCl4 (0.43 mL,
(10% EtOAc/hexane) 0.5; ½a D25
ꢂ
þ61.4 (c 0.09, CH2Cl2); FTIR (liquid
film), nmax, cmꢀ1: 3088, 3064, 3031, 2973, 2940, 2881,1462; 1H NMR
3.92 mmol) was added into a cooled solution of triethylphospho-
noacetate (1 mL, 5.22 mmol) in CH2Cl2 (18 mL) then a solution of
triethylamine (1.60 mL, 11.4 mmol) in CH2Cl2 (3.5 mL) was added
into the mixture and stirred for 30 min at 0 ꢁC under a nitrogen
atmosphere. A solution of 8 (1.00 g, 3.26 mmol) in CH2Cl2 (3 mL)
was added into the reaction mixture and stirred for 2 h at 0 ꢁC.
Water was added to the mixture, which was then extracted with
CH2Cl2 and washed with satd aq sodium bicarbonate. The com-
bined organic phase was washed with water, brine, dried (Na2SO4),
and concentrated. Purification of the residue by flash column
chromatography on silica gel (ethyl acetate/hexane, 15:85) gave
unsaturated phosphonate ester 9 (0.853 g, 51%) as a pale yellow oil;
(CDCl3, 400 MHz),
d 0.77e0.87 (m, 12H, eCH3), 1.47e1.64 (m, 8H,
eCH2e), 3.81 (dd, J¼8.4, 6.0 Hz, 1H, H-6), 3.90 (dd, J¼7.2, 3.4 Hz, 1H,
H-6), 4.03 (dd, J¼8.4, 6.5 Hz,1H, H-4), 4.34 (dd, J¼6.4,13.8 Hz,1H, H-
5), 4.40 (d, J¼11.9 Hz, 1H, eCH2Ph), 4.54 (d, J¼11.6 Hz, 1H, eCH2Ph),
4.57 (d, J¼5.8 Hz, 1H, H-2), 4.69 (dd, J¼3.4, 5.9 Hz, 1H, H-3), 5.00 (s,
1H, H-1), 7.20e7.28 (m, 5H, ePh); 13C NMR (CDCl3, 100 MHz),
d 7.7,
7.9, 8.1, 8.3 (C-10, C-11, C-15, C-16), 28.8, 28.8, 29.2, 29.6 (C-8, C-9, C-
13, C-14), 67.4 (C-6), 69.0 (eCH2Ph), 73.1 (C-5), 79.9 (C-4), 80.8 (C-3),
85.4 (C-2),105.9 (C-1),112.8 (Cq),116.8 (Cq),127.7,127.7,127.9,127.9,
128.4 (ePh),137.3 (Cq); (ESI-TOF) m/z: [MþNa]þ calcd for C23H34O6:
429.2253, found: 429.2253.
Rf (50% EtOAc/hexane) 0.3; ½a D25
ꢀ4.10 (c 0.18, CH2Cl2); FTIR (KBr)
ꢂ
4.1.3. Benzyl 2,3-O-isopentylidene-5-a-D-mannofuranoside (7). To
nmax, cmꢀ1: 3089, 3064, 3031, 2977, 2939, 1720, 1463, 1455; 1H NMR
a cooled solution of 6 (3.76 g) in methanol (70 mL) was added concd
hydrochloric acid (1 mL). This solution was diluted with water and
stirred for 3 h at room temperature. Then the reaction mixture was
neutralized by addition of concd aq ammonia solution. The solvent
was removed and the residue was extracted with dichloromethane
and water. The organic layer was collected and concentrated in
vacuo to afford 7 (2.22 g) as a colorless oil. The crude diol 7 was
used in the next step without further purification. For analysis data:
(CDCl3, 400 MHz),
d
0.75, 0.82 (t, J¼7.4 Hz, 2ꢃ 3H, H-10, H-11),
1.23e1.32 (m, 9H, eOCH2CH3), 1.44,1.58 (q, J¼7.5 Hz, 2ꢃ 2H, H-8, H-
9), 4.03e4.25 (m, 6H, eOCH2CH3), 4.39 (d, J¼11.8 Hz,1H, eOCH2Ph),
4.59 (d, J¼11.8 Hz, 1H, eOCH2Ph), 4.59 (d, J¼5.8 Hz, 1H, H-2), 4.94
(dd, J¼3.8, 5.8 Hz, 1H, H-3), 5.06e5.07 (m, 1H, H-4), 5.08 (s, 1H, H-
1), 7.08, 7.10 (d, J¼6.1 Hz, 1H, H-5), 7.19e7.28 (m, 5H, eOCH2Ph)
ppm; 13C NMR (CDCl3, 100 MHz),
d 7.5, 8.3 (C-10, C-11), 14.0, 16.1,
16.2 (eOCH2CH3), 28.7, 29.0 (C-8, C-9), 61.4 (COOCH2CH3), 62.6a,

N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
6807
62.6b, 62.6a, 62.7b (Pe(OCH2CH3)2), 68.8 (eOCH2Ph), 78.8a, 79.0b (C-
4), 82.2a, 82.2b (C-3), 85.2 (C-2), 105.6 (C-1), 116.8 (Cq), 126.2, 126.4
(d, J¼190 Hz, CeP coupling, C-6), 127.7, 127.9, 127.9, 128.0, 128.0
(Ph), 137.1 (Cq), 155.2a, 155.2b (C-5), 163.8 (Cq) ppm; HRMS (ESI-
TOF) m/z [MþH]þ calcd for C25H37O9P: 513.2253, found: 513.2252.
(t, J¼7.2 Hz, 3H), 1.63e1.65 (m, 4H), 3.00 (d, J¼21.6 Hz, 1H), 3.81 (d,
J¼21.6 Hz, 1H), 4.25 (q, J¼7.2 Hz, 2H), 4.69 (d, J¼5.4 Hz, 1H), 4.85 (s,
1H), 6.80 (s,1H),13C NMR (100 MHz, CDCl3)
d 8.0, 8.1,14.0, 20.8, 29.5,
30.3, 61.1, 73.4, 73.5,114.3,126.8,135.6,152.5,166.1; HRMS (ESI-TOF)
m/z [MþH]þ calcd for C14H22NO5: 284.1498, found: 284.1498.
4.1.6. Ethyl(benzyl-5,6-dideoxy-6-diethoxyphosphoryl-2,3-O-iso-
4.1.9. Ethyl-3,4-O-isopentylidene-5a-amino shikimate (13a). To
pentylidene-
a
-
D
-lyxoheptofuranosid) uronate (10). PdeC 5% (48 mg)
a mixture of oxime 12 (511 mg, 1.73 mmol) and MoO3 (344 mg,
2.39 mmol) in MeOH (17 mL) was added NaBH4 (654 mg,17.3 mmol)
portionwise. An exothermic reaction occurred with vigorous gas
evolution. The reaction mixture was stirred at room temperature for
30 min or until complete by TLC. To the reaction mixture was added
brine and the precipitate was filtered off. The filtrate was extracted
with EtOAc (3ꢃ10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure to give
amine 13a (448 mg, 92%) as a yellow-brown oil.11b Rf (5% MeOH/
CH2Cl2) 0.29; FTIR (KBr), nmax, cmꢀ1: 3364, 2974, 1718, 1651, 1463,
was added into a solution of unsaturated phosphonate ester 9
(300 mg, 0.59 mmol) in ethanol (9 mL). The mixture was stirred for
5 days under a hydrogen atmosphere at room temperature. The
mixture was filtered through Celite and removal of the solvent
afforded crude 10 (300 mg) as a pale yellow oil, which was used in
the next reaction without further purification.
4.1.7. Ethyl-3,4-O-isopentylidene-5a-hydroxy shikimate (11). A so-
lution of 10 (300 mg) in tetrahydrofuran (1.5 mL) was added into
a cooled mixture of 60% sodium hydride (35.1 mg, 1.46 mmol) in
tetrahydrofuran (1 mL) at 0 ꢁC under a nitrogen atmosphere. The
reaction mixture was warmed up to room temperature and stirred
for 45 min 1 M aq sodium dihydrogenphosphate was added into the
solution and extracted with CH2Cl2. The combined organic phases
were washed with water, brine, dried (Na2SO4), and concentrated.
Purification of the residue by flash column chromatography on
silica gel (ethyl acetate/hexane, 20:80) gave protected shikimate
(11) (82 mg, 52% for two steps) as a solid (recrystallized from
heptanes; mp 59e61 ꢁC) (reported mp 60e62 ꢁC);13 Rf (30% EtOAc/
hexane) 0.33; FTIR (KBr), nmax, cmꢀ1: 3435, 2977, 1723, 1652; 1H
1246; 1H NMR (400 MHz, CDCl3)
d
0.75 (t, J¼7.5 Hz, 3H), 0.85 (t,
J¼7.5 Hz, 3H), 1.23 (t, J¼7.2 Hz, 3H), 1.50 (q, J¼7.5 Hz, 2H), 1.58e1.60
(m, 2H), 2.12e2.14 (m,1H), 2.51 (dt, J¼5.2,11.9 Hz,1H), 2.94e2.96 (m,
1H), 4.14 (q, J¼7.2 Hz, 2H), 4.26 (d, J¼4.9 Hz, 1H), 4.65e4.67 (m, 1H),
6.66 (t, J¼2.8 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 7.9, 8.4,14.1, 28.7,
29.5, 30.0, 49.3, 60.8, 73.1, 76.6,113.1,130.5,134.9,166.5; HRMS (ESI-
TOF) m/z [MþH]þ calcd for C14H24NO4: 270.1705, found: 270.1705.
4.1.10. Ethyl-3-(1-ethyl-propoxy)-5a-butoxycarbonylamino shikima-
te (13b). To a solution of 12 (627 mg, 2.23 mmol) in MeOH (10 mL)
was added Boc2O (585 mg, 2.68 mmol) and stirred at room tem-
perature for 3 h. The solvent was removed under reduced pressure.
The crude product was purified by flash column chromatography
(silica gel, EtOAc/hexane,1:4) to give 13b (590 mg, 70%) as a colorless
NMR (CDCl3, 400 MHz),
d
0.82, 0.85 (t, J¼7.4 Hz, 2ꢃ 3H, H-10, H-11),
1.23 (t, J¼7.1 Hz, 3H, eOCH2CH3), 1.60 (q, J¼7.5 Hz, 4H, H-8, H-9),
2.01 (br s, 1H, eOH), 2.17 (dd, J¼8.2, 17.6 Hz, 1H, H-6), 2.71 (dd,
J¼4.5,17.6 Hz,1H, H-6), 3.82e3.87 (m,1H, H-5), 4.04 (t, J¼7.1 Hz,1H,
H-4), 4.15 (q, J¼7.1 Hz, 2H, eOCH2CH3), 4.68e4.70 (m, 1H, H-3),
oil; ½a 2D5
ꢂ
þ17.26 (c 0.24, CHCl3); FTIR (KBr), nmax, cmꢀ1: 3362, 2976,
1714,1653,1504,1242; 1H NMR (400 MHz, CDCl3)
d
0.74 (t, J¼7.5 Hz,
6.85e6.87 (m, 1H, H-2); 13C NMR (100 MHz, CDCl3)
d
7.8, 8.5 (C-10,
3H), 0.84 (t, J¼7.5 Hz, 3H),1.23 (t, J¼7.1 Hz, 3H),1.39 (s, 9H),1.55e1.58
(m, 4H), 2.09e2.11 (m, 1H), 2.62 (dd, J¼11.5, 5.1 Hz, 1H), 3.84e3.86
(m, 1H), 4.14 (q, J¼7.1 Hz, 2H), 4.29e4.30 (m, 1H), 4.68, 4.69 (m, 1H),
4.95 (d, J¼9.4 Hz, 1H), 6.66 (t, J¼3.4 Hz, 1H); 13C NMR (100 MHz,
C-11), 14.1 (OeCH2CH3), 29.1, 29.3 (eCH2CH3), 29.6 (C-6), 61.0
(OeCH2CH3), 68.8 (C-5), 72.2 (C-3), 77.8 (C-4), 113.6 (C-7), 130.3 (C-
1), 134.0 (C-2), 166.2 (eCOe); HRMS (ESI-TOF) m/z [MþH]þ calcd
for C14H23O5: 271.1545, found: 271.1548.
CDCl3) d 7.9, 8.4, 14.1, 27.4, 28.4, 29.6, 30.1, 48.1, 60.9, 72.9, 74.7, 79.7,
113.6, 130.2, 134.8, 155.2, 166.3; HRMS (ESI-TOF) m/z [M]þ calcd for
4.1.8. Ethyl-3,4-O-isopentylidene-5-hydroxylamine shikimate (12).
To a cooled suspension of trichloroisocyanuric acid (3.44 g,
14.8 mmol) in CH2Cl2 (38 mL) was added TEMPO (11.6 mg,
0.07 mmol) followed by a solution of alcohol 11 (2.00 g, 7.41 mmol)
in CH2Cl2 (5 mL). The mixture was stirred at room temperature for
45 min. After this time, the reaction mixture was filtered through
Celite and concentrated under reduced pressure. The crude ketone
was used in the next step without further purification. For spec-
troscopic data: the crude ketone was purified by flash column
chromatography (20:80, EtOAc/hexane) (The pure compound is not
quite stable); FTIR (liquid film), nmax, cmꢀ1: 2976, 1720, 1659, 1463,
C19H31NO6: 369.2151, found: 369.2153.
4.1.11. Ethyl-3-(1-ethyl-propoxy)-5a-p-toluenesulfonylamino shiki-
mate (13c). To a solution of 13a (273 mg, 0.84 mmol) in pyridine
(1.0 mL) was added DMAP (150 mg, 1.27 mmol) followed by TsCl
(225 mg, 1.69 mmol). The reaction mixture was stirred at room
temperature for 12 h. EtOH was added and the mixture was
evaporated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, EtOAc/hexane, 1:4) to give
13c (284 mg, 80%) as a colorless oil; ½a D25
þ16.11 (c 0.53, CHCl3);
ꢂ
FTIR (KBr), nmax, cmꢀ1: 3309, 2979, 1716, 1442, 1330, 1257; 1H NMR
1251; 1H NMR (400 MHz, CDCl3)
d
0.81 (t, J¼7.5 Hz, 3H), 0.85 (t,
(400 MHz, CDCl3)
d
0.70 (t, J¼7.4 Hz, 3H), 0.75 (t, J¼7.4 Hz, 3H), 1.20
J¼7.5 Hz, 3H), 1.25 (t, J¼7.1 Hz, 3H), 1.59e1.62 (m, 4H), 3.10e3.17
(dm, J¼19.5 Hz, 1H), 3.29e3.36 (dt, J¼19.5, 1.8 Hz, 1H), 4.18 (q,
J¼7.1 Hz, 2H), 4.38 (d, J¼6.5, 1H), 4.99e5.00 (m, 1H), 6.83e6.89 (m,
(t, J¼7.1 Hz, 3H), 1.45 (q, J¼7.4 Hz, 4H), 2.08e2.10 (m, 1H), 2.36 (s,
3H), 2.44e2.45 (m, 1H), 3.52e3.54 (m, 1H), 4.01e4.03 (m, 1H), 4.10
(dq, J¼7.1, 0.8 Hz, 2H), 4.53e4.58 (m, 1H, H-3), 5.03 (d, J¼9.8 Hz,
1H), 6.61 (t, J¼3.3 Hz, 1H), 7.27 (dd, J¼8.3, 0.45 Hz, 2H), 7.71 (d,
1H), 13C NMR (100 MHz, CDCl3)
d 8.0, 8.2, 14.0, 29.2, 29.9, 36.5, 61.4,
75.9, 77.4, 115.5, 129.1, 133.7, 165.0, 203.2.
J¼8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 7.9, 8.3, 14.1, 21.5, 25.8,
To the crude ketone (7.41 mmol) in EtOH (14 mL) was added
hydroxylamine hydrochloride (1.43 g, 14.8 mmol) followed by pyr-
idine (14 mL). The reaction mixture was stirred at room temperature
for 2 h. The solution was poured into water and extracted with
CH2Cl2 (3ꢃ50 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude oxime 12 was purified by (20:80, EtOAc/hexane) to give 12
(1.55 g, 71%, two steps); as a yellowoil;11b Rf (5% MeOH/CH2Cl2) 0.56;
FTIR (liquid film), nmax, cmꢀ1: 3382, 2976, 1716, 1661, 1241; 1H NMR
29.4, 30.0, 51.2, 61.0, 72.7, 74.2,113.7,126.9,129.7,129.8,134.6,138.4,
143.6, 165.9, HRMS (ESI-TOF) m/z [M]þ calcd for C21H29NO6S:
423.1716, found: 423.1718.
4.1.12. Ethyl-3-(1-ethyl-propoxy)-5a-acetamide shikimate (13d). To
a solution of 13a (335 mg,1.19 mmol) in pyridine (2.5 mL) was added
DMAP (29 mg, 0.24 mmol) followed by Ac2O (0.23 mL, 2.38 mmol).
The reaction mixture was stirred at room temperature for 3 h. Satd
aq NaHCO3 was added and the mixture was extracted with EtOAc
(3ꢃ20 mL). The combined organic layers were dried (Na2SO4),
(400 MHz, CDCl3)
d
0.85 (t, J¼7.5 Hz, 3H), 0.93 (t, J¼7.5 Hz, 3H), 1.33

6808
N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
filtered, and concentrated under reduced pressure. Traces of Ac2O
and pyridine were removed by co-evaporation with a mixture of
toluene and ethanol. The crude product was purified by flash col-
umn chromatography (silica gel, EtOAc/hexane, 1:1) to give 13d as
an oil (336 mg, 87%); FTIR (KBr), nmax, cmꢀ1: 3283, 2976, 1714, 1659,
J¼5.3, 12.1 Hz, 1H), 2.91 (q, J¼5.9, 2.5 Hz, 1H), 3.35 (q, J¼5.7 Hz, 1H),
3.93e2.95 (m, 1H), 4.02e4.04 (m, 1H), 4.13 (q, J¼7.2 Hz, 2H), 6.60 (s,
1H); 13C NMR (100 MHz, CDCl3)
d 9.4, 9.7, 14.2, 26.1, 26.3, 29.7, 49.7,
60.7, 69.8, 74.4, 81.6, 130.6, 135.8, 166.4; HRMS (ESI-TOF) m/z
[MþH]þ calcd for C14H25NO4: 272.1862, found: 272.1865.
1538, 1463, 1243; 1H NMR (400 MHz, CDCl3)
d
0.77 (t, J¼7.5 Hz, 3H),
To a solution of 14a (7.12 mmol) in MeOH (30 mL) was added
Boc2O (2.33 g, 10.7 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,
4:1 ethyl acetate/hexane) to give 14b (2.72 g, 66%, two steps) as
0.85 (t, J¼7.5 Hz, 3H),1.24 (t, J¼7.2 Hz, 3H),1.51e1.53 (m, 2H),1.59 (q,
J¼7.5 Hz, 2H), 2.11e2.13 (m, 1H), 1.99 (s, 3H), 2.62 (dd, J¼5.1, 11.1 Hz,
1H), 4.15 (q, J¼7.2 Hz, 1H), 4.22e4.24 (m, 1H), 4.28e4.30 (m, 1H),
4.71e4.73 (m, 1H), 6.01 (d, J¼8.7 Hz, 1H), 6.69 (t, J¼3.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d
7.9, 8.3,14.1, 23.2, 24.8, 29.6, 30.0, 46.5, 60.9,
a yellow solid; Rf (35% EtOAc/hexane) 0.56; ½a D25
ꢀ38.35 (c 0.53,
ꢂ
72.8, 74.3, 113.6, 130.0, 134.8, 166.1, 169.6; HRMS (ESI-TOF) m/z [M]þ
CHCl3) (reported ½a D20
ꢂ
ꢀ52.5 (c 1.0, CHCl3));11a,15 FTIR (KBr), nmax
,
calcd for C16H25NO5: 311.1733, found: 311.1731.
cmꢀ1: 3390, 2973, 1714, 1505, 1246; 1H NMR (400 MHz, CDCl3)
d
0.91 (t, J¼7.4 Hz, 6H), 1.27 (t, J¼7.2 Hz, 3H), 1.43 (s, 9H), 1.54e1.60
4.1.13. Ethyl-3-(1-ethyl-propoxy)-5
a-benzylamino shikimate (13e).
(m, 4H), 2.30e2.35 (m, 1H), 2.51 (br s, 1H), 2.57 (dd, J¼11.8, 5.7 Hz,
1H), 3.40 (q, J¼5.7 Hz, 1H), 3.85 (q, J¼9.1, 6.1 Hz, 1H), 4.13 (s, 1H),
4.02 (s, 1H), 4.18 (q, J¼7.2 Hz, 2H), 5.16 (d, J¼8.1 Hz, 1H), 6.65 (s, 1H);
To a solution of 13a (555 mg, 1.98 mmol) in DMF (10 mL) was added
Cs2CO3 (641 mg,1.98 mmol) followed by addition of benzyl bromide
(0.33 mL, 1.98 mmol). The reaction mixture was stirred at room
temperature for 20 min. Water was added and the mixture was
extracted with CH2Cl2 (3ꢃ15 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(silica gel, EtOAc/hexane,1:20) to give 13e (75 mg,10%) as a colorless
oil and N,N-dibenzyl pentylidene acetal (226 mg, 30%).
13C NMR (100 MHz, CDCl3)
d 9.6, 14.1, 26.0, 26.2, 27.0, 28.3, 48.6,
68.0, 73.7, 79.5, 81.6, 130.5, 135.6, 155.4, 166.1; HRMS (ESI-TOF) m/z
[MþNa]þ calcd for C19H33NNaO6: 394.2206, found: 394.2209.
4.2.2. Ethyl (3R,4R,5S)-3-(1-ethyl-propoxy)-4-azido-5-
butoxycarbonylamino-cyclohex-1-ene-1-carboxylate (16). To a solu-
tion of 14b (0.62 g,1.67 mmol) and pyridine (0.27 mL, 3.33 mmol) in
dry CH2Cl2 (8.5 mL) at ꢀ10 ꢁC under a nitrogen atmosphere was
added dropwise trifluoromethanesulfonic anhydride (0.33 mL,
1.83 mmol). The mixture was stirred at 0 ꢁC for 30 min. To the
cooled reaction mixture was added H2O (10 mL). The organic phase
was separated and aqueous phase was extracted with CH2Cl2
(3ꢃ30 mL). The combined organic phases were washed with satd
aq NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried
(Na2SO4), filtered, and evaporated to dryness. The residue was
dissolved in acetone/H2O (9:1; 5 mL) and NaN3 (0.12 g, 1.83 mmol)
was added to the solution. The reaction mixture was stirred at room
temperature for 15 h. The solvent was evaporated and the residue
was dissolved in EtOAc (50 mL). The organic phase was washed
with water (2ꢃ30 mL) and brine (30 mL). The aqueous phase was
extracted with EtOAc (50 mL) and the combined organic phases
were dried (Na2SO4), filtered, and evaporated to dryness. The crude
product 16 (0.83 g) was used in the next step without further pu-
Compound 13e. FTIR (KBr), nmax, cmꢀ1: 2974, 1712, 1653, 1462,
1364, 1242; 1H NMR (400 MHz, CDCl3)
d
0.73 (t, J¼7.5 Hz, 3H), 0.84
(t, J¼7.5 Hz, 3H), 1.21 (t, J¼7.1 Hz, 3H), 1.49 (q, J¼7.5 Hz, 2H),
1.57e1.59 (m, 2H), 2.05e2.07 (m, 1H), 2.68 (dd, J¼11.6, 4.9 Hz, 1H),
2.75e2.77 (m, 1H), 3.86 (q, J¼13.3, 15.7 Hz, 2H), 4.13 (q, J¼7.2 Hz,
2H), 4.38e4.60 (m, 1H), 4.58e4.60 (m, 1H), 6.62 (t, J¼3.4 Hz, 1H),
7.31e7.13 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 7.8, 8.4, 14.1, 25.5,
29.6, 30.0, 50.4, 53.8, 60.7, 73.0, 74.0, 113.0, 126.9, 128.0 (2), 128.3,
130.4, 135.0, 140.0, 166.6; HRMS (ESI-TOF) m/z [MþH]þ calcd for
C21H29NO4: 306.2175, found: 306.2176.
4.2. General procedure for reductive ring opening of
pentylidene ketal
To a solution of pentylidene ketal shikimate 13aed (1 mmol), in
CH2Cl2 (10 mL) at ꢀ40 ꢁC was added Et3SiH (0.16 mL, 1.32 mmol). A
solution of TiCl4 (0.12 mL, 1.12 mmol) in CH2Cl2 (2.5 mL) was added
dropwise at a rate such that the temperature of the reaction mixture
did not exceed ꢀ32 ꢁC. The reaction mixture was further stirred at
e40 ꢁC for 1 h. Then the reaction mixture was rapidly added to
a stirred ice/water mixture and extracted with CH2Cl2. The organic
layer was washed with satd aq NaHCO3, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by flash column chromatography to give the product.
rification. ½a 2D5
ꢂ
ꢀ47.89 (c 0.14, CHCl3) (reported½a D25
ꢀ61.2 (c 1.0,
ꢂ
CHCl3));15 1H NMR (400 MHz, CDCl3)
d
0.85 (t, J¼7.4, 3H), 0.87 (t,
J¼7.3, 3H), 1.22 (t, J¼7.1, 3H), 1.39 (s, 9H), 1.44e1.54 (m, 4H), 2.26
(ddd, J¼18.0, 8.6, 2.5 Hz, 1H), 2.70 (ddd, J¼18.0, 5.5, 1.5 Hz, 1H), 3.39
(quint, J¼5.7 Hz, 1H), 3.53 (dd, J¼9.6, 6.8 Hz, 1H), 3.74e3.76 (m, 1H),
3.93e3.95 (m, 1H), 4.52 (q, J¼7.1 Hz, 2H), 4.85 (d, J¼6.2 Hz, 1H,
NHAc), 6.70 (ddd, J¼3.7, 2.5, 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
9.4, 9.5, 14.2, 25.6, 26.2, 28.3, 30.2, 48.4, 61.0, 65.1, 75.3, 80.0, 82.1,
129.4, 135.8, 155.2, 165.9; HRMS (ESI-TOF) m/z [MþNa]þ calcd for
4.2.1. Ethyl (3R,4S,5S)-3-(1-ethyl-propoxy)-4-hydroxy-5-
butoxycarbonylamino-cyclohex-1-ene-1-carboxylate (14a). To a so-
lution of 13a (2.00 g, 7.12 mmol) in CH2Cl2 (20 mL) at ꢀ78 ꢁC was
added Et3SiH (1.50 mL, 9.26 mmol). A solution of TiCl4 (0.97 mL,
8.54 mmol) was added dropwise. The reaction mixture was
warmed to ꢀ10 ꢁC and stirred at this temperature for 6 h. TiCl4
(0.23 mL, 2.14 mmol) was added and stirred for 1 h. 10% aq NH4OH
(5 mL) was added and the suspension was filtered. The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (3ꢃ50 mL). The combined organic layers were dried
(Na2SO4) filtered, and concentrated under reduced pressure. The
crude amino alcohol was used in the next step without further
purification. For the spectroscopic data: the crude product was
purified by flash column chromatography (10:90, MeOH/CH2Cl2) to
give 14a as a yellow solid. Rf (10% MeOH/CH2Cl2) 0.0.32; 1H NMR
C19H32N4NaO5: 419.2270, found: 419.2265.
4.2.3. Ethyl (3R,4R,5S)-3-(1-ethyl-propoxy)-4-acetamido-5-
butoxycarbonylamino-cyclohex-1-ene-1-carboxylate (17). To a mix-
ture of crude 16 (0.83 g) and 2,6-lutidine (1.94 mL, 16.7 mmol) in
CHCl3 (3 mL) was added thioacetic acid (1.19 mL, 16.7 mmol) and
stirred for 5 h at reflux temperature. The solvent was evaporated
and the residue was purified by flash column chromatography
(1:99 MeOH/CH2Cl2) to give 17 (0.58 g, 71%) as a white solid; mp
145e146 ꢁC, Rf 0.3 (35% EtOAc/hexane) 0.2; ½a 2D5
ꢀ68.83 (c 0.32,
ꢂ
EtOH) (reported ½a D20
ꢂ
ꢀ21.54 (c 0.5, CHCl3));15 FTIR (KBr), nmax
,
cmꢀ1: 3312, 2958, 1714, 1685, 1246; 1H NMR (400 MHz, CDCl3)
d
0.81 (t, J¼7.6, 3H), 0.83 (t, J¼7.4, 3H), 1.22 (t, J¼7.1 Hz, 3H), 0.35 (s,
9H), 1.41e1.44 (m, 4H), 1.91 (s, 3H), 2.22 (ddd, J¼17.5, 9.8, 2.5 Hz,
1H), 2.67 (dd, J¼17.5, 5.2 Hz, 1H), 3.28 (quint, J¼5.7 Hz, 1H),
3.71e2.73 (m, 1H), 3.53 (d, J¼7.7 Hz, 1H), 4.00 (q, J¼9.2 Hz, 1H), 4.13
(dq, J¼7.1, 1.6 Hz, 2H), 5.04 (d, J¼9.0 Hz, 1H, NHBoc), 5.72 (d,
(400 MHz, CDCl3)
(t, J¼7.2 Hz, 3H), 1.48e1.51 (m, 4H), 2.19e2.21 (m, 1H), 2.46 (dd,
d
0.86 (t, J¼7.4 Hz, 3H), 0.87 (t, J¼7.4 Hz, 3H), 1.22

N. Chuanopparat et al. / Tetrahedron 68 (2012) 6803e6809
6809
J¼9.2 Hz, 1H, NHAc), 6.72 (dd, J¼2.3, 1.6 Hz, 1H), 13C NMR (100 MHz,
financial support from the TRF, 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 Re-
search and Development Institute (KURDI) are also gratefully
acknowledged.
CDCl3)
d 9.2, 9.5, 14.2, 23.4, 25.7, 26.1, 28.3, 31.0, 49.0, 54.4, 60.9,
75.9, 79.7, 82.2, 129.3, 137.6, 156.3, 166.0, 170.8; HRMS (ESI-TOF) m/z
[MþNa]þ calcd for C21H36N2NaO6: 435.2471, found: 435.2477.
4.2.4. Oseltamivir phosphate (1). To an ice-cooled solution of 17
(100 mg, 0.24 mmol) in CH2Cl2 (1 mL) was added TFA (0.24 mL,
3.23 mmol) and the reaction mixture was stirred at room temper-
ature for 1 h. The reaction mixture was cooled and diluted with
CH2Cl2 (5 mL), H2O (3 mL) and toluene (10 mL). The mixture was
evaporated and the residue was partitioned between water (30 mL)
and EtOAc (25 mL). The aqueous layer was extracted with EtOAc
(3ꢃ25 mL) and the combined organic layers were washed with satd
aq NaHCO3 (25 mL). The separated organic phase was dried
(Na2SO4), filtered, and evaporated to dryness. The residue was
dissolved in EtOH (1.5 mL) and 1.0 M H3PO4 in EtOH (0.29 mL,
0.29 mmol) was added to the stirred solution. The mixture was
warmed to 55 ꢁC until white crystals were formed. The mixture was
slowly cooled down to 0 ꢁC. The crystals were collected and washed
with acetone and hexane to yield 1 (0.08 g, 75%) as white crystals,
References and notes
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mp 200e201 ꢁC (dec). ½a 2D5
ꢂ
ꢀ31.59 (c 0.31, H2O) (reported½a D20
ꢂ
ꢀ31.7 (c 1.0, H2O));16 FTIR (KBr), nmax, cmꢀ1: 3508, 1735, 1607, 1142;
1H NMR (400 MHz, CDCl3)
d
0.71 (t, J¼7.4, 3H), 0.76 (t, J¼7.4, 3H),
1.14e1.17 (m, 3H), 1.38e1.29 (m, 1H), 1.46e1.39 (m, 3H), 2.40 (m,
1H), 1.96 (s, 3H), 2.84 (dd, J¼17.4, 5.5 Hz, 1H), 3.41 (quint, J¼5.7 Hz,
1H), 3.46e3.48 (m, 1H), 4.15e4.09 (m, 2H), 3.91e3.93 (m, 1H),
4.22e4.19 (m, 1H), 6.71e6.72 (m, 1H); 8.6. 8.7, 13.5, 22.6, 25.2, 25.6,
28.3, 49.3, 52.8, 62.6, 75.3, 84.4, 127.8, 138.1, 167.6, 175.4,
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N.C. is a Ph.D. student under the Royal Golden Jubilee Pro-
gram, the Thailand Research Fund (TRF). We are grateful for