Formal synthesis of (-)-oseltamivir phosphate

Article abstract of DOI:10.1055/s-0032-1317948

The formal synthesis of (-)-oseltamivir phosphate (Tamiflu^tm) was accomplished starting from (S)-pyroglutamic acid. The synthesis comprised two carbon-carbon bond forming reactions, the first one being a diastereoselective, indium-mediated allylation of a pyroglutamic aldehyde derivative. However, attempts to effect the second carbon-carbon bond formation - cyclohexene ring closure - using an enol-exo aldolization of a dialdehyde resulted in the formation of a product with the opposite regioselectivity. This shortcoming could be overcome by using a reaction sequence of Mannich methylenation/ring-closing metathesis, which provided the desired regioisomer in high yield. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0032-1317948

PAPER
▌389
paper
Formal Synthesis of (–)-Oseltamivir Phosphate
Synthesis of (–)-Oseltamivir Phosphate
Milos Trajkovic, Zorana Ferjancic,* Radomir N. Saicic*
Faculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158 Belgrade 118, Serbia
Fax +381(11)3282537; E-mail: rsaicic@chem.bg.ac.rs
Received: 01.11.2012; Accepted after revision: 05.12.2012
Abstract: The formal synthesis of (–)-oseltamivir phosphate
(TamifluTM) was accomplished starting from (S)-pyroglutamic acid.
CHO
CO2Et
O
CO2Et
The synthesis comprised two carbon–carbon bond forming reac-
tions, the first one being a diastereoselective, indium-mediated al-
lylation of a pyroglutamic aldehyde derivative. However, attempts
to effect the second carbon–carbon bond formation – cyclohexene
ring closure – using an enol-exo aldolization of a dialdehyde result-
ed in the formation of a product with the opposite regioselectivity.
This shortcoming could be overcome by using a reaction sequence
of Mannich methylenation/ring-closing metathesis, which provided
the desired regioisomer in high yield.
HO
AcHN
NHBoc
–
NHBoc
+
H2PO4
NH3
3
1
2
O
BocN
O
BocN
O
Boc
N
CHO
Key words: antiviral agents, allylation, cyclization, metathesis,
total synthesis
OH
5
4
6
OH
CHO
O
O
As the most important therapeutic agent against the avian
flu, oseltamivir (TamifluTM) has attracted considerable at-
tention from the synthetic community. While the commer-
cial production still relies on the semi-synthetic route
reported by Gilead and Roche scientists,1,2 a number of to-
tal syntheses have been developed.3,4 Whereas the synthe-
sis by Hayashi3aa will hardly be surpassed in terms of
efficiency, numerous synthetic studies and ingenious syn-
thetic approaches to this small, but densely functionalized
molecule enable access to structural analogues, which
may also be of interest to medicinal chemists; in addition,
these studies contribute to the development of synthetic
methodology.
Boc
N
NH
CO2H
CHO
7
Scheme 1 Retrosynthetic analysis of TamifluTM
tion of thioesters into aldehydes was developed by
Fukuyama,6 and we have shown previously that it can be
successfully applied to the synthesis of optically enriched
amidoaldehydes, such as the Garner aldehyde.7 In the
present case, aldehyde 7 was obtained in 85% yield (over
three steps) and with an optical purity of 95.5% ee.8
Our approach to the enantioselective synthesis of Tami-
fluTM (1) targeted optically pure amine 2 – a key interme-
diate in the syntheses of TamifluTM by Corey3a and by
Kann.3f Retrosynthetic simplification of this compound,
delineated in Scheme 1, proceeds via the unsaturated alde-
hyde 3, which is in turn obtainable by an intramolecular
aldol reaction. The suitable precursor for the latter reac-
O
O
O
Boc
a, b
c
N
NBoc
NBoc
CHO
CO2H
COSEt
8
9
7
tion – dialdehyde 4 – could be formed by a double oxida- Scheme 2 Reagents and conditions: a) i-BuOCOCl, Et3N, THF,
0 °C; b) EtSH, Et3N, 0 °C to r.t., 14 h (90%); c) Et3SiH, Pd/C, acetone,
r.t., 30 min (94%).
tion of the unsaturated alcohol 5. Indium-mediated
allylation of pyroglutamic aldehyde 7, followed by reduc-
tive opening of the intermediary amide 6, should produce
alcohol 5 in optically pure form.
The formation of the carbon skeleton commenced with an
indium-mediated allylation of aldehyde 7 under aqueous
conditions, which produced homoallylic alcohol 6 stereo-
selectively (82%, anti/syn = 9:1; Scheme 3). Reductive
opening of the lactam ring with aqueous sodium borohy-
dride afforded unsaturated diol 10 (86%), which was pro-
N-Boc-protected pyroglutamic aldehyde 7 was prepared
according to a three-step procedure, comprising the con-
version of N-Boc-protected pyroglutamic acid5 into the
corresponding ethyl thioester 9, which was then reduced
to aldehyde 7 (Scheme 2). The palladium-mediated reduc-
tected as aminal
5
upon treatment with 2,2-
dimethoxypropane (95%). A NOESY experiment on this
cyclic derivative 5 confirmed its cis-configuration, and
hence the anti-stereochemical outcome of the allylation
reaction. The original synthetic plan now called for the
SYNTHESIS 2013, 45, 0389–0395
Advanced online publication: 20.12.2012
DOI: 10.1055/s-0032-1317948; Art ID: SS-2012-T0851-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

390
M. Trajkovic et al.
PAPER
double oxidation of alkenol 5 into dialdehyde 4. The first basic conditions (46% over two steps, i.e., from 3; in our
step – oxidation of the primary alcohol into aldehyde 11 – hands, direct oxidation of aldehyde to the ester did not
was accomplished by treatment of 5 with Dess–Martin work). Mesylation of the hydroxyl group in 15, followed
periodinane9 in 85% yield. Subsequent alkene cleavage by DBU-induced elimination, could be accomplished as a
was effected with osmium tetroxide/sodium periodate. one-pot procedure, to give the required intermediate 2
Dialdehyde 4 was too unstable to be purified by chroma- (51% over two steps); however, better yields were ob-
tography; therefore, crude 4 was directly exposed to con- tained when mesylation (89%) and elimination (87%)
ditions for cyclization. Unfortunately, the base-catalyzed steps were performed separately. Intermediate 2 thus ob-
cyclization produced regioselectively the undesired iso- tained was identical to the compound reported in the liter-
mer 12; similar results were obtained by enamine cataly- ature in all respects,3a,f thus completing the formal
sis.
synthesis of (–)-oseltamivir phosphate.
O
O
NHBoc
OH
CHO
BocN
BocN
a
b
O
O
NBoc
CHO
NBoc
OH
a
b
O
NBoc
7
CHO
11
OH
10
CHO
14
6
13
c
c
CO2Et
CHO
CO2Et
e
d
BocN
BocN
BocN
O
O
O
d
e
HO
HO
MsO
NHBoc
15
NHBoc
3
NHBoc
16
CHO
CHO
CHO
11
4
OH
5
f
f or g
CO2Et
ref. 3a,f
O
CO2Et
OHC
CHO
AcHN
+
NHBoc
2
+NH2
1
PO4
–
O
O
H2
NBoc
NBoc
Scheme 4 Reagents and conditions: a) Me2N=CH2I, Et3N, CH2Cl2,
r.t., 15 h, 87%; or aq CH2O, propanoic acid (cat.), pyrrolidine (cat.),
i-PrOH, r.t., 66%; b) Grubbs 2nd generation Ru-catalyst (cat.)
CH2Cl2, 35 °C, 1 h, 92%; c) LiCl, AcOH, H2O, r.t., 3 h, 70%; d) 1.
Oxone®, DMF, r.t., 1 h; 2. EtI, K2CO3, DMSO, r.t., 40 h, 46% from 3;
e) MsCl, Et3N, CH2Cl2, 89%; f) DBU, CH2Cl2, 87%.
12
13
Scheme 3 Reagents and conditions: a) In, allyl bromide, THF, r.t.,
15 h, 82%; b) NaBH4, THF, H2O, r.t., 15 h; c) 2,2-dimethoxypropane,
p-TsOH (cat.), CH2Cl2, 95%; d) DMP, CH2Cl2, r.t., 15 min, 85%; e)
OsO4 (cat.), NaIO4, THF, H2O; f) DBA·TFA (cat.), toluene, r.t., 15 h,
27% from 11, 12/13 = 5.5:1; g) KOH, CH2Cl2, H2O, TEBA (cat.), r.t.,
32% from 11, 12/13 = >10:1.
To summarize, a formal synthesis of (–)-oseltamivir phos-
phate was achieved starting from the pyroglutamic alde-
hyde derivative as a chiral synthon. Characteristic features
of the synthesis are the indium-promoted diastereoselec-
tive allylation of the amidoaldehyde and the application of
the methylenation/ring-closing metathesis reaction se-
quence as a means to effect the regioselective closure of
the cyclohexene ring, which could not be accomplished
under conditions of the aldol reaction.
Therefore, in order to circumvent this regioselectivity
problem, a modification of the original synthetic plan was
needed. Thus, we resorted to the ring-closing metathesis
as a suitable method for the regioselective ring closure.
The aldehyde 11 was not oxidatively fragmented, but ex-
posed to Eschenmoser’s salt instead, to give enal 14 (87%;
Scheme 4). Although the methylenation reaction under
these conditions worked well, an organocatalyzed variant
was also tried. In the presence of catalytic amounts of pyr-
rolidine and propanoic acid, in aqueous formaldehyde, the
starting aldehyde was smoothly converted into enal 14.10
Upon treatment with second generation Grubbs’ metathe-
sis catalyst,11 14 was converted into cyclohexenecarbalde-
hyde 13 in high yield (92%). The remaining steps for the
conversion of 13 into 2 were straightforward: after depro-
tection of the aminal with lithium chloride in acetic acid,12
the aldehyde functionality in 3 was oxidized into carbox-
ylic ester 15. After some experimentation, we found that
this transformation was best accomplished by treatment
with Oxone® in DMF,13 followed by esterification under
All chromatographic separations were performed on silica gel, 10–
18, 60 Å (dry-flash) and 100–200 60Å (column chromatography),
ICN Biomedicals. Standard techniques were used for the purifica-
tion of reagents and solvents. Petroleum ether (PE) refers to the
fraction boiling at 70–72 °C. NMR spectra were recorded on Bruker
Avance III 500 (1H NMR at 500 MHz, 13C NMR at 125 MHz) and
Varian Gemini 200 spectrometers (1H NMR at 200 MHz, 13C NMR
at 50 MHz). Chemical shifts are expressed in ppm (δ) using TMS as
the internal standard. IR spectra were recorded on a Nicolet 6700 FT
instrument, and are expressed in cm–1. Mass spectra were obtained
on Agilent technologies 6210 TOF LC/MS instrument (LC: series
1200). Microanalyses were performed using the Vario EL III instru-
ment CHNOS Elementar Analyzer, Elementar Analysensysteme
Synthesis 2013, 45, 389–395
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (–)-Oseltamivir Phosphate
391
GmbH, Hanau, Germany. Melting points were determined on a
Kofler hot-stage apparatus and are uncorrected. Optical rotation
was determined on a Rudolph Research Analytical AUTOPOL IV
Automatic Polarimeter.
(MgSO4), and concentrated under reduced pressure. The residue
was and purified by dry-flash chromatography (SiO2, eluent: PE–
EtOAc, 1:2) to give 775 mg (82%) of alcohol 6 as colorless crystals;
mp 152–154 °C; Rf = 0.54 (SiO2, PE–EtOAc, 1:2); [α]D20 –78.5 (c
1.03, CHCl3).
tert-Butyl (S)-2-(Ethylthiocarbonyl)-5-oxopyrrolidine-1-car-
boxylate (9)
IR (ATR): 3437, 3075, 2975, 2936, 1787, 1695, 1638, 1393, 1320,
1292, 1255, 1162, 1027, 910, 856 cm–1.
Isobutyl chloroformate (0.89 g, 0.85 mL, 6.50 mmol) and Et3N
(0.76 g, 1.05 mL, 7.53 mmol) were added to a cold (0 °C) solution
of (S)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid
(8;5 1.14 g, 4.95 mmol) in THF (17 mL), under an argon atmo-
sphere. The reaction mixture was vigorously stirred for 30 min at
0 °C; then ethanethiol (0.70 g, 0.85 mL, 11.36 mmol) and Et3N
(0.76 g, 1.05 mL, 7.53 mmol) were added. The resulting solution
was stirred for 30 min at 0 °C and 45 min at r.t. The mixture was di-
luted with CH2Cl2 (25 mL) and the organic layer was washed with
H2O (40 mL). The aqueous layer was extracted with CH2Cl2 (2 × 30
mL), the combined organic extracts were dried (MgSO4), and con-
centrated under reduced pressure. The residue was purified by dry-
flash chromatography (SiO2; eluent: PE–EtOAc, 7:3) to give 1.22 g
(90%) of the title compound 9 as colorless crystals; mp 53–56 °C
1H NMR (500 MHz, CDCl3): δ = 5.82 (ddt, J = 17.2, 10.2, 7.1 Hz,
1 H), 5.20–5.12 (m, 2 H), 4.14 (dt, J = 9.2, 1.6 Hz, 1 H), 4.11–4.07
(m, 1 H), 2.75 (dt, J = 17.7, 10.1 Hz, 1 H), 2.38 (ddd, J = 17.7, 10.2,
2.5 Hz, 1 H), 2.31 (d, J = 4.0 Hz, 1 H), 2.30–2.20 (m, 2 H), 2.09 (ddt,
J = 12.2, 9.9, 2.3 Hz, 1 H), 2.03–1.93 (m, 1 H), 1.53 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 175.3 (C), 150.2 (C), 134.0 (CH),
118.4 (CH2), 83.0 (C), 71.4 (CH), 61.3 (CH), 38.4 (CH2), 32.6
(CH2), 28.1 (CH3), 17.5 (CH2).
HRMS (ESI): m/z calcd for C13H21NO4 [M + Na]+: 278.1363; found:
278.1363.
Anal. Calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C,
60.83; H, 8.00; N, 5.61.
20
(Lit.8 mp 58.7–60.9 °C); Rf = 0.47 (SiO2, PE–EtOAc, 7:3); [α]D
–45.9 (c 1.05, CHCl3) {Lit.8 [α]D20 –47.4 (c 1.02, CHCl3)}.
tert-Butyl (4S,5R)-1,5-Dihydroxyoct-7-en-4-ylcarbamate (10)
A mixture of NaBH4 (452 mg, 11.95 mmol) and alcohol 6 (750 mg,
2.94 mmol) in THF–H2O (25 mL, v/v = 4:1) was stirred for 18 h at
r.t. The reaction mixture was quenched by the addition of sat. aq
NH4Cl (20 mL) and stirred until excess NaHB4 completely decom-
posed. The mixture was diluted with H2O (20 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic extracts were
washed with brine (20 mL), dried (MgSO4), and concentrated under
reduced pressure. Purification of the crude product by dry-flash
chromatography (SiO2, PE–EtOAc, 1:4) afforded 657 mg (86%) of
the title compound 10 as colorless crystals; mp 96–100 °C; Rf = 0.33
(SiO2, PE–EtOAc, 1:4); [α]D20 –25.6 (c 1.10, CHCl3).
IR (ATR): 2974, 2931, 2874, 1797, 1707, 1678, 1369, 1309, 1257,
1160, 1025, 992, 842 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.72 (dd, J = 9.6, 2.6 Hz, 1 H),
3.03–2.90 (m, 2 H), 2.66 (ddd, J = 17.6, 10.2, 9.8 Hz, 1 H), 2.49
(ddd, J = 17.6, 9.5, 3.1 Hz, 1 H), 2.40–2.28 (m, 1 H), 2.09–1.99 (m,
1 H), 1.50 (s, 9 H), 1.29 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 199.1 (C), 173.3 (C), 148.8 (C),
83.7 (C), 65.2 (CH), 30.7 (CH2), 27.8 (CH3), 23.1 (CH2), 22.2
(CH3), 14.5 (CH3).
HRMS (ESI): m/z calcd for C12H19NO4S [M + Na]+: 296.0927;
IR (ATR): 3352, 2981, 2935, 2875, 1686, 1531, 1446, 1368, 1342,
1303, 1252, 1174, 1044, 976, 911 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.89–5.81 (m, 1 H), 5.18–5.10 (m,
2 H), 4.90 (d, J = 8.8 Hz, 1 H), 3.67 (t, J = 6.0, 2 H), 3.66–3.62 (m,
2 H), 2.79 (s, 1 H), 2.44 (s, 1 H), 2.32–2.27 (m, 1 H), 2.23–2.17 (m,
1 H), 1.75–1.53 (m, 3 H), 1.44 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 156.4 (C), 134.8 (CH), 118.0
(CH2), 79.5 (C), 73.5 (CH2), 62.4 (CH2), 54.5 (CH), 38.2 (CH2),
28.9 (CH2), 28.4 (CH3), 25.9 (CH2).
found: 296.0933.
Anal. Calcd for C12H19NO4S: C, 52.73; H, 7.01; N, 5.12; S, 11.73.
Found: C, 52.63; H, 6.99; N, 5.12; S, 11.57.
tert-Butyl (S)-2-Formyl-5-oxopyrrolidine-1-carboxylate (7)
Et3SiH (1.46 g, 2.0 mL, 12.52 mmol) was added over 30 min to a
suspension of thioester 9 (1.15 g, 4.21 mmol) and 10% Pd/C (220
mg, 0.21 mmol) in acetone (40 mL) at r.t. under an argon atmo-
sphere. The reaction mixture was stirred for an additional 15 min,
then filtered, and concentrated under reduced pressure. The residue
was purified by dry-flash chromatography (SiO2; eluent: PE–
EtOAc, 1:2) to give 0.84 g (94%) of the aldehyde 7 as a colorless
oil;8 Rf = 0.25 (SiO2, PE–EtOAc, 1:1); [α]D20 –42.4 (c 1.11, CHCl3).
HRMS (ESI): m/z calcd for C13H25NO4 [M + Na]+: 282.1676;
found: 282.1680.
Anal. Calcd for C13H25NO4: C, 60.21; H, 9.72; N, 5.40. Found: C,
59.89; H, 9.89; N, 5.68.
IR (ATR): 3460, 2980, 2936, 1786, 1741, 1714, 1459, 1368, 1313,
1256, 1155, 1024, 847 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.60 (d, J = 2.0 Hz, 1 H), 4.59
(ddd, J = 9.5, 4.8, 2.0 Hz, 1 H), 2.61–2.47 (m, 2 H), 2.30–2.22 (m,
1 H), 2.10–2.03 (m, 1 H), 1.51 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 196.9 (CH), 173.0 (C), 149.3 (C),
84.2 (C), 64.2 (CH), 31.1 (CH2), 27.8 (CH3), 18.2 (CH2).
tert-Butyl (4S,5R)-5-Allyl-4-(3-hydroxypropyl)-2,2-dimethyl-
oxazolidine-3-carboxylate (5)
A solution of 2,2-dimethoxypropane (0.72 g, 0.85 mL, 6.91 mmol),
p-TsOH (23.7 mg, 0.12 mmol) and diol 10 (600 mg, 2.31 mmol) in
CH2Cl2 (23 mL) was stirred for 45 min at r.t., and then concentrated
under reduced pressure (when it turned red). Purification of the
crude product by dry-flash chromatography (SiO2, PE–EtOAc, 7:3)
afforded 599 mg (86%) of the title compound 5 as a colorless vis-
HRMS (ESI): m/z calcd for C10H15NO4 [M + Na]+: 236.0893; found:
236.0888.
20
cous oil; Rf = 0.42 (SiO2, PE–EtOAc, 7:3); [α]D +5.6 (c 1.13,
Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C,
56.00; H, 7.16; N, 6.51.
CHCl3).
IR (ATR): 3448, 3079, 2979, 2933, 2869, 1697, 1456, 1395, 1255,
1179, 1130, 1072, 917 cm–1.
tert-Butyl (S)-2-[(R)-1-Hydroxybut-3-enyl]-5-oxopyrrolidine-1-
carboxylate (6)
1H NMR (500 MHz, 65 °C, DMSO-d6): δ = 5.82 (ddt, J = 17.0, 10.3,
6.5 Hz, 1 H), 5.15 (dq, J = 17.3, 1.6 Hz, 1 H), 5.06 (dq, J = 10.3, 1.3
Hz, 1 H), 4.14 (s, 1 H), 4.07 (ddd, J = 7.3, 6.3, 5.1 Hz, 1 H), 3.81 (s,
1 H), 3.41 (dd, J = 11.7, 6.1 Hz, 2 H), 2.34–2.28 (m, 2 H), 1.66–1.59
(m, 1 H), 1.52–1.36 (m, 3 H), 1.48 (s, 3 H), 1.46 (s, 3 H), 1.43 (s, 9
H).
Allyl bromide (1.34 g, 0.96 mL, 11.09 mmol) and In powder (460
mg, 4.00 mmol) were added to a solution of aldehyde 7 (790 mg,
3.70 mmol) in H2O–THF (36 mL, v/v = 3:1). The reaction mixture
was vigorously stirred for 16 h, diluted with H2O (25 mL), and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The com-
bined organic extracts were washed with brine (50 mL), dried
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 389–395

392
M. Trajkovic et al.
PAPER
13C NMR (126 MHz, 65 °C, DMSO-d6): δ = 151.1 (C), 134.3 (CH),
116.4 (CH2), 91.4 (C), 78.5 (C), 75.5 (CH), 60.7 (CH2), 58.0 (CH),
32.4 (CH2), 29.2 (CH2), 27.8 (CH3), 26.7 (CH3), 25.8 (CH2), 23.4
(CH3).
HRMS (ESI): m/z calcd for C16H29NO4 [M + Na]+: 322.1989;
found: 322.1993.
1H NMR (500 MHz, CDCl3): δ = 9.57 (s, 1 H), 7.12 (s, 1 H), 4.70
(s, 1 H), 3.95–3.74 (m, 1 H), 2.55–2.50 (m, 1 H), 2.35–2.11 (m, 2
H), 1.67–1.45 (m, 17 H).
13C NMR (126 MHz, CDCl3): δ = 192.3 (CH), 154.9 (CH), 152.3
(C), 138.2 (C), 93.5 (C), 80.3 (C), 65.3 (CH), 55.0 (CH), 28.5
(CH3), 27.4 (CH3), 25.2 (CH3), 24.2 (CH2), 23.6 (CH2).
Anal. Calcd for C16H29NO4: C, 64.18; H, 9.76; N, 4.68. Found: C,
64.25; H, 9.68; N, 4.80.
HRMS (ESI): m/z calcd for C14H21NO4 [M + Na]+: 304.1519;
found: 304.1509.
tert-Butyl (4S,5R)-5-Allyl-2,2-dimethyl-4-(3-oxopropyl)oxazoli-
dine-3-carboxylate (11)
tert-Butyl (3aS,7aR)-7-Formyl-2,2-dimethyl-3a,4,5,7a-tetrahy-
drobenzo[d]oxazole-3(2H)-carboxylate 12 (KOH-Catalyzed
Cyclization)
Dess–Martin periodinane (DMP; 1.17 g, 2.76 mmol) was added to
a solution of aminoacetal 5 (550 mg, 1.84 mmol) in CH2Cl2 (18.5
mL) and the reaction mixture was stirred for 15 min at r.t. The mix-
ture was diluted with CH2Cl2 (30 mL). The organic layer washed
with 10% aq Na2S2O3 (25 mL) and sat. aq NaHCO3 (25 mL), dried
(MgSO4), and concentrated under reduced pressure. Purification of
the crude product by dry-flash chromatography (SiO2, PE–EtOAc,
8:2) afforded 465 mg (85%) of the title compound 11 as a colorless
tert-Butyl (4S,5R)-2,2-Dimethyl-5-(2-oxoethyl)-4-(3-oxopropyl)ox-
azolidine-3-carboxylate (4): NaIO4 (43.0 mg, 0.201 mmol) and a
2.5% solution of OsO4 (0.5 mg, 20 μL, 0.02 mmol) were added to a
solution of aldehyde 11 (10.4 mg, 0.035 mmol) in H2O–THF (1.6
mL, v/v = 1:2). The reaction mixture was stirred for 3 h at r.t.,
quenched with NaHSO3 (100 mg), and stirred for an additional 30
min at r.t. The mixture was diluted with EtOAc (15 mL) and H2O
(15 mL). The organic layer was washed with 10% aq Na2S2O3 (15
mL), sat. aq NaHCO3 (15 mL), and H2O (15 mL). The organic ex-
tract was dried (MgSO4), concentrated under reduced pressure, and
the residue was used in the next step without further purification.
20
viscous oil; Rf = 0.46 (SiO2, PE–EtOAc, 8:2); [α]D –2.4 (c 1.01,
CHCl3).
IR (ATR): 3079, 2980, 2937, 2874, 2825, 2722, 1726, 1695, 1645,
1389, 1254, 1178, 1132, 1072, 918 cm–1.
tert-(3aS,7aR)-Butyl 7-Formyl-2,2-dimethyl-3a,4,5,7a-tetrahydro-
benzo[d]oxazole-3(2H)-carboxylate (12): A solution of dialdehyde
4 (10.5 mg, 0.035 mmol), Et3BnCl (TEBAC; 8.0 mg, 0.035 mmol),
CH2Cl2 (0.21 mL), and 10% solution of KOH (0.21 mL) was vigor-
ously stirred at 35 °C for 16 h. The mixture was diluted with CH2Cl2
(10 mL), washed with sat. aq NH4Cl (10 mL), dried (MgSO4), and
concentrated under reduced pressure. Purification of the residue by
column chromatography (SiO2; eluent: PE–EtOAc, 7:3) afforded
3.2 mg (32%, over two steps, i.e., from aldehyde 11) of a mixture of
compounds 12 and 13 (in a molar ratio 12/13 = 8:1, as determined
by 1H NMR analysis) as a colorless viscous oil, whose physical data
were identical to those of the sample prepared using DBA·TFA
(see, above).
1H NMR (500 MHz, 65 °C, DMSO-d6): δ = 9.68 (s, 1 H), 5.83 (ddt,
J = 17.0, 10.3, 6.5 Hz, 1 H), 5.16 (dq, J = 17.2, 1.7 Hz, 1 H), 5.08
(dq, J = 10.3, 1.3 Hz, 1 H), 4.13–4.03 (m, 1 H), 3.83 (br s, 1 H),
2.53–2.38 (m, 2 H), 2.34–2.27 (m, 2 H), 1.95–1.82 (m, 1 H), 1.67–
1.59 (m, 1H), 1.48 (s, 3 H), 1.47 (s, 3 H), 1.43 (s, 9 H).
13C NMR (126 MHz, 65 °C, DMSO-d6): δ = 201.9 (CH), 151.2 (C),
134.1 (CH), 116.7 (CH2), 91.7 (C), 78.9 (C), 75.2 (CH), 57.3 (CH),
39.4 (CH2), 32.3 (CH2), 27.7 (CH3), 26.8 (CH3), 24.2 (CH3), 21.4
(CH2).
HRMS (ESI): m/z calcd for C16H27NO4 [M + Na]+: 320.1832; found:
320.1838.
Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C,
64.42; H, 9.35; N, 4.78.
tert-Butyl (4S,5R)-5-Allyl-4-(2-formylallyl)-2,2-dimethyloxa-
zolidine-3-carboxylate (14) (Using the Eschenmoser’s Salt)
A solution of Eschenmoser’s salt (208 mg, 1.12 mmol), Et3N (145.2
mg, 0.2 mL, 1.43 mmol), and aldehyde 11 (62.2 mg, 0.21 mmol) in
CH2Cl2 (10.5 mL) was stirred for 18 h at r.t. Without workup and
concentration, the reaction mixture was purified by dry-flash chro-
matography (by pouring the CH2Cl2 solution directly onto the col-
umn; SiO2, PE–EtOAc, 85:15) to give 56.5 mg (87%) of the title
compound 14 as a colorless viscous oil; Rf = 0.41 (SiO2, PE–EtOAc,
85:15); [α]D20 –0.6 (c 1.07, CHCl3).
tert-Butyl (3aS,7aR)-7-Formyl-2,2-dimethyl-3a,4,5,7a-tetrahy-
drobenzo[d]oxazole-3(2H)-carboxylate (12) (Organocatalyzed
Cyclization)
tert-Butyl (4S,5R)-2,2-Dimethyl-5-(2-oxoethyl)-4-(3-oxopropyl)oxa-
zolidine-3-carboxylate (4): NaIO4 (27.0 mg, 0.126 mmol) and a
2.5% solution of OsO4 (1.25 mg, 50 μL, 0.05 mmol) were added to
a solution of aldehyde 11 (7.0 mg, 0.024 mmol) in H2O–THF (1.05
mL, v/v = 1:2). The reaction mixture was stirred for 3 h at r.t.,
quenched with NaHSO3 (100 mg), and stirred for an additional 30
min at r.t. The mixture was diluted with EtOAc (15 mL) and H2O
(15 mL). The organic layer was washed with 10% aq Na2S2O3 (15
mL), sat. aq NaHCO3 (15 mL), and H2O (15 mL). The organic ex-
tract was dried (MgSO4), concentrated under reduced pressure, and
the residue was used in the next step without further purification.
IR (ATR): 2981, 2935, 2872, 1740, 1695, 1644, 1386, 1246, 1178,
1133, 1078, 1050, 947 cm–1.
1H NMR (500 MHz, 65 °C, DMSO-d6): δ = 9.52 (br s, 1 H), 6.41–
5.91 (m, 2 H), 5.81 (ddt, J = 17.0, 10.3, 6.6 Hz, 1 H), 5.16 (ddd, J =
17.3, 3.5, 1.6 Hz, 1 H), 5.09 (ddd, J = 10.3, 3.2, 1.3 Hz, 1 H), 4.13–
4.07 (m, 1 H), 4.04 (br s, 1 H), 2.54 (dd, J = 13.4, 4.3 Hz, 1 H), 2.33–
2.24 (m, 2 H), 2.12 (dd, J = 13.3, 9.3 Hz, 1 H), 1.55 (s, 3 H), 1.46
(s, 3 H), 1.36 (s, 9 H).
13C NMR (126 MHz, DMSO-d6): δ = 193.9 (CH), 151.1 (C), 146.2
(C), 135.5 (CH2), 133.8 (CH), 116.8 (CH2), 91.7 (C), 78.8 (CH),
75.3 (C), 56.6 (CH), 32.3 (CH2), 28.1 (CH2), 27.6 (CH3), 24.5
(CH3), 23.3 (CH3).
tert-Butyl (3aS,7aR)-7-Formyl-2,2-dimethyl-3a,4,5,7a-tetrahydro-
benzo[d]oxazole-3(2H)-carboxylate (12): A solution of dialdehyde
4 (~7 mg, 0.024 mmol) and dibenzylamine trifluoroacetate
(DBA·TFA; 9.1 mg, 0.031 mmol) in toluene (0.26 mL) was stirred
at r.t. for 18 h. The mixture was diluted with CH2Cl2 (10 mL), the
organic layer washed with H2O (10 mL), dried (MgSO4), and con-
centrated under reduced pressure. Purification of the residue by dry-
flash chromatography (SiO2; eluent: benzene–EtOAc, 7:3) afforded
1.8 mg (27%, over two steps, i.e., from aldehyde 11) of a mixture of
compounds 12 and 13 (in a molar ratio 12/13 = 5.5:1, as determined
by 1H NMR analysis) as a colorless viscous oil.
HRMS (ESI): m/z calcd for C17H27NO4 [M + Na]+: 332.1832;
found: 332.1817.
Anal. Calcd for C17H27NO4: C, 65.99; H, 8.80; N, 4.53. Found: C,
65.84; H, 8.79; N, 4.56.
Spectral Data for 12
IR (film): 2978, 2936, 2876, 2814, 1693, 1391, 1254, 1215, 1174,
1147, 1089, 1022, 886 cm–1.
Synthesis 2013, 45, 389–395
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (–)-Oseltamivir Phosphate
393
tert-Butyl (4S,5R)-5-Allyl-4-(2-formylallyl)-2,2-dimethyloxa-
zolidine-3-carboxylate (14) (Organocatalyzed Reaction)
A solution of 38% aq formaldehyde (0.34 g, 0.31 mL, 4.28 mmol),
propionic acid (24.8 mg, 25 μL, 0.34 mmol), pyrrolidine (21.3 mg,
25 μL, 0.30 mmol), and aldehyde 11 (381.5 mg, 1.28 mmol) in
i-PrOH (4.5 mL) was stirred for 18 h at r.t. The mixture was diluted
with EtOAc (50 mL) and the EtOAc layer was washed with H2O (25
mL), dried (MgSO4), and concentrated under reduced pressure. Pu-
rification of the crude product by dry-flash chromatography (SiO2,
PE–EtOAc, 85:15) afforded 261 mg (66%) of the title compound 14
as a colorless viscous oil, whose physical data were identical to
those of the sample prepared using the Eschenmoser salt (see
above).
(MgSO4), concentrated under reduced pressure. The crude product
was used in the next step without further purification.
Ethyl (4R,5S)-5-(tert-Butoxycarbonylamino)-4-hydroxycyclohex-1-
enecarboxylate (15): A solution of the crude acid from the previous
step (~14 mg, 0.054 mmol) and K2CO3 (22.8 mg, 0.165 mmol) in
EtOH–H2O (0.3 mL, v/v = 5:1) was stirred for 30 min at r.t. The sol-
vent was removed under reduced pressure and the solid residue was
dissolved in DMSO (0.3 mL). To this was added EtI (97 mg, 0.05
mL, 0.622 mmol) and the resulting solution was stirred for 40 h at
r.t. The reaction mixture was diluted with EtOAc (10 mL) and H2O
(10 mL). Aq 1.5 M HCl was added till pH reached ~3, and the or-
ganic layer was washed with H2O (10 mL), dried (MgSO4), and
concentrated under reduced pressure. Purification of the residue by
column chromatography (SiO2, PE–EtOAc, 6:4) afforded 7.1 mg
(46% calculated on the bases of starting aldehyde 3) of the title com-
tert-Butyl (3aS,7aR)-5-Formyl-2,2-dimethyl-3a,4,7,7a-tetrahy-
drobenzo[d]oxazole-3(2H)-carboxylate (13)
20
A solution of the 2nd generation Grubbs catalyst10 (26.1 mg, 0.03
mmol) and aldehyde 14 (299.1 mg, 0.97 mmol) in CH2Cl2 (16.1
mL) was stirred at 35 °C for 1 h under an argon atmosphere. The re-
action mixture was concentrated and purified by dry-flash chroma-
tography (SiO2, PE–EtOAc, 8:2) to afford 250 mg (92%) of the title
compound 13 as a pale yellow viscous oil; Rf = 0.26 (SiO2, PE–
EtOAc, 8:2); [α]D20 +85.2 (c 1.01, CHCl3).
pound 15 as a colorless oil; Rf = 0.33 (SiO2, PE–EtOAc, 8:2); [α]D
–9.3 (c 0.74, CHCl3).
IR (film): 3377, 2979, 2933, 1705, 1513, 1390, 1369, 1250, 1171,
1087, 1047 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.90–6.85 (m, 1 H), 4.83 (br d, J =
7.4 Hz, 1 H), 4.19 (q, J = 7.1, 2 H), 4.06 (br s, 1 H), 3.88 (br s, 1 H),
2.77 (br s, 1 H), 2.71–2.63 (m, 1 H), 2.62–2.54 (m, 1 H), 2.42–2.31
(m, 2 H), 1.45 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 166.3 (C), 156.4 (C), 135.9 (CH),
128.0 (C), 80.0 (C), 67.4 (CH), 60.6 (CH2), 49.6 (CH), 32.7 (CH2),
28.3 (CH3), 27.6 (CH2), 14.2 (CH3).
IR (ATR): 3449, 2979, 2936, 1693, 1455, 1394, 1372, 1257, 1175,
1097, 1034, 867 cm–1.
1H NMR (500 MHz, 65 °C, DMSO-d6): δ = 9.49 (s, 1 H), 6.98–6.93
(m, 1 H), 4.40 (td, J = 5.7, 2.0 Hz, 1 H), 3.88 (dd, J = 12.7, 6.6 Hz,
1 H), 2.76 (dqd, J = 19.5, 3.9, 1.8 Hz, 1 H), 2.67 (dd, J = 16.6, 7.0
Hz, 1 H), 2.58 (ddt, J = 19.6, 4.3, 1.9 Hz, 1 H), 1.99 (ddq, J = 16.6,
6.8, 1.9 Hz, 1 H), 1.50–1.40 (m, 15 H).
HRMS (ESI): m/z calcd for C14H23NO5 [M + Na]+: 308.1468; found:
308.1454.
13C NMR (126 MHz, 65 °C, DMSO-d6): δ = 192.2 (CH), 150.9 (C),
147.7 (CH), 138.4 (C), 91.8 (C), 78.8 (C), 70.0 (CH), 53.3 (CH),
28.2 (CH2), 27.8 (CH3), 26.7 (CH3), 23.5 (CH3), 23.2 (CH2).
HRMS (ESI): m/z calcd for C15H23NO4 [M + Na]+: 304.1519; found:
304.1507.
Ethyl (4R,5S)-5-(tert-Butoxycarbonylamino)-4-(methylsulfonyl-
oxy)cyclohex-1-enecarboxylate (16)
A solution of MsCl (2.37 mg, 1.60 μL, 0.021 mmol), Et3N (3.63 mg,
5.00 μL, 0.036 mmol), DMAP (0.33 mg, 0.003 mmol), and alcohol
15 (3.8 mg, 0.013 mmol) in CH2Cl2 (0.16 mL) was stirred for 30
min at r.t.. The mixture was diluted with EtOAc (10 mL) and the
EtOAc layer was washed with H2O (10 mL). The aqueous layer was
extracted with EtOAc (3 × 10 mL), the combined organic extracts
were dried (MgSO4), and concentrated under reduced pressure. Pu-
rification of the residue by column chromatography (SiO2, PE–
EtOAc, 6:4) afforded 4.3 mg (89%) of the title compound 16 as col-
orless crystals; mp not determined (unstable).
tert-Butyl (1S,6R)-3-Formyl-6-hydroxycyclohex-3-enylcarba-
mate (3)
A solution of aldehyde 13 (53.7 mg, 0.19 mmol) and LiCl (29.0 mg,
0.50 mmol) in AcOH–H2O (0.65 mL, v/v = 9:1) was stirred for 1 h
at r.t., and then diluted with EtOAc (10 mL). The EtOAc layer was
washed with H2O (10 mL) and the aqueous layer was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Purification of
the crude product by dry-flash chromatography (SiO2, PE–EtOAc,
1:1) afforded 32.1 mg (70%) of the title compound 3 as a colorless
viscous oil; Rf = 0.33 (SiO2, PE–EtOAc, 1:1); [α]D20 –28.1 (c 0.88,
CHCl3).
1H NMR (200 MHz, CDCl3): δ = 6.83 (br s, 1 H), 5.13 (br s, 1 H),
4.86 (br d, J = 7.3 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.05–3.81 (m,
1 H), 3.04 (s, 3 H), 2.78–2.67 (m, 3 H), 2.40–2.15 (m, 1 H), 1.45 (s,
9 H), 1.30 (t, J = 7.1 Hz, 3 H).
Ethyl (S)-5-(tert-Butoxycarbonylamino)cyclohexa-1,3-diene-
carboxylate (2)
IR (ATR): 3372, 2978, 2831, 2820, 2724, 1682, 1646, 1519, 1393,
1367, 1284, 1249, 1167, 1077, 1045, 1022, 914, 875 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.46 (s, 1 H), 6.71 (br t, J = 3.7
Hz, 1 H), 4.88 (br s, 1 H), 4.16–4.13 (m, 1 H), 3.91–3.79 (m, 1 H),
3.09 (br s, 1 H), 2.74–2.69 (m, 1 H), 2.64–2.49 (m, 2 H), 2.34–2.21
(m, 1 H), 1.45 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 192.8 (CH), 156.3 (C), 146.9
(CH), 138.9 (C), 80.2 (C), 67.6 (CH), 49.3 (CH), 33.5 (CH2), 28.3
(CH3), 24.4 (CH2).
DBU (4.45 mg, 4.37 μL, 0.029 mmol) was added to a solution of
mesylate 16 (4.3 mg, 0.012 mmol) in CH2Cl2 (0.2 mL). The reaction
mixture was stirred for 5 min at r.t. and concentrated under reduced
pressure. Purification of the residue by column chromatography
(SiO2, PE–EtOAc, 85:15) afforded 2.9 mg (92%) of the title com-
20
pound 2 as a colorless oil; Rf = 0.4 (SiO2, PE–EtOAc, 6:4); [α]D
–219.7 (c 0.20, CHCl3) {Lit.3f –217, c 1.10, CHCl3)}.
IR (film): 3351, 2978, 2929, 1708, 1514, 1367, 1255, 1169, 1097,
1048, 1024, 718 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.07–7.03 (m, 1 H), 6.20–6.10 (m,
2 H), 4.63 (br s, 1 H), 4.44 (br s, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 2.74
(dd, J = 17.7, 6.5 Hz, 1 H), 2.66 (dd, J = 18.6, 7.9 Hz, 1 H), 1.44 (s,
9 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 166.9 (C), 154.8 (C), 132.5 (CH),
131.7 (CH), 127.0 (C), 124.8 (CH), 79.7 (C), 60.6 (CH2), 43.4 (CH),
28.9 (CH2), 28.4 (CH3), 14.3 (CH3).
HRMS (ESI): m/z calcd for C12H19NO4 [M + K]+: 280.0946; found:
280.0939.
Ethyl (4R,5S)-5-(tert-Butoxycarbonylamino)-4-hydroxycyclo-
hex-1-enecarboxylate (15)
(4R,5S)-5-(tert-Butoxycarbonylamino)-4-hydroxycyclohex-1-ene-
carboxylic Acid: A mixture of aldehyde 3 (13.0 mg, 0.054 mmol),
Oxone® (82.8 mg, 0.269 mmol), and DMF (0.3 mL) was stirred at
r.t. for 4.5 h. The reaction mixture was diluted with EtOAc (10 mL),
the organic layer was washed with H2O (2 × 10 mL), dried
HRMS (ESI) m/z calcd for C14H21NO4 [M + K]+: 306.1102; found:
306.1112.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 389–395

394
M. Trajkovic et al.
PAPER
Ethyl (S)-5-(tert-Butoxycarbonylamino)cyclohexa-1,3-diene-
carboxylate (2) (One-Pot Procedure)
N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem.
Int. Ed. 2007, 46, 5734. (e) Yamatsugu, K.; Kamijo, S.;
Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007,
48, 1403. (f) Bromfield, K. M.; Graden, H.; Hagberg, D. P.;
Olsson, T.; Kann, N. Chem. Commun. 2007, 3183. (g) Mita,
T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M. Org.
Lett. 2007, 9, 259. (h) Kipassa, N. T.; Okamura, H.; Kina,
K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815.
(i) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem.
2008, 73, 4895. (j) Matveenko, M.; Willis, A. C.; Banwell,
M. G. Tetrahedron Lett. 2008, 49, 7018. (k) Shie, J.-J.; Fang,
J.-M.; Wong, C.-H. Angew. Chem. Int. Ed. 2008, 47, 5788.
(l) Trost, B. M.; Zhang, T. Angew. Chem. Int. Ed. 2008, 47,
3759. (m) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew.
Chem. Int. Ed. 2009, 48, 1304. (n) Yamatsugu, K.; Yin, L.;
Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew.
Chem. Int. Ed. 2009, 48, 1070. (o) Mandai, T.; Oshitari, T.
Synlett 2009, 783. (p) Oshitari, T.; Mandai, T. Synlett 2009,
787. (q) Sun, H.; Lin, Y.-J.; Wu, Y.-L.; Wu, Y. Synlett 2009,
2473. (r) Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T.
Angew. Chem. Int. Ed. 2009, 48, 4229. (s) Osato, H.; Jones,
I. L.; Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12, 60.
(t) Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.;
Chan, A. S. C.; Lu, G. J. Org. Chem. 2010, 75, 3125.
Synthesis of racemic TamifluTM: (u) Kamimura, A.; Nakano,
T. J. Org. Chem. 2010, 75, 3133. (v) Ko, J. S.; Keum, J. E.;
Ko, S. Y. J. Org. Chem. 2010, 75, 7006. (w) Wichienukul,
P.; Akkarasamiyo, S.; Kongkathip, N.; Kongkathip, B.
Tetrahedron Lett. 2010, 51, 3208. (x) Ma, J.; Zhao, Y.; Ng,
S.; Zhang, J.; Zeng, J.; Than, A.; Chen, P.; Liu, X.-W. Chem.
Eur. J. 2010, 16, 4533. (y) Zhu, S.; Yu, S.; Wang, Y.; Ma, D.
Angew. Chem. Int. Ed. 2010, 49, 4656. (z) Werner, L.;
Machara, A.; Hudlicky, T. Adv. Synth. Catal. 2010, 352,
195. (aa) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.;
Hayashi, Y. Chem. Eur. J. 2010, 16, 12616. (ab) Trost, B.
M.; Zhang, T. Chem. Eur. J. 2011, 17, 3630. (ac) Raghavan,
S.; Babu, V. S. Tetrahedron 2011, 67, 2044. (ad) Tanaka, T.;
Tan, Q.; Kawakubo, H.; Hayashi, M. J. Org. Chem. 2011,
76, 5477. (ae) Werner, L.; Machara, A.; Sullivan, B.;
Carrera, I.; Mosher, M.; Adams, D. R.; Hudlicky, T.;
Andraos, J. J. Org. Chem. 2011, 76, 10050. (af) Trajkovic,
M.; Ferjancic, Z.; Saicic, R. N. Org. Biomol. Chem. 2011, 9,
6927. (ag) Gunasekara, D. S. Synlett 2012, 23, 573.
(ah) Chuanopparat, N.; Kongkathip, N.; Kongkathip, B.
Tetrahedron 2012, 68, 6803. (ai) Rawat, V.; Dey, S.;
Sudalai, A. Org. Biomol. Chem. 2012, 10, 3988. (aj) Oh, H.-
S.; Kang, H.-Y. J. Org. Chem. 2012, 77, 8792.
MsCl (3.45 mg, 2.33 μL, 0.030 mmol), Et3N (6.32 mg, 8.70 μL,
0.062 mmol), and DMAP (0.50 mg, 0.004 mmol) were added to a
solution of alcohol 15 (5.0 mg, 0.018 mmol) in CH2Cl2 (0.16 mL).
The reaction mixture was stirred for 30 min at r.t., then DBU (15.27
mg, 15.0 μL, 0.100 mmol) was added and the resulting solution was
stirred for an additional 15 min at r.t. The mixture was diluted with
CH2Cl2 (10 mL) and the organic layer was washed with H2O (10
mL). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (MgSO4) and concentrat-
ed under reduced pressure. Purification of the residue by column
chromatography (SiO2, PE–EtOAc, 85:15) afforded 2.4 mg (51%)
of the title compound 2 as a colorless oil. The physical and spectral
data for the product were identical with the sample obtained by the
two-step procedure (see above).
Acknowledgment
This work was supported by the Serbian Ministry of Education, Sci-
ence and Technological Development (Project No. 172027).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
References
(1) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang,
L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.;
Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C.
J. Am. Chem. Soc. 1997, 119, 681. (b) Rohloff, J. C.; Kent,
K. M.; Postish, M. J.; Becker, M. W.; Chapman, H. H.;
Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe,
E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem.
1998, 63, 4545. (c) Karpf, M.; Trussardi, R. J. Org. Chem.
2001, 66, 2044.
(2) For review articles on the development of the industrial
synthesis, see: (a) Abrecht, S.; Federspiel, M. C.;
Estermann, H.; Fischer, R.; Karpf, M.; Mair, H.-J.;
Oberhauser, T.; Rimmler, G.; Trussardi, R.; Zutter, U.
Chimia 2007, 61, 93. (b) Abrecht, S.; Harrington, P.; Iding,
H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. Chimia
2004, 58, 621. For improvements and more detailed
accounts on industrial synthesis, see: (c) Harrington, P. J.;
Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res.
Dev. 2004, 8, 86. (d) Federspiel, M.; Fisher, R.; Henning,
M.; Mair, H. J.; Oberhauser, T.; Rimmler, G.; Albiez, T.;
Bruhin, J.; Estermann, H.; Gandert, C.; Gockel, V.; Gotzo,
S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.;
Rockel-Stabler, O.; Trussardi, R.; Zwahlen, A. G. Org.
Process Res. Dev. 1999, 3, 266. For other semi-syntheses
from shikimic acid, see: (e) Nie, L.-D.; Shi, X.-X.
Tetrahedron: Asymmetry 2009, 20, 124. (f) Nie, L.-D.; Shi,
X.-X.; Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970.
(g) Karpf, M.; Trussardi, R. Angew. Chem. Int. Ed. 2009, 48,
5760. (h) Nie, L.-D.; Shi, X.-X.; Quan, N.; Wang, F.-F.; Lu,
X. Tetrahedron: Asymmetry 2011, 22, 1692. (i) Nie, L.-D.;
Ding, W.; Shi, X.-X.; Quan, N.; Lu, X. Tetrahedron:
Asymmetry 2012, 23, 742. (j) Kim, H.-K.; Park, K.-J. J.
Tetrahedron Lett. 2012, 53, 1561.
(4) For review articles on synthetic strategies to oseltamivir, see:
(a) Magano, J. Tetrahedron 2011, 67, 7875. (b) Magano, J.
Chem. Rev. 2009, 109, 4398. (c) Shibasaki, M.; Kanai, M.
Eur. J. Org. Chem. 2008, 1839. (d) Farina, V.; Brown, J. D.
Angew. Chem. Int. Ed. 2006, 45, 7330.
(5) Suaifan, G. A. R. Y.; Arafatb, T.; Threadgilla, M. D. Bioorg.
Med. Chem. 2007, 15, 3474.
(6) (a) Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.;
Fukuyama, T. Synthesis 2002, 1121. (b) For a review article
on this reaction, see: Fukuyama, T.; Tokuyama, H.
Aldrichimica Acta 2004, 37, 87.
(7) Trajkovic, M.; Ferjancic, Z.; Saicic, R. N. Tetrahedron:
Asymmetry 2012, 23, 602.
(8) (a) Recently, aldehyde 7 was prepared by essentially the
same procedure: Hoye, A. T.; Wipf, P. Org. Lett. 2011, 13,
2634. (b) However, the aldehyde 7 was not purified, nor has
its optical purity been determined; instead, it was
(3) (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 6310. (b) Fukuta, Y.; Mita, T.; Fukuda, N.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6312. (c) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.;
Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.;
Wong, C.-H. J. Am. Chem. Soc. 2007, 129, 11892. (d) Satoh,
immediately methylenated in a Wittig reaction, to give the
product of 70% ee. According to our results, the reported
decrease in optical purity of the product is not a consequence
Synthesis 2013, 45, 389–395
© Georg Thieme Verlag Stuttgart · New York

PAPER
of the aldehyde’s inherent instability, but most probably of
Synthesis of (–)-Oseltamivir Phosphate
395
(9) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(10) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538.
(11) [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]di-
chloro(phenylmethylene)(tricyclohexylphosphine)rutheniu
m: Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(12) Blot, V.; Jacquemard, U.; Reissig, H.-U.; Kleuser, B.
Synthesis 2009, 759.
(13) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org.
Lett. 2003, 5, 1031.
basic conditions used in the cited work. The optical purity of
the aldehyde was determined by its oxidation to acid 8 with
Oxone® and comparison of the optical rotation data.
Reduction to the corresponding alcohol proved unsuitable,
due to side reactions, such as the migration of Boc group
during reduction with NaBH4. (c) For the side reaction, see:
Bunch, L.; Norrby, P.-O.; Frydenvang, K.; Krogsgaard-
Larsen, P.; Madsen, U. Org. Lett. 2001, 3, 433. (d) For 1H
and 13C NMR spectra of aldehyde 7, see: Rassu, G.; Zanardi,
F.; Battistini, L.; Gaetani, E.; Casiraghi, G. J. Med. Chem.
1997, 40, 167.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 389–395