Synthesis of (-)-oseltamivir phosphate (tamiflu) starting from cis-2,3-bis(hydroxymethyl)aziridine

Article abstract of DOI:10.1021/jo3015853

Oseltamivir phosphate (Tamiflu) has been synthesized from cis-2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis(hydroxymethyl)aziridine with a Boc group, desymmetrization provided a chiral aziridine, which was a key intermediate to install the required stereogenic center containing a nitrogen atom. Allylation and ring closing metathesis are the key reactions to obtain the cyclic product that was successfully converted to the desired oseltamivir phosphate.

Full text of DOI:10.1021/jo3015853

Note
pubs.acs.org/joc
Synthesis of (−)-Oseltamivir Phosphate (Tamiflu) Starting from cis-
2,3-Bis(hydroxymethyl)aziridine
Hong-Se Oh and Han-Young Kang*
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea
S
* Supporting Information
ABSTRACT: Oseltamivir phosphate (Tamiflu) has been synthesized from cis-
2,3-bis(hydroxymethyl)aziridine. After protection of the cis-2,3-bis-
(hydroxymethyl)aziridine with a Boc group, desymmetrization provided a chiral
aziridine, which was a key intermediate to install the required stereogenic center
containing a nitrogen atom. Allylation and ring closing metathesis are the key
reactions to obtain the cyclic product that was successfully converted to the
desired oseltamivir phosphate.
euraminidase, responsible for cleaving sialic acid residues,
to secure the required stereogenic centers in oseltamivir
phosphate.5,6 Our retrosynthetic analysis is shown in Figure 1.
N
is a popular target for developing anti-influenza drugs.1
Oseltamivir (Tamiflu) and zanamivir (Relenza) were originally
designed as transition state analogues according to the
proposed mechanism of the action of neuraminidase. They
are two of the most typical inhibitors for neuraminidase. The
recent worldwide outbreak of swine flu (H1N1 human flu) and
potential threat of avian flu have drawn attention to securing
anti-influenza drugs in order to safeguard public health.
Importantly, many countries are in need of a large stock of
Tamiflu, which was first developed by Gilead Sciences, in order
to prepare for a possible influenza outbreak. This recent global
need for Tamiflu has led to intensive studies aimed at the
development of new synthetic pathways for this neuraminidase
inhibitor.2 Thus far, many synthetic schemes utilizing readily
available and inexpensive starting materials and key inter-
mediates have been reported. Many of them already contain a
cyclohexane ring or are linear materials that undergo cyclization
at the later stage of the synthesis.
Aziridines are key intermediates useful for establishing
stereogenic centers containing nitrogen atoms.3 Since Tamiflu
(oseltamivir) contains three stereogenic centers, two of which
are attached to nitrogen atoms, this led us to examine a
synthetic scheme in which an aziridine ring can be used to
establish the stereogenic centers existing in Tamiflu. In fact,
ring-opening of epoxide and/or aziridine intermediates has
been employed for the purpose of introducing the nitrogen-
containing stereogenic centers in previously reported syntheses
of oseltamivir. Utilization of aziridines for the synthesis of
oseltamivir was reported by Shibasaki et al. They used a
synthetic pathway based on the asymmetric ring-opening of N-
3,5-dinitrobenzoylaziridine with TMSN3 in the presence of an
yttrium catalyst.4
Figure 1. Retrosynthetic analysis of oseltamivir.
The target, oseltamivir (1), could be derived from cyclic
aziridine 2. This aziridine could, in principle, be synthesized by
addition of an organometallic reagent derived from allyl halide
3 to an aldehyde 4 followed by ring-closing metathesis.7
Aldehyde 4, in turn, could be derived from cis-aziridine 5.
Our plan for our asymmetric synthesis of oseltamivir (1) is
based on enzymatic desymmetrization of cis-aziridinediol 5a,
which was prepared from protected aziridine 65 through Boc-
protection of nitrogen followed by deprotection of the hydroxyl
groups using TBAF. Amano Lipase PS was best for our
purpose8 for the subsequent desymmetrization,9 which
successfully gave acetate 7 [[α]25 +16.8 (c 4.50, CHCl3)].
D
The enatiomeric purity of 7 was determined after converting to
7a (>99% ee). Protection of 7 with TBS group followed by
hydrolysis provided alcohol 9. Oxidation of alcohol 9 offered
aldehyde 4a. The next key step was allylation. Addition of the
allylzinc reagent,10 prepared by the reaction of Zn and allyl
We were interested in the synthesis of oseltamivir utilizing an
enantiomerically pure aziridine intermediate. We realized that
cis-2,3-bis(hydroxymethyl)aziridine (5), which is a meso
analogue and easily convertible to an enatiomerically pure
starting material by enzymatic desymmetrization, could be used
Received: July 26, 2012
© XXXX American Chemical Society
A
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Note
bromide 3a, to aldehyde 4a successfully produced homoallyl
alcohols 10a and 10b in a ratio of ca. 3:1 (71 and 25% yield,
respectively).
At this point, we hopefully assumed that the major isomer
10a had the stereochemistry as shown in Scheme 1, although
was increased to 68% after unreacted starting material was
recovered and resubjected to RCM conditions. The second-
generation Hoveyda−Grubbs catalyst11 did not show improve-
ment in the yield of this RCM reaction. An attempt to remove
the Boc protection group (in order to replace it with an acetyl
group) by exposure to acid (TFA, CH2Cl2) led to
decomposition of the product, presumably resulting from a
process involving opening of the aziridine ring, and this forced
us to alter the synthetic route.
Scheme 1. Synthesis of Homoallyl Alcohol 10
The aziridine ring in 14 was opened regioselectively with 3-
pentanol in the presence of a Lewis acid, successfully producing
15 (Scheme 3). The Boc group was converted to an acetyl
Scheme 3. Completion of the Total Synthesis
group upon treating with TFA followed by Ac2O. The product
16 exhibited spectral properties identical to those reported in
the literature.2b This confirmed that 10a obtained after
allylation did in fact have the correct stereochemistry for the
synthesis of oseltamivir. The total synthesis was completed
according to the previously reported three-step pathway to give
oseltamivir (1) as a phosphate salt, the spectroscopic properties
of which were identical to those reported in the literature.2h
In conclusion, oseltamivir phosphate (Tamiflu) was success-
fully synthesized. The method relies on an aziridine ring, which
was utilized to provide the required stereocenters, and an RCM
reaction, which was employed to achieve the cycilization. The
total synthesis shown here successfully opens another synthetic
route for this important, biologically active compound.
the stereochemistry was not confirmed until after it was
converted to the final target. Nonetheless, 10a was treated with
MsCl to provide mesylate 11 (Scheme 2). The TBS group was
removed to give the alcohol, which was oxidized to give
aldehyde 12. The Wittig reaction provided olefin 13, which set
the stage for the critical cyclization. Ring-closing metathesis
using the second-generation Grubbs catalyst successfully
provided the desired compound 14, in 55% yield. The yield
EXPERIMENTAL SECTION
■
General Methods. 1H NMR spectra were recorded on 400 or 500
MHz spectrometer at ambient temperature with CDCl3 as the solvent
unless otherwise stated. 13C NMR spectra were recorded on 100 or
125 MHz spectrometer (with complete proton decoupling) at ambient
temperature. High-resolution FAB mass spectra were recorded with a
double-focusing magnetic sector mass spectrometer in positive ion
mode. Flash chromatography was performed using 230−400 mesh
silica gel.
Scheme 2. Synthesis of 14
(2S,3R)-tert-Butyl 2-(acetoxymethyl)-3-(hydroxymethyl)-
aziridine-1-carboxylate (7). To a solution of cis-2,3-bis(t-butyl-
dimethylsilyloxymethyl)aziridine (6)5 (5.3 g, 16.0 mmol) in CH2Cl2
(50 mL) at 0 °C were added triethylamine (4.5 mL, 32.0 mmol) and
di-tert-butyl dicarbonate (5.2 g, 24.0 mmol). The solution was stirred
for 10 min at 0 °C before it was warmed to room temperature. After
additional stirring for 2 h at room temperature aqueous saturated
NaHCO3 (30 mL) was added to the solution. The mixture was
extracted with CH2Cl2 (3 × 30 mL). The organic layer was separated,
dried (MgSO4), and concentrated. Purification by flash chromatog-
raphy (hexane/EtOAc = 7:1) offered the desired Boc-protected
aziridine (6.10 g, 88%) as a colorless liquid: IR (film) 2929, 2857,
B
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Note
1
1728, 1472, 1391, 1368, 1304, 1257, 1168, 1093, 1007, 939 cm−1; H
NMR (400 MHz, CDCl3) δ 0.02 (s, 6H), 0.02 (s, 6H), 0.85 (s, 18H),
1.38 (s, 9H), 2.57 (m, 2H), 3.58 (ddd, J = 1.4, 4.0, 11.4 Hz, 2H), 3.74
(ddd, J = 1.8, 4.2, 11.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
162.0, 80.8, 61.4, 42.3, 27.8, 25.8, 18.2, −5.4, −5.5; HRMS (FAB)
calcd for C21H45NO4Si2 + H 432.2965, found 432.2963.
To a stirred solution of the Boc-protected aziridine (6.10 g, 14.1
mmol), prepared in the preceding procedure, in dry THF (100 mL) at
room temperature was added 1.0 M in THF solution of
tetrabutylammonium fluoride (TBAF) (33.9 mL, 33.9 mmol) via a
syringe. After 2 h, the reaction mixture was concentrated. Purification
by flash chromatography (EtOAc) offered the desired cis-Boc-
protected aziridine diol 5a (2.2 g, 76%) as a colorless liquid: IR
(film) 3369, 2975, 1716, 1459, 1369, 1304, 1158, 1046, 838, 785 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.32 (s, 9H), 2.62 (m, 2H), 2.75 (m,
(s, 3H), 2.66 (m, 1H), 2.74 (m, 1H), 3.56 (dd, J = 6.5, 11.4 Hz, 1H),
3.86 (dd, J = 5.5, 11.4 Hz, 1H), 4.06 (dd, J = 7.2, 11.9 Hz, 1H), 4.18
(dd, J = 5.3, 11.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.6,
161.5, 81.3, 62.2, 61.1, 42.0, 38.8, 27.7, 25.7, 20.7, 18.1, −5.4, −5.5;
HRMS (FAB) calcd for C17H33NO5Si + H 360.2206, found 360.2202.
(2R,3S)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-
(hydroxymethyl)aziridine-1-carboxylate (9). To a solution of
TBS-protected aziridine 8 (1.36 g, 3.78 mmol) in methanol (15 mL)
was added potassium carbonate (K2CO3) (627 mg, 4.54 mmol) at
room temperature, and the solution was stirred for 2 h at room
temperature. After reaction was completed, aqueous saturated NH4Cl
solution (15 mL) was added. The mixture was extracted with ether (3
× 10 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification by flash chromatography (hexane/EtOAc =
7:1) offered the alcohol 9 (1.04 g, 87%) as a colorless oil: [α]21D +22.7
(c 1.52, CHCl3); IR (film) 3435, 2936, 1727, 1467, 1368, 1303, 1161,
2H), 3.78 (m, 2H), 4.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
162.0, 81.6, 59.6, 41.5, 27.5; HRMS (FAB) calcd for C9H17NO4 + H
204.1236, found 204.1232.
1
1094, 836, 776 cm−1; H NMR (500 MHz, CDCl3) δ 0.09 (s, 3H),
010 (s, 3H), 0.89 (s, 9H), 1.44 (s, 9H), 2.50 (m, 1H), 2.74 (m, 2H),
3.51 (dd, J = 8.1, 11.5 Hz, 1H), 3.56 (ddd, J = 4.4, 7.2 12.0 Hz, 1H),
3.89 (ddd, J = 5.5, 9.0, 12.0 Hz, 1H), 4.09 (dd, J = 5.3, 11.4 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 161.7, 81.6, 61.6, 60.8, 41.6, 41.2,
27.8, 18.2, −5.4, −5.5; HRMS (FAB) calcd for C15H31NO4Si + H
318.2101, found 318.2103.
To a solution of Boc-protected aziridinediol 5a (1.00 g, 4.92 mmol)
in n-hexane/THF = 10:1 (55 mL) at room temperature were added
vinyl acetate (2.26 mL, 24.6 mmol) and amano lipase PS (500 mg).
The mixture was stirred for 3 h at 37 °C. After TLC showed that the
reaction was completed, the mixture was filtered through a pad of
Celite. The Celite pad was washed with EtOAc (3 × 10 mL). After the
combined filtrate was concentrated, purification by flash chromatog-
raphy (hexane/EtOAc = 4:1) offered the desired chiral aziridine 7
(818 mg, 68%) as a colorless liquid: [α]25D +16.8 (c 4.50, CHCl3); IR
(film) 3437, 2979, 1722, 1452, 1370, 1306, 1231, 1158, 1043, 843
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 9H), 1.99 (s, 3H), 2.64
(m, 2H), 3.19 (bs, 1H), 3.54 (m, 1H), 3.74 (dq, J = 5.4, 12.1 Hz, 1H),
4.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.8, 161.4, 81.5,
61.6, 59.7, 41.8, 38.8, 27.5, 20.5; HRMS (FAB) calcd for C11H19NO5 +
H 246.1341, found 246.1344.
(2R,3S)-1-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-
formylaziridine-1-carboxylate (4a). The alcohol 9 (1.62 g, 5.10
mmol) was dissolved in CH2Cl2 (50 mL). To this solution was added
Dess−Martin periodinane (DMP) (4.30 g, 10.2 mmol). The resulting
solution was stirred for 2 h at room temperature. After the reaction
was completed, aqueous saturated NaHCO3 (30 mL) and aqueous
saturated Na2S2O3 (15 mL) were added. The mixture was extracted
with CH2Cl2 (3 × 30 mL). The organic layer was separated, dried
(MgSO4), and concentrated. Purification by flash chromatography
(hexane/EtOAc = 7:1) offered the desired aldehyde 4a (1.40 g, 87%)
as a colorless oil: [α]22D −70.8 (c 1.32, CHCl3); IR (film) 2931, 2857,
(2S,3R)-tert-Butyl 2-(acetoxymethyl)-3-(benzoyloxymethyl)-
aziridine-1-carboxylate (7a). To a solution of cis-chiral aziridine 7
(8.0 mg, 0.033 mmol) in CH2Cl2 (3 mL) at 0 °C were added DMAP
(2.1 mg, 0.017 mmol), triethylamine (7.0 μL, 0.050 mmol) and
benzoyl chloride (5.0 μL, 0.043 mmol). The solution was stirred for 20
min at 0 °C before it was warmed to room temperature. After
additional stirring for 2 h at room temperature aqueous saturated
NH4Cl (5 mL) was added to the solution. The mixture was extracted
with CH2Cl2 (3 × 5 mL). The organic layer was separated, dried
(MgSO4), and concentrated. Purification by flash chromatography
(hexane/EtOAc = 4:1) offered the desired Bz-protected aziridine (9.0
mg, 75%) as a colorless liquid. The ee of 7a was determined by chiral
HPLC: Chiralcel OD-H column, n-hexane/2-propanol = 95:5, 0.5 mL
min−1, 40 °C isothermal; λdetector = 229 nm; Retention times tR = 16.4 min
(major), tR = 19.0 min (minor) [major/minor = 99.9:0.1 → (>99%
1
1729, 1472, 1392, 1368, 1293, 1256, 1159, 839 cm−1; H NMR (400
MHz, CDCl3) δ 0.01 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H), 1.41 (s, 9H),
2.90 (m, 1H), 2.98 (dd, J = 4.8, 6.9 Hz, 1H), 3.79 (dd, J = 4.4, 11.7 Hz,
1H), 3.91 (dd, J = 4.3, 11.7 Hz, 1H), 9.33 (d, J = 4.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 197.0, 160.3, 82.3, 60.1, 45.8, 45.0, 27.7,
25.7, 18.2, −5.6; HRMS (FAB) calcd for C15H29NO4Si + H 316.1944,
found 316.1945.
(2R,3S)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-
((R)-3-(ethoxycarbonyl)-1-hydroxybut-3-en-1-yl)aziridine-1-
carboxylate (10a) and (2R,3S)-tert-Buyl 2-((tert-butyldimethyl-
silyloxy)methyl)-3-[(S)-3-(ethoxycarbonyl)-1-hydroxybut-3-en-
1-yl]aziridine-1-carboxylate (10b). To a solution of aldehyde 4a
(1.40 g, 4.44 mmol) in a mixture of THF (30 mL) and aqueous
saturated NH4Cl (30 mL) were added zinc dust (844 mg, 13.3 mmol)
and ethyl 3-bromomethylacrylate (3a) (2.57 g, 13.3 mmol) at 0 °C.
The mixture was stirred for 4 h at 0 °C and then diluted with ether (30
mL) and water (30 mL). The mixture was extracted with ether (3 × 30
mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification by flash chromatography (hexane/EtOAc
= 4:1) offered the desired alcohol 10a (1.35 g, 71%) and alcohol 10b
ee)] [α]30 +0.60 (c 0.90, CHCl3); IR (film) 2977, 2928, 1727, 1602,
D
1
1452, 1369, 1271, 1158, 1113, 1039, 979 cm−1; H NMR (400 MHz,
CDCl3) δ 1.43 (s, 9H), 2.06 (s, 3H), 2.87 (q, J = 6.4 Hz, 1H), 2.96 (q,
J = 6.4 Hz, 1H), 4.19 (dd, J = 6.2, 12.0 Hz, 1H), 4.27 (dd, J = 6.6, 12.0
Hz, 1H), 4.42 (dd, J = 2.1, 6.7 Hz, 2H), 7.45 (m, 2H), 7.58 (m, 1H),
8.08 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.6, 166.2, 161.1,
133.2, 129.7, 129.7, 128.4, 81.9, 62.6, 62.1, 38.9, 38.7, 27.8, 20.7;
HRMS (ESI) calcd for C11H23NO6 + Na 372.1418, found 372.1422.
(2S,3R)-tert-Butyl 2-(acetoxymethyl)-3-((tert-butyldimethyl-
silyloxy)methyl)aziridine-1-carboxylate (8). To a stirred solution
of the chiral aziridine 7 (810 mg, 3.30 mmol) in CH2Cl2 (10 mL) were
added imidazole (337 mg, 4.95 mmol) and TBSCl (597 mg, 3.96
mmol) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C
before it was warmed to room temperature. After additional stirring for
1 h at room temperature aqueous saturated NaCl (10 mL) was added
to the solution. The mixture was extracted with CH2Cl2 (3 × 10 mL)
and the organic layer was separated, dried (MgSO4), and concentrated.
Purification by flash chromatography (hexane/EtOAc = 7:1) offered
the desired TBS-protected aziridine 8 (1.01 g, 94%) as a colorless oil:
[α]22D +18.0 (c 1.30, CHCl3); IR (film) 2929, 2856, 1727, 1465, 1369,
1304, 1230, 1159, 1097, 1038, 838 cm−1; 1H NMR (400 MHz,
CDCl3) δ 0.05 (s, 3H), 0.06 (s, 3H), 0.87 (s, 9H), 1.42 (s, 9H), 2.07
(480 mg, 25%) as a colorless oil. 10a: [α]21 +13.1 (c 1.73, CHCl3);
D
IR (film) 3460, 2937, 2364, 1719, 1629, 1467, 1368, 1302, 1264, 1161,
1
950, 836 cm−1; H NMR (400 MHz, CDCl3) δ - 0.04 (s, 3H), - 0.03
(s, 3H), 0.77 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H), 1.31 (s, 9H), 2.38 (dd, J
= 6.5, 8.6 Hz, 1H), 2.48 (dd, J = 8.4, 14.6 Hz, 1H), 2.57 (q, J = 6.2 Hz,
1H), 2.73 (dd, J = 3.6, 14.7 Hz, 1H), 3.14 (d, J = 2.0 Hz, 1H), 3.50 (m,
2H), 3.91 (dd, J = 6.0, 11.4 Hz, 1H), 4.07 (dq, J = 1.3, 7.1 Hz, 2H),
5.66 (d, J = 1.0 Hz, 1H), 6.14 (d, J = 1.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 167.1, 161.2, 136.5, 127.1, 80.9, 68.7, 61.7, 60.4, 44.7,
41.3, 37.2, 27.5, 25.5, 17.9, 13.8, −5.7, −5.8; HRMS (FAB) calcd for
C21H39NO6Si + H 430.2625, found 430.2622. 10b: [α]21 +0.44 (c
D
1.66, CHCl3); IR (film) 3451, 2930, 2857, 1720, 1631, 1472, 1392,
1368, 1302, 1255, 1159, 1082, 942 cm−1; 1H NMR (400 MHz,
CDCl3) δ −0.05 (s, 3H), −0.03 (s, 3H), 0.78 (s, 9H), 1.17 (t, J = 7.1
Hz, 3H), 1.33 (s, 9H), 2.43 (m, 2H), 2.56 (m, 2H), 2.70 (bs, 1H), 3.58
(m, 2H), 3.70 (dd, J = 6.2, 11.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 5.62
C
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Note
(d, J = 1.1 Hz, 1H), 6.15 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 166.7, 161.6, 136.3, 127.4, 81.0, 67.7, 61.1, 60.4, 45.8, 42.8,
37.5, 27.6, 25.6, 17.9, 13.9, −5.6, −5.7; HRMS (FAB) calcd for
C21H39NO6Si + H 430.2625, found 430.2621.
dried (MgSO4), and concentrated. Purification by flash chromatog-
raphy (hexane/EtOAc = 4:1) offered the desired vinylaziridine 13
(420 mg, 63%) as a colorless oil: [α]20 +25.1 (c 1.33, CHCl3); IR
D
(film) 2979, 2932, 1717, 1629, 1502, 1338, 1246, 1175, 1094, 957
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.41 (s,
9H), 2.71 (m, 2H), 2.89 (s, 3H), 2.99 (dd, J = 3.3, 14.6 Hz, 1H), 3.10
(t, J = 6.0 Hz, 1H), 4.17 (m, 2H), 4.60 (ddd, J = 3.6, 8.2, 9.4 Hz, 1H),
5.35 (d, J = 11.0 Hz, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.74 (s, 1H), 5.80
(ddd, J = 5.9, 10.4, 16.8 Hz, 1H), 6.28 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 166.1, 161.1, 134.9, 131.0, 128.9, 120.1, 81.7, 76.4, 60.8,
44.5, 43.4, 38.5, 36.6, 27.7, 14.0; HRMS (FAB) calcd for C17H27NO7S
+ Na 412.1406, found 412.1402.
Ethyl (1S,5R,6S)-7-(tert-butoxycarbonyl)-5-(methanesulfony-
loxy)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate (14). To a
stirred solution of vinylaziridine 13 (44 mg, 0.12 mmol) in dry CH2Cl2
(10 mL) at at room temperature was added Grubbs catalyst (second
generation) (10 mg, 0.012 mmol), producing a light brown solution,
which was stirred for 18 h at 40 °C. The mixture was then
concentrated. Purification by flash chromatography (hexane/EtOAc =
4:1) offered the desired aziridine 14 (24 mg, 55%) as a brown oil:
[α]22D −8.29 (c 1.62, CHCl3); IR (film) 2980, 2940, 1711, 1360, 1291,
1256, 1175, 1078, 951 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.26 (t, J
= 7.2 Hz, 3H), 1.44 (s, 9H), 2.37 (ddd, J = 3.4, 10.2, 13.6 Hz, 1H),
3.03 (ddd, J = 1.8, 6.7, 8.5 Hz, 1H), 3.10 (dd, J = 4.7, 6.3 Hz, 1H), 3.17
(s, 3H), 3.35 (td, J = 2.0, 6.4 Hz, 1H), 4.19 (dq, J = 1.4, 7.2 Hz, 2H),
4.98 (ddd, J = 2.3, 6.7, 9.0 Hz, 1H), 7.09 (dd, J = 3.5, 4.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 164.9, 160.4, 132.6, 131.2, 82.5, 75.1, 61.1,
40.7, 39.3, 36.0, 27.7, 26.5, 14.1; HRMS (FAB) calcd for C15H23NO7S
+ Na 384.1093, found 384.1095.
(2R,3S)-1-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-
((R)-3-(ethoxycarbonyl)-1-(methanesulfonyloxy)but-3-en-1-yl)-
aziridine-1-carboxylate (11). To a stirred solution of the alcohol
10a (1.35 g, 3.14 mmol) in CH2Cl2 (50 mL) were added triethylamine
(1.53 mL, 11.0 mmol) and methanesulfinyl chloride (0.73 mL, 9.42
mmol) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C
before it was warmed to room temperature. After additional stirring for
2 h at room temperature water (50 mL) was added to the solution.
The mixture was extracted with CH2Cl2 (3 × 50 mL). The organic
layer was separated, dried (MgSO4), and concentrated. Purification by
flash chromatography (hexane/EtOAc = 4:1) offered the desired Ms-
protected aziridine 11 (1.33 g, 84%) as a colorless oil: [α]22D −1.55 (c
1.33, CHCl3); IR (film) 2937, 1713, 1630, 1518, 1337, 1186, 1044,
1
964, 915 cm−1; H NMR (400 MHz, CDCl3) δ 0.08 (s, 3H), 0.09 (s,
3H), 0.89 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.44 (s, 9H), 2.71 (m, 3H),
3.00 (s, 3H), 3.02 (m, 1H), 3.82 (m, 2H), 4.21 (dq, J = 2.5, 7.2 Hz,
2H), 4.73 (ddd, J = 3.6, 7.4, 9.4 Hz, 1H), 5.78 (s, 1H), 6.32 (d, J = 0.9
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.2, 161.2, 134.9, 129.0,
81.6, 77.0, 61.0, 60.8, 43.4, 42.7, 38.6, 36.8, 27.7, 25.8, 18.2, 14.0, −5.4,
−5.5; HRMS (FAB) calcd for C22H41NO8SSi + H 508.2400, found
508.2402.
(2S,3R)-tert-Butyl 2-((R)-3-(ethoxycarbonyl)-1-(methane-
sulfonyloxy)but-3-en-1-yl)-3-formylaziridine-1-carboxylate
(12). To a stirred solution of Ms-protected aziridine 11 (1.33 g, 2.62
mmol) in dry THF (50 mL) at 0 °C was added tetrabutylammonium
fluoride (TBAF) [5.24 mL (1.0 M in THF), 5.24 mmol] via a syringe.
After 2 h, the reaction mixture was concentrated. Purification by flash
chromatography (hexane/EtOAc = 2:1) offered the desired alcohol
Ethyl (3R,4S,5R)-4-(tert-butoxycarbonylamino)-3-(1-ethyl-
propoxy)-5-(methanesulfonyloxy)cyclohex-1-ene-1-carboxy-
late (15). To a stirred solution of aziridine 14 (60 mg, 0.17 mmol) in
3-pentanol (5 mL) at −8 °C was added BF3·OEt2 (31 μL, 0.25 mmol)
in 3-pentanol (2 mL) via a syringe. The reaction mixture was stirred
for 1 h at −8 °C. The mixture was diluted with EtOAc (10 mL) and an
aqueous solution of potassium carbonate (15% w/v, 10 mL). The
organic phase was separated and washed with water (5 mL) and brine
(5 mL). The organic layer was dried (MgSO4), and concentrated.
Purification by flash chromatography (hexane/EtOAc = 4:1) offered
the compound 15 (62 mg, 84%) as a white solid: mp 157−158.5 °C;
[α]19D −75.4 (c 1.52, CHCl3); IR (film) 3363, 2968, 2929, 1720, 1681,
(744 mg, 72%) as a colorless oil: [α]22 +1.78 (c 1.23, CHCl3); IR
D
(film) 3400, 2979, 1718, 1511, 1369, 1258, 1172, 1090, 1061, 944, 859
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 3H), 1.35 (s,
9H), 2.62−2.73 (m, 3H), 2.86 (bs, 1H), 2.93 (s, 3H), 2.98 (m, 1H),
3.54 (m, 1H), 3.81 (m, 1H), 4.13 (m, 2H) 4.65 (ddd, J = 3.5, 9.2, 9.2
Hz, 1H), 5.72 (s, 1H), 6.24 (d, J = 1.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 166.1, 160.9, 134.8, 128.9, 81.7, 76.2, 60.7, 59.3, 43.1, 43.0,
38.1, 36.6, 27.5, 13.9; HRMS (FAB) calcd for C16H27NO8S + Na
416.1355, found 416.1352.
1
1523, 1459, 1344, 1259, 1173, 1066, 984 cm−1; H NMR (500 MHz,
The alcohol (744 mg, 1.89 mmol), prepared in the preceding
procedure, was dissolved in CH2Cl2 (40 mL). To this solution was
added Dess−Martin periodinane (DMP) (1.60 g, 3.78 mmol). The
resulting solution was stirred for 2 h at room temperature. After the
reaction was completed, aqueous saturated NaHCO3 (20 mL) and
aqueous saturated Na2S2O3 (10 mL) were added. The mixture was
extracted with CH2Cl2 (3 × 30 mL). The organic layer was separated,
dried (MgSO4), and concentrated. Purification by flash chromatog-
raphy (hexane/EtOAc = 2:1) offered the desired aldehyde 12 (670
CDCl3) δ 0.89−0.94 (m, 6H), 1.29 (t, J = 7.1 Hz, 3H), 1.43 (s, 9H),
1.49−1.55 (m, 4H), 2.76 (m, 2H), 3.04 (s, 3H), 3.39 (m, 1H), 3.99
(m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.77 (bd, J = 4.1 Hz, 1H), 5.22 (bs,
1H), 6.85 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 165.6, 155.4,
136.5, 127.8, 82.4, 80.2, 77.6, 72.8, 61.1, 52.8, 38.8, 29.6, 29.3, 28.3,
26.3, 26.0, 14.1, 9.6, 9.3; HRMS (FAB) calcd for C20H35NO8S + Na
472.1981, found 472.1981.
Ethyl (3R,4S,5R)-4-(acetamido)-3-(1-ethylpropoxy)-5-
(methanesulfonyloxy)cyclohex-1-ene-1-carboxylate (16). The
compound 15 (51 mg, 011 mmol) was dissolved in CH2Cl2 (10 mL)
at 0 °C. To this solution was added TFA (168 μL, 2.26 mmol). The
resulting solution was stirred for 1 h at 0 °C, before it was warmed to
room temperature. After additional stirring for 18 h at room
temperature, the solution was concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 (10 mL) at 0 °C. To this
solution were added triethylamine (78 μL, 0.57 mmol) and acetic
anhydride (16 μL, 0.17 mmol). The solution was stirred for 10 min at
0 °C before it was warmed to room temperature. After additional
stirring for 3 h at room temperature, the reaction mixture was
concentrated. Purification by flash chromatography (hexane/EtOAc =
4:1) offered the desired acetyl-protected 16 (41 mg, 93%) as a white
mg, 91%) as a colorless oil: [α]20 +48.6 (c 1.54, CHCl3); IR (film)
D
1
2982, 1727, 1633, 1368, 1293, 1156, 919, 848 cm−1; H NMR (500
MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.38 (s, 9H), 2.67 (dd, J =
9.1, 14.5 Hz, 1H), 2.87 (s, 3H), 2.94 (t, J = 7.1 Hz, 1H), 2.98 (m, 1H),
3.16 (dd, J = 4.1, 6.4 Hz, 1H), 4.17 (m, 2H), 4.72 (ddd, J = 3.9, 7.3, 9.1
Hz, 1H), 5.74 (d, J = 0.5 Hz, 1H), 6.28 (d, J = 0.9 Hz, 1H), 9.37 (d, J
= 4.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 195.3, 166.0, 159.1,
134.2, 129.5, 83.0, 75.7, 60.9, 45.2, 45.0, 38.1, 36.3, 27.5, 13.9; HRMS
(FAB) calcd for C16H25NO8S + H 392.1379, found 392.1382.
(2S,3S)-tert-Butyl 2-((R)-3-(ethoxycarbonyl)-1-
(methanesulfonyloxy)but-3-en-1-yl)-3-vinylaziridine-1-carbox-
ylate (13). To a solution of methyltriphenylphosphonium bromide
(1.83 g, 5.13 mmol) in THF (15 mL) was added potassium
bis(trimethylsilyl)amide (KHMDS) (10.26 mL (0.5 M in toluene),
5.13 mmol), and the mixture was stirred for 30 min at −20 °C. After
dropwise addition of a solution of aldehyde 12 (670 mg, 1.71 mmol)
in THF (3 mL) to the above solution via cannula, the reaction mixture
was stirred for 3 h at −20 °C. After the reaction was completed,
aqueous saturated NH4Cl (20 mL) was added. The mixture was
extracted with ether (3 × 20 mL). The organic layer was separated,
solid: mp 137−138.5 °C; [α]24 −82.6 (c 1.20, EtOAc); IR (film)
D
3298, 2967, 2932, 1716, 1650, 1543, 1344, 1260, 1175, 1098, 1042,
1
906 cm−1; H NMR (500 MHz, CDCl3) δ 0.92 (t, J = 7.4 Hz, 6H),
1.31 (t, J = 7.1 Hz, 3H), 1.49−1.59 (m, 4H), 2.03 (s, 3H), 2.70 (m,
1H), 2.86 (m, 1H), 3.05 (s, 3H), 3.39 (m, 1H), 4.07 (m, 1H), 4.24 (q,
J = 7.1 Hz, 2H), 4.32 (ddd, J = 2.4, 8.0, 10.4 Hz, 1H), 5.25 (ddd, J =
2.5, 4.4, 6.9, 1H), 5.72 (d, J = 8.0, 1H), 6.88 (s, 1H); 13C NMR (125
D
dx.doi.org/10.1021/jo3015853 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
MHz, CDCl3) δ 170.5, 165.7, 136.9, 127.6, 82.3, 77.9, 72.5, 61.2, 51.6,
38.7, 29.7, 26.3, 25.9, 23.3, 14.2, 9.5, 9.4; HRMS (FAB) calcd for
C17H30NO7S + H 392.1743, found 392.1745.
Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron 2009, 65, 3239.
(f) 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. (g) Kamimura, A.; Nakano, T. J.
Org. Chem. 2010, 75, 3133. (h) Ma, J.; Zhao, Y.; Ng, S.; Zhang, J.;
Zeng, J.; Than, A.; Chen, P.; Liu, X.-W. Chem.Eur. J. 2010, 16, 4533.
(i) Osato, H.; Jones, I. L.; Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12,
60. (j) Wichienukul, P.; Akkarasamiyo, S.; Kongkathip, N.;
Kongkathip, B. Tetrahedron Lett. 2010, 51, 3208. (k) Nakano, H.;
Osone, K.; Takeshita, M.; Kwon, E.; Seki, C.; Matsuyama, H.; Takano,
N.; Kohari, Y. Chem. Commun. 2010, 46, 4827. (l) Zhu, S.; Yu, S.;
Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656. (m) Ko, J. S.;
Keum, J. E.; Ko, S. Y. J. Org. Chem. 2010, 75, 7006. (n) Ishikawa, H.;
Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem.Eur. J. 2010,
16, 12616. (o) Tanaka, T.; Tan, Q.; Kawakubo, H.; Hayashi, M. J. Org.
Chem. 2011, 76, 5477. (p) Ishikawa, H.; Bondzic, B. P.; Hayashi, Y.
Eur. J. Org. Chem. 2011, 6020.
(3) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006.
(4) (a) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 6312. (b) Mita, T.; Fukuda, N.; Roca, F. X.;
Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 259.
(5) Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y.; Taga, T.; Miwa, Y.
Tetrahedron Lett. 1990, 31, 6663.
(6) Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron.
Oseltamivir Phosphate (1). To a solution of compound 16 (40
mg, 0.10 mmol) in a mixture of DMF (5 mL) and water (1 mL) was
added sodium azide (26 mg, 0.40 mmol). The mixture was heated to
90 °C and stirred at this temperature for 18 h. After the reaction
solution was cooled down to room temperature, toluene (15 mL) and
water (15 mL) were added. The organic phase was separated and
washed with water (5 mL). The organic layer was dried (Na2SO4) and
concentrated. Purification by flash chromatography (hexane/EtOAc =
4:1) offered the desired azide (32 mg, 94%) as a white solid: mp 138−
139 °C; [α]21 −44.7 (c 0.83, CHCl3); IR (film) 3726, 2969, 2100,
D
1718, 1659, 1554, 1455, 1315, 1312, 1254, 1084 cm−1; 1H NMR (500
MHz, CDCl3) δ 0.88 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 1.28
(t, J = 7.2 Hz, 3H), 1.46−1.54 (m, 4H), 2.03 (s, 3H), 2.22 (m, 1H),
2.85 (dd, J = 5.3, 17.3 Hz, 1H), 3.33 (m, 2H), 4.20 (m, 2H), 4.25
(ddd, J = 5.8, 10.6, 16.6 Hz, 1H), 4.55 (m, 1H), 6.03 (bs, 1H), 6.77 (t,
J = 2.3, 1H); 13C NMR (125 MHz, CDCl3) δ 171.1, 165.8, 137.9,
128.1, 82.0, 73.4, 61.0, 58.0, 57.2, 30.5, 26.2, 25.6, 23.5, 14.1, 9.5, 9.3;
HRMS (FAB) calcd for C16H26N4O4 + H 339.2032, found 339.2035.
To a solution of azide (12 mg, 0.035 mmol) prepared in the
previous procedure in ethanol (5 mL) was treated with Lindlar’s
catalyst (12 mg) under an atmosphere of hydrogen for 18 h at room
temperature. After filtration through a pad of Celite with ethanol (3 ×
5 mL), the solution was concentrated. The residue was dissolved in
ethanol (1 mL) and added slowly in portions to a solution of
phosphoric acid (85%, 4.0 mg, 0.042 mmol) in ethanol (1 mL). The
mixture was heated to 55 °C and stirred at this temperature for 30
min. White solids formed, and the suspension was cooled to room
temperature. Filtration and rinsing with cooled acetone afforded
oseltamivir phosphate 1 (12 mg, 86%) as a white solid: mp 202−203
°C; [α]29D −30.8 (c 0.70, H2O); 1H NMR (500 MHz, D2O) δ 0.73 (d,
J = 7.4 Hz, 3H), 0.77 (d, J = 7.4 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H),
1.33−1.48 (m, 4H), 1.97 (s, 3H), 2.41 (m, 1H), 2.85 (dd, J = 5.1, 17.2
Hz, 1H), 3.48 (m, 2H), 3.95 (t, J = 11.1 Hz, 1H), 4.14 (m, 2H), 4.22
(d, J = 8.7, 1H), 6.74 (s, 1H); 13C NMR (125 MHz, D2O) δ 175.2,
167.4, 137.8, 127.6, 84.3, 75.0, 62.3, 52.6, 49.1, 28.1, 25.4, 25.0, 22.3,
13.2, 8.5, 8.4; HRMS (FAB) calcd for C16H31N2O8P + Na 433.1716,
found 433.1719.
2001, 57, 1801.
(7) Metathesis in Natural Product Synthesis; Cossy, J., Arseniyadis, S.,
Meyer, C., Eds.; Wiley-VCH: Weinheim, 2010.
(8) Davoli, P.; Caselli, E.; Bucciarelli, M.; Forni, A.; Torre, G.; Prati,
F. J. Chem. Soc., Perkin Trans. 1 2002, 1948.
(9) (a) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611.
(b) Takabe, K.; Hashimoto, H.; Sugimoto, H.; Nomoto, M.; Yoda, H.
Tetrahedron: Asymmetry 2004, 15, 909.
(10) (a) Kameda, Y.; Nagano, H. Tetrahedron 2006, 62, 9751.
(b) Richter, F.; Bauer, M.; Perez, C.; Maichle-Mossmer, C.; Maier, M.
̈
E. J. Org. Chem. 2002, 67, 2474.
(11) (a) Kinsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) for 5a, 4a, 7, 7a, 8−16, and 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hykang@chungbuk.ac.kr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2009-0074078).
REFERENCES
■
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109, 4398. (b) Nie, L.-D.; Shi, X.-X. Tetrahedron: Asymmetry 2009, 20,
124. (c) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem. 2009, 121,
1330; Angew. Chem., Int. Ed. 2009, 48, 1304. (d) Nie, L.-D.; Shi, X.-X.;
Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970. (e) Satoh, N.;
E
dx.doi.org/10.1021/jo3015853 | J. Org. Chem. XXXX, XXX, XXX−XXX