A practical synthesis of (-)-oseltamivir

Article abstract of DOI:10.1016/j.tet.2008.09.103

Oseltamivir phosphate (Tamiflu) is a potent inhibitor of neuraminidase, and is used worldwide as a drug for type A or B influenza. The industrial synthesis of oseltamivir uses shikimic acid as a starting material, but the price fluctuates, depending on the supply of star anise. We have developed a practical synthesis of oseltamivir from pyridine, which features an asymmetric Diels-Alder reaction of dihydropyridine using MacMillan's catalyst, a bromolactonization, Hofmann rearrangement with PhI(OAc)₂, and a domino transformation of the bicyclo[2.2.2] system into an aziridine compound.

Full text of DOI:10.1016/j.tet.2008.09.103

Tetrahedron 65 (2009) 3239–3245
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A practical synthesis of (ꢀ)-oseltamivir
Nobuhiro Satoh, Takahiro Akiba, Satoshi Yokoshima, Tohru Fukuyama
*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Oseltamivir phosphate (TamifluÒ) is a potent inhibitor of neuraminidase, and is used worldwide as a drug
for type A or B influenza. The industrial synthesis of oseltamivir uses shikimic acid as a starting material,
but the price fluctuates, depending on the supply of star anise. We have developed a practical synthesis
of oseltamivir from pyridine, which features an asymmetric Diels–Alder reaction of dihydropyridine
using MacMillan’s catalyst, a bromolactonization, Hofmann rearrangement with PhI(OAc)2, and a domino
transformation of the bicyclo[2.2.2] system into an aziridine compound.
Article history:
Received 26 August 2008
Received in revised form 24 September
2008
Accepted 26 September 2008
Available online 10 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
a Hofmann rearrangement with PhI(OAc)2, and a domino trans-
formation of bicyclo[2.2.2] system into aziridine compound.3 Herein
In 1999, oseltamivir phosphate (1$H3PO4, TamifluÒ, Fig. 1) was
launched as a drug for type A as well as type B influenza.1 Oselta-
mivir itself is a prodrug, and the corresponding carboxylic acid,
which can be formed by hydrolysis after absorption, displays potent
inhibitory activities for influenza neuraminidases. The recent
spread of the avian virus H5N1 has prompted governments to
stockpile Tamiflu as a precautionary measure against a flu pan-
demic. Hence, the supplier, Roche, has increased the production of
Tamiflu. In addition to its remarkable potency as a drug and the
social demand, the structure of oseltamivir, including a trans-1,2-
we report our synthetic studies of oseltamivir in detail.
2. Results and discussion
2.1. Retrosynthesis
Our retrosynthetic analysis of oseltamivir is outlined in Scheme 1.
According to a report from Gilead Science, the 3-pentyl ether
could be installed by the opening of aziridine 2, which could be
formed from alcohol 3. The addition of a leaving group X to the
diamine moiety, 3-pentyl ether, and a,b-unsaturated ester in the
b-position of the ester followed by lactam formation would give
cyclohexene core, has attracted the attention of synthetic chemists.
With the goal of establishing a practical route to this densely
functionalized compound, synthetic studies toward oseltamivir
have been initiated. While numerous syntheses of oseltamivir have
been reported to date,2 we reported in 2007 an efficient synthesis of
oseltamivir, which features an asymmetric Diels–Alder reaction of
dihydropyridine using MacMillan’s catalyst, a bromolactonization,
bicyclo[2.2.2] intermediate 4. We then envisaged that 4 could
be derived from carboxylic acid 5 either by a Curtius rear-
rangement or by
a Hofmann rearrangement of the corre-
sponding amide. Lactone 6, a precursor of 5, could in turn be
derived from 7 by halolactonization. Finally, bicyclic system 7
could be constructed using an asymmetric Diels–Alder reaction
between dihydropyridine 8 and acrylic acid derivative 9.4
2.2. Synthesis of lactone 21
Our synthesis commenced with preparation of dihydropyridine
11. Thus, the reduction of pyridine (10) with sodium borohydride
in the presence of benzyl chloroformate at ꢀ50 to ꢀ35 ꢁC fur-
nished 11 in almost quantitative yield (Scheme 2).5 Higher re-
action temperature caused decomposition of CbzCl, resulting in
lower yield of 11. The Diels–Alder reaction between 11 and acro-
lein, catalyzed by MacMillan’s catalyst 12,6 afforded a mixture of
aldehydes with more than two aldehydic peaks observed in the 1H
NMR spectrum. Since it was difficult to separate these aldehydes
and fully assign the peaks in the 1H NMR spectrum because of the
rotamers about the benzyl carbamate bond, the structure of the
O
CO2Et
AcHN
NH2•H3PO4
oseltamivir phosphate (1.H3PO4)
Figure 1. Structure of oseltamivir phosphate.
* Corresponding author.
E-mail address: fukuyama@mol.f.u-tokyo.ac.jp (T. Fukuyama).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.103

3240
N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
CbzN
Cbz
2
5
N
H
O
HO
3
4
1
CO2Et
CO2Et
Cbz
N
RN
+H2O
Bn
N
Bn
AcHN
N
NH2
NH2
O
N
H
O
H
16
O
Me
oseltamivir (1)
2
N
Me
Me
15
Me
Me
O
O
2
Me
3
1
CO2Et
HO
R
R
2
N
N
X
3
X
5
4
RHN
3
5
5
Cbz
NHCbz
NH2
N
OR NHR
4
CO2H
OR
Bn
5
3
+H2O
O
N
O
H
O
N
O
N
R
+
Me
Me
17
18
8
Me
R
N
R
N
X
Scheme 3. Plausible reaction pathway of the Diels–Alder reaction.
O
CO2H
O
O
X
NaClO2
7
6
9
NaH2PO4
Cbz
Cbz
Cbz
2-methyl-
2-butene
Scheme 1. Retrosynthesis.
N
N
N
partition
t-BuOH-H2O
0 °C to rt
EtOAc
aq NaHCO3
CO2H
CO2
CHO
16
19
20
O
Me
N
12
Cbz
Cbz
Me
Me
NHCbz
Bn
N
N
N
Br2
Br
Br
HCl
H
extraction
aqNaHCO3
CH2Cl2,rt
CbzCl
+
NaBH4
MeOH
acrolein
CH3CN-H2O
rt
26%
(4steps)
a mixture of
aldehydes
O
O
N
N
CO2
O
O
Cbz
11
-50 to -35 °C
21
21
22
10
NaBH4
EtOH
Scheme 4. Bromolactonization.
Cbz
NHCbz
N
2.3. Elaboration of the bicyclic system
+
Having developed a highly efficient route to the key in-
termediate, we next focused on oxidation of the methylene group
next to the nitrogen in order to cleave the bicyclic skeleton. Since
ruthenium oxidation of 21 did not afford any desired product due to
the oxidation of the benzyl group, the Cbz group in 21 was con-
verted into a Boc group by hydrogenolysis in the presence of Boc2O
(92% yield, Scheme 5).8 Oxidation of 23 with a catalytic amount of
RuO2$nH2O (10 mol %) and NaIO4 proceeded smoothly to give imide
24 in 86% yield. In addition to rather toxic 1,2-dichloroethane,
n-propyl acetate, a much safer solvent, proved to be useful for this
mild oxidation (85% yield).
OH
OH
14
8%
13
28%
Scheme 2. Asymmetric Diels–Alder reaction.
products was determined by reducing the aldehydes with sodium
borohydride. While endo-adduct 13 and cyclohexadiene 14 were
obtained in 28 and 8% yields, respectively, the exo-adduct was not
obtained. We could not deny the possibility that a selective de-
composition of the exo-adduct occurred. The fact that a prolonged
reaction time did not change the ratio of the products suggests
O
Boc
Boc
Br
Cbz
Br
that cyclohexadiene 18 might be formed via
amine 17 (Scheme 3).
b-elimination of en-
RuO2
NaIO4
H2,Pd-C
Boc2O
N
N
N
Br
ClCH2CH2Cl
H2O
Since chromatographic separation of the aldehydes was tedious
and impractical, the crude mixture was subjected to the Kraus
oxidation without purification (Scheme 4).7 The crude reaction
mixture, which contained the desired endo-carboxylic acid 19, was
taken up in ethyl acetate and washed with dilute HCl to remove the
basic impurities. The carboxylic acids were then extracted into an
aqueous sodium bicarbonate solution. Upon addition of bromine,
a facile bromolactonization proceeded to give the desired bromo-
lactone 21. Because other acidic by-products, including 22,
remained in the aqueous phase, a simple extraction and subsequent
crystallization from methanol afforded practically pure 21 (>99%
ee) in 26% yield from benzyl chloroformate. It should be empha-
sized that neither tedious chromatographic separations nor
expensive reagents were needed to prepare bromolactone 21.
EtOH-THF
rt, 2 h
O
O
O
O
O
O
80°C,1.5h
21
23
24
92%
86%
Scheme 5. Ruthenium oxidation.
The relatively expensive ruthenium catalyst could easily be re-
covered by quenching the reaction with 2-propanol to form a black
precipitate of RuO2, which was collected on filter paper. After
drying, the recovered ruthenium catalyst could be used for the
same transformation without a loss of activity (Table 1).
Hence, the next task was to introduce the nitrogen atom at C5.
Ammonolysis of the lactone 24 proceeded selectively with the
N-Boc lactam intact (Scheme 6). The resulting alcohol 25 was

N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
3241
Table 1
It is worth mentioning that, under the same reaction conditions,
acetate 31 gave a mixture of 32 and 33 (Scheme 8). Thus the
electron withdrawing nature of the substituent at C3 seemed to
affect the reactivity of the N-Boc lactam.
Recovery of the ruthenium catalyst
O
Boc
Boc
RuO2
N
N
Br
Br
NaIO4
ClCH2CH2Cl
H2O,80 °C
O
O
O
O
HO
CO2Et
O
O
Boc
NaOEt
EtOH
0°C
N
HN
23
24
Br
+ Br
BocHN
Run
Yield (%)
Recovery of Ru catalyst (%)
NHAlloc
32
OAc NHAlloc
31
OH NHAlloc
33
1
2
3
4
90
80
79
87
88
65
75
d
Scheme 8.
Installing the 3-pentyl ether moiety proved to be a challenging
task. Upon treatment with a Lewis acid in the presence of 3-pen-
tanol, aziridine 30 underwent cleavage to give the desired 34 in
moderate to low yields along with oxazolidinone 35. To suppress
the concomitant formation of the undesired 35, optimization of the
reaction conditions was performed.
converted into its mesylate 26 to form the aziridine ring at a later
stage. Treatment with iodobenzene diacetate and allyl alcohol
caused amide 26 to undergo a Hofmann rearrangement to give allyl
carbamate 27 in 88% yield.9
Since the reactions with 3-pentanol under basic or neutral
conditions did not give acceptable results, we screened a variety of
acids (Table 2). Brønsted acids such as PPTS preferentially formed
oxazolidinone 35 (entry 1). Because chloride ion tended to cleave
the aziridine ring, we employed metal triflates or perchlorates as
Lewis acids. Among the several Lewis acids, Sc(OTf)3 afforded 34
with a relatively good selectivity in moderate yield (entries 2–8).
Although the addition of CH2Cl2 as a co-solvent improved the yield,
the selectivity was unchanged (entry 9). Moreover, BF3$OEt2 was
confirmed to be a good acid for this transformation.1 While the
addition of a co-solvent did not increase the selectivity (entries 10–
15), lowering the reaction temperature improved both the selec-
tivity and the yield (entry 16). Finally, the desired product 34 was
obtained in 62% yield after purification by silica gel column
chromatography.
O
O
Boc
MsCl
Et3N
Boc
N
NH3
t-BuOH
THF,0°C
N
Br
Br
CH2Cl2
rt,1h
O
OH
CONH2
O
N
95%
91%
24
25
O
O
allyl alcohol
PhI(OAc)2
toluene
60 °C,10 h
Boc
Br
Boc
Br
N
OMs CONH2
26
OMs NHAlloc
27
88%
Scheme 6. Introduction of the amino group via a Hoffmann rearrangement.
2.5. Completion of the synthesis
The final steps of the synthesis were carried out as shown in
Scheme 9. Deprotection of the Boc group of 34 with trifluoroacetic
acid and subsequent acetylation furnished acetamide 36 in 88%
yield. The Alloc group was removed by treatment with palladium
on carbon in the presence of triphenylphosphine and 1,3-dime-
thylbarbituric acid. After complete consumption of 36, the reaction
mixture was filtered and concentrated to afford crude oseltamivir,
which was directly subjected to salt formation with phosphoric
acid in ethanol to furnish crystalline oseltamivir phosphate
(1$H3PO4) in 76% yield. The spectroscopic data of oseltamivir
phosphate thus obtained were consistent with those reported in
the literature.2a
2.4. Transformation into the cyclohexene skeleton and
installation of 3-pentyl ether
Having fully arranged the functionalities, we next attempted to
cleave the bicyclic system. As initially planned, upon treatment
with a slight excess of sodium ethoxide (2.02 equiv) at 0 ꢁC, 27
underwent a series of transformations involving the ethanolysis of
the N-Boc lactam, a dehydrobromination, and an aziridine forma-
tion via an intramolecular SN2 reaction to provide 30 in 87% yield
(Scheme 7). Aziridine 30 turned out to be quite sensitive to nu-
cleophilic attack. Upon exposure to aqueous HCl during partition-
ing or neutralization, a chloride ion attacked to cleave the aziridine
ring at the allylic position.
3. Conclusion
In conclusion, we have successfully synthesized oseltamivir
phosphate 1$H3PO4 in 22% yield from the readily available lactone
21, featuring an asymmetric Diels–Alder reaction, a bromolactoni-
zation, and a Hofmann rearrangement. Finally it should be noted
that our synthetic route has the potential to generate a wide range
of hitherto inaccessible Tamiflu analogs.
O
EtO
NH
O
Boc
Br
Br
OEt
Boc
N
NaOEt
MsO
Br
O
OEt
H
EtOH
0 °C
BocHN
OMs NHAlloc
OEt
OMs NHAlloc
NHAlloc
CO2Et
28
27
4. Experimental section
4.1. General
MsO
BocN
CO2Et
BocN
87%
NHAlloc
30
NHAlloc
29
Nuclear magnetic resonance (1H NMR (400 MHz), 13C NMR
(100 MHz), 31P NMR (162 MHz)) spectra were determined on
Scheme 7. Formation of the aziridine ring.

3242
N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
Table 2
Screening of the conditions to install the 3-pentyl ether
CO2Et
O
CO2Et
CO2Et
O
Lewis acid
solvent
temperature
BocN
O
+
N
H
BocHN
NHAlloc
35
NHAlloc
NHAlloc
34
30
Entry
Acid
Temperature (ꢁC)
Solvent
Ratio (34:35)a
Yield (%, 34)b
1
2
3
4
5
6
7
8
PPTS
LiClO4
rt
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol
3-Pentanol/CH2Cl2
3-Pentanol
3-Pentanol/THF
3-Pentanol/Et2O
3-Pentanol/MeCN
3-Pentanol/CH2Cl2
3-Pentanol/toluene
3-Pentanol
3-Pentanol/CH2Cl2
3-Pentanol/toluene
1.0:7
1.2:1
1.0:1
2.3:1
1.9:1
1.5:1
1.3:1
2.4:1
2.3:1
1.8:1
0.5:1
0.7:1
1.1:1
1.5:1
1.5:1
2.6:1
1.0:1
0.8:1
ND
ND
ND
39
46
30
ND
45
54
rt to 70
rt
Mg(ClO4)2
Cu(OTf)2
In(OTf)3
Sm(OTf)3
Yb(OTf)3
Sc(OTf)3
ꢀ20 to 0
ꢀ20
ꢀ20 to rt
0
ꢀ20 to 0
9
ꢀ20
10
11
12
13
14
15
16
17
18
BF3$OEt2
0
0
0
0
0
0
46
ND
ND
ND
ND
ND
62
ꢀ20
ꢀ40
ꢀ40
37
31
ND: not determined.
a
The ratio was determined by 1H NMR.
Isolated yields.
b
analytical plates, 0.25 mm thick, silica gel 60 F254. Preparative TLC
separations were made on Merck precoated analytical plates,
0.50 mm thick, silica gel 60 F254. Compounds were eluted from the
adsorbent with ethyl acetate. Flash chromatography separations
were performed on KANTO CHEMICAL Silica Gel 60 (40–100 mesh).
Reagents and solvents were of the commercial grades. All solvents
were used after being dried over molecular sieves 3 Å or 4 Å. All
reactions sensitive to oxygen or moisture were conducted under an
argon atmosphere.
1) TFA
CH2Cl2
CO2Et
O
O
CO2Et
0 °C to rt
2) Ac2O
pyridine
BocHN
AcHN
NHAlloc
34
NHAlloc
36
88% (2 steps)
Pd/C,Ph3P
1,3-dimethyl-
barbituric acid
O
CO2Et
4.2. (1R,2S,3S,6R,7R)-8-Benzyloxycarbonyl-2-bromo-4-oxa-
EtOH
reflux, 40 min;
H3PO4
AcHN
oseltamivir phosphate (1 H3PO4)
8-azatricyclo[4,3,1,03,7]decan-5-one (21)
NH2•H3PO4
.
To a stirred solution of pyridine (10) (10.0 ml, 124 mmol) in
methanol (200 ml) was added sodium borohydride (5.12 g,
135 mmol) at about ꢀ40 ꢁC. To this was added benzyl chloro-
formate (16.1 ml, 113 mmol) dropwise through the dropping funnel
over a period of 30 min at such a rate that inner temperature was
maintained between ꢀ47 and ꢀ35 ꢁC. After stirring for 20 min, the
resulting solution was gradually warmed to 0 ꢁC. Water (200 ml)
was added and the mixture was extracted three times with diethyl
ether (200 mlꢂ2 and 100 mlꢂ1). The combined organic extracts
were washed with 1 N HCl (200 ml), 1 N NaOH (200 ml), water
(100 ml), and brine (100 ml), dried over sodium sulfate, and con-
centrated under reduced pressure to give the crude dihydropyr-
idine 11 (23.5 g, 109 mmol, 96.4%) as a pale yellow oil, which was
used to the next reaction without purification. To a stirred solution
of 11 (23.5 g, 109 mmol) and the MacMillan’s catalyst 12 (2.80 g,
11.0 mmol) in acetonitrile (114 ml) and water (6 ml) was added
acrolein (22.0 ml, 32.9 mmol) at room temperature. After stirring
for 14 h, the reaction mixture was diluted with diethyl ether
(400 ml), and washed with water (400 ml). The aqueous layer was
diluted with water (100 ml) and extracted with diethyl ether
(500 ml). The combined organic extracts were washed with water
(300 ml), brine (300 ml), dried over sodium sulfate, and concen-
trated under reduced pressure to give aldehyde 16 as a pale yellow
76%
Scheme 9. Completion of the synthesis.
a JEOL-LA400 instrument unless otherwise noted. Chemical shifts
for 1H NMR are reported in parts per million downfield from tet-
ramethylsilane (d) as the internal standard and coupling constants
are in hertz (Hz). Chemical shifts in D2O are reported in the scale
relative to HOD (4.79 ppm) for 1H NMR. The following abbrevia-
tions are used for spin multiplicity: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad. Chemical shifts for 13C NMR
were reported in parts per million relative to the center line of
a triplet at 77.0 ppm for deuteriochloroform. Chemical shifts in D2O
are reported in parts per million relative to the singlet at 66.5 ppm
for 1,4-dioxane. Infrared (IR) spectra were recorded on a JASCO FT/
IR-410 Fourier Transform Infrared Spectrophotometer and were
reported in wavenumbers (cmꢀ1). High-resolution mass spectra
(HRMS) were recorded on JEOL JMS-GCmate or JEOL JMS-700 under
fast atom bombardment (FAB) conditions with polyethylene glycol
(PEG) as the matrix. Melting points (mp) were determined on
a Yanaco Micro Melting Point Apparatus. Analytical thin layer
chromatography (TLC) was performed on Merck precoated

N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
3243
oil, which was used to the next reaction without purification. To
4.4. (1R,2S,3S,6R,7R)-2-Bromo-8-t-butoxycarbonyl-4-oxa-
a stirred solution of the aldehyde 16 in tert-butyl alcohol (180 ml)
and water (60 ml) were added sodium dihydrogenphosphate
dihydrate (25.7 g, 165 mmol) and 2-methyl-2-butene (60.0 ml,
566 mmol). To this was added sodium chlorite (29.8 g, 329 mmol)
portionwise at 0 ꢁC. After 10 min, the solution was warmed to room
temperature and stirring was continued for an additional 1 h. The
reaction was then quenched with sodium sulfite, and the reaction
mixture was partitioned between ethyl acetate (450 ml) and 3 N
HCl (360 ml). The aqueous layer was thoroughly extracted with
ethyl acetate (400 ml). The combined organic extracts were washed
with water (350 ml), brine (350 ml), and concentrated under re-
duced pressure. The concentrated solution was diluted with ethyl
acetate and extracted four times with a saturated aqueous sodium
bicarbonate solution (360 mlꢂ4). To a vigorously stirred mixture of
the combined aqueous extracts and dichloromethane (120 ml) was
added bromine until the reddish color of bromine persisted. The
reaction was quenched with sodium sulfite, and the reaction mix-
ture was extracted three times with ethyl acetate (360 mlꢂ3). The
combined organic extracts were washed with water (300 ml), brine
(300 ml), dried over sodium sulfate, and concentrated under re-
duced pressure. The residue was left at room temperature over-
night, during which time crystallization took place. The crude
product was treated with methanol to promote crystallization and
then concentrated to a small volume under reduced pressure. The
crystals were filtered and washed with cold methanol three times
to afford bromolactone 21 (10.64 g, 29.1 mmol, 25.8% from pyri-
dine, >99% ee). The enantiomeric excess of the bromolactone 21
was determined by HPLC (DAICEL-CHIRALCEL-OD-H, hexane/i-
8-azatricyclo[4,3,1,06,7]decan-5,9-dione (24)
To a solution of 23 (4.50 g, 13.6 mmol) and ruthenium dioxide
n-hydrate (0.335 g, 1.35 mmol) in dichloroethane (63 ml) were
added water (32 ml) and sodium periodate (8.69 g, 40.6 mmol). The
resulting solution was stirred at 80 ꢁC for 3 h. Additional sodium
periodate (1.45 g, 0.678 mmol) was added to the reaction mixture,
which was stirred at 80 ꢁC for another 30 min before quenching
with isopropyl alcohol (1 ml). After addition of water (30 ml), the
reaction mixture was filtered through filter paper to recover
ruthenium dioxide n-hydrate. The filtrate was then partitioned
between water and dichloromethane. The aqueous phase was
extracted once with dichloromethane. The combined organic ex-
tracts were washed with aqueous sodium sulfite solution, brine,
dried over sodium sulfate, filtered, and concentrated under reduced
pressure to give 24 (4.00 g, 11.6 mmol, 85.3%) as white crystals. The
combined aqueous layer containing black precipitate was filtered
through filter paper again, and the combined black precipitate was
dried in vacuo to give ruthenium dioxide n-hydrate (0.313 g, 93.4%),
which was reused without further purification to convert 23
23
(4.20 g, 12.6 mmol) into 24 (3.75 g, 10.8 mmol, 85.6%). [
a
]
ꢀ41.8 (c
D
1.14, CHCl3). Mp 160.1–161.4 ꢁC (ethyl acetate). 1H NMR (400 MHz,
CDCl3):
d
5.51 (1H, dd, J¼5.3, 5.0 Hz), 5.05 (1H, dd, J¼5.3, 0.9 Hz),
4.26 (1H, dd, J¼3.9, 0.9 Hz), 3.19 (1H, m), 2.88 (1H, ddd, J¼10.6, 5.0,
0.7 Hz), 2.42 (1H, ddd, J¼15.4, 10.6, 2.3 Hz), 2.25 (1H, ddd, J¼15.4,
2.7, 0.7 Hz), 1.58 (9H, s). 13C NMR (100 MHz, CDCl3):
d 174.1, 166.9,
150.1, 85.3, 79.9, 53.6, 47.5, 43.4, 34.8, 27.9, 26.2. IR (neat, cmꢀ1):
1799, 1784, 1750, 1722, 1398, 1297, 1285, 1249, 1150, 974. Anal. Calcd
for C13H16BrNO5: C, 45.10; H, 4.66; N, 4.05. Found: C, 45.34; H, 4.64;
N, 3.79.
PrOH¼70:30, flow rate¼0.8 ml/min, tD¼22.6 min, tL¼27.9 min).
23
[
a]
37.0 (c 1.15, CHCl3). Mp 132.9–133.6 ꢁC (methanol). 1H NMR
D
(400 MHz, CDCl3):
d 7.38 (5H, m), 5.20 (2H, m), 5.01 ((2/3)1H, t,
J¼5.2 Hz), 4.91 ((2/3)1H, t, J¼5.2 Hz), 4.86 ((1/3)1H, m), 4.85 ((1/
3)1H, m), 4.28 (1H, d, J¼11.2 Hz), 4.05 (1H, d, J¼11.2 Hz), 3.33 (1H, d,
J¼11.2 Hz), 2.86 (1H, m), 2.50 ((1/3)1H, br s), 2.44 ((2/3)1H, br s),
2.26 (1H, dd, J¼13.5, 11.2 Hz), 2.03 (1H, d, J¼13.5 Hz). 13C NMR
4.5. (1S,4R,5S,6S,7S)-5-Bromo-6-hydroxy-2-t-butoxycarbonyl-
2-azabicyclo[2,2,2]octan-3-one-7-carboxamide (25)
Ammonia gas was passed through an ice-cold solution of
lactone 24 (4.30 g, 12.4 mmol) in tetrahydrofuran (80 ml) and tert-
butyl alcohol (80 ml) over a period of 2.5 h. After concentration of
the reaction mixture under reduced pressure, the crude product
was purified by silica gel column chromatography (methanol/
(100 MHz, CDCl3):
d 175.3, 175.2, 155.4, 154.6, 136.0, 135.7, 128.6,
128.5, 128.4, 128.2, 127.9, 81.5, 81.4, 67.8, 67.6, 49.2, 48.6, 48.4, 48.1,
44.8, 44.7, 36.4, 36.3, 32.6, 32.5, 26.9, 26.9. IR (neat, cmꢀ1): 1795,
1704,1422,1354,1330,1309,1118, 998. Anal. Calcd for C16H16BrNO4:
C, 52.48; H, 4.40; N, 3.82. Found: C, 52.45; H, 4.35; N, 3.62.
dichloromethane¼1:9) to give 25 (4.29 g, 95.1%) as white crystals.
23
[a
]
8.70 (c 1.21, DMF). Mp 137.7–138.7 ꢁC (methanol). 1H NMR
D
(400 MHz, CDCl3):
d 6.10–5.85 (1H, br s), 5.85–5.60 (1H, br s), 4.91
4.3. (1R,2S,3S,6R,7R)-2-Bromo-8-t-butoxycarbonyl-4-oxa-
(1H, m), 4.84 (1H, dd, J¼3.2, 2.8 Hz), 4.39 (1H, m), 4.08 (1H, t,
8-azatricyclo[4,3,1,06,7]decan-5-one (23)
J¼3.2 Hz), 3.02 (1H, m), 2.92 (1H, ddd, J¼14.2, 6.9, 2.0 Hz), 1.56 (9H,
s). 13C NMR (100 MHz, CDCl3):
d 175.6, 168.5, 149.8, 84.8, 79.0, 55.6,
To a stirred solution of 21 (2.52 g, 6.88 mmol) and di-t-butyl
pyrocarbonate (1.65 g, 7.56 mmol) in ethanol (8 ml) and tetrahy-
drofuran (8 ml) was added 10% Pd/C (AD wet supplied by Kawaken,
1.00 g). The flask was charged with hydrogen gas (1 atm) at room
temperature. The resulting suspension was vigorously stirred for
2 h. The reaction mixture was then filtered through a Celite pad and
concentrated under reduced pressure. The crude product was pu-
50.6, 48.5, 41.8, 28.0, 27.5. IR (neat, cmꢀ1): 1772, 1732, 1716, 1668,
1370, 1291, 1255, 1150. Anal. Calcd for C13H19BrN2O5: C, 42.99; H,
5.27; N, 7.71. Found: C, 42.69; H, 5.33; N, 7.53.
4.6. (1S,4R,5S,6S,7S)-5-Bromo-6-methanesulfonyloxy-2-
t-butoxycarbonyl-2-azabicyclo[2,2,2]octan-3-one-7-
carboxamide (26)
rified by silica gel chromatography (dichloromethane) to give 23
23
(2.42 g, 91.7%) as white crystals. [
a
]
D
ꢀ35.6 (c 1.11, CHCl3). Mp
To a solution of alcohol 25 (1.95 g, 5.37 mmol) and triethylamine
(2.25 ml, 16.11 mmol) in dichloromethane (50 ml) was added
132.8–133.7 ꢁC (methanol). 1H NMR (400 MHz, CDCl3):
d
4.95 ((2/
3)1H, t, J¼5.3 Hz), 4.89 ((2/3)1H, d, J¼5.3 Hz), 4.86 ((1/3)1H, d,
J¼5.1 Hz), 4.76 ((1/3)1H, t, J¼5.1 Hz), 4.26 (1H, d, J¼3.6 Hz), 3.94
(1H, d, J¼11.2 Hz), 3.25 (1H, d, J¼11.2 Hz), 2.84 (1H, m), 2.48 ((1/
3)1H, br s), 2.42 ((2/3)1H, br s), 2.26 (1H, dd, J¼14.4, 10.8 Hz), 2.01
methanesulfonyl chloride (499
temperature. After stirring for 15 min, additional methanesulfonyl
chloride (120 l, 1.55 mmol) was added. The reaction mixture was
stirred for an additional 25 min before quenching with aqueous
saturated sodium bicarbonate. After the aqueous phase was satu-
rated with sodium chloride, the organic phase was separated and
the aqueous layer was extracted twice with dichloromethane. The
combined organic extracts were dried over sodium sulfate and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (methanol/
ml, 6.45 mmol) slowly at room
m
(1H, d, J¼14.4 Hz), 1.50 (9H, s). 13C NMR (100 MHz, CDCl3):
d 175.7,
175.6, 154.7, 154.0, 81.7, 81.5, 81.3, 81.0, 49.5, 48.7, 48.3, 48.0, 45.0,
44.3, 36.6, 36.4, 32.8, 32.7, 27.0, 27.0. IR (neat, cmꢀ1): 2978, 1798,
1697, 1412, 1364, 1334, 1313, 1173, 1152, 1123, 999. Anal. Calcd for
C13H18BrNO4: C, 47.00; H, 5.46; N, 4.22. Found: C, 46.87; H, 5.41; N,
3.92.

3244
N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
dichloromethane¼1:19 to 1:9) to give 26 (2.15 g, 4.87 mmol, 90.7%)
4.9. (3S,4S,5S)-5-Allyloxycarbonylamino-4-t-butoxy-
carbonylamino-1-ethoxycarbonyl-3-(3-pentyloxy)-cyclohex-
2-ene (34)
23
as a white solid. [
a
]
ꢀ4.4 (c 0.91, DMF). Mp 161.9–162.7 ꢁC
D
(methanol). 1H NMR (400 MHz, CDCl3):
d 5.80–5.50 (1H, br s), 5.75–
5.45 (1H, br s), 5.21 (1H, dd, J¼3.7, 2.8 Hz), 5.14 (1H, dd, J¼3.7,
3.6 Hz), 4.25 (1H, dd, J¼3.6, 2.8 Hz), 3.13 (3H, s), 3.04 (1H, m), 2.95
(1H, m), 2.76 (1H, ddd, J¼14.7, 6.4, 2.8 Hz), 2.17 (1H, ddd, J¼14.7,
Aziridine 30 (442.1 mg, 1.207 mmol) was dissolved in hot
3-pentanol (6.0 ml) and then cooled to ꢀ20 ꢁC. To the stirred
suspension was added 0.50 M solution of boron trifluoride
diethyl ether complex in 3-pentanol (2.88 ml, 1.44 mmol) at
ꢀ20 ꢁC over 20 min. After stirring for an additional 30 min, the
reaction mixture was warmed to 0 ꢁC and quenched with aque-
ous saturated sodium bicarbonate. The mixture was extracted
twice with toluene, and the combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (dichloromethane/
11.0, 3.7 Hz), 1.61 (9H, s). 13C NMR (100 MHz, CDCl3):
d 170.3, 167.6,
149.8, 85.4, 83.0, 55.4, 48.1, 45.1, 39.5, 38.3, 28.0, 24.7. IR (neat,
cmꢀ1): 3452, 3331, 1776, 1715, 1685, 1372, 1334, 1271, 1171, 1156,
957, 867. Anal. Calcd for C14H21BrN2O7S: C, 38.10; H, 4.80; N, 6.35.
Found: C, 38.01; H, 4.75; N, 6.36.
4.7. (1S,4R,5S,6S,7S)-5-Bromo-7-allyloxycarbonyl-6-
methanesulfonyloxy-2-t-butoxycarbonyl-2-
azabicyclo[2,2,2]octan-3-one (27)
hexane¼1:3) to give 34 (341.0 mg, 0.750 mmol, 62.2%) as a white
23
amorphous solid. [
a
]
ꢀ37.7 (c 1.27, CHCl3). 1H NMR (400 MHz,
D
To a mixture of 26 (2.259 g, 5.118 mmol), allyl alcohol (17.4 ml,
256 mmol), and molecular sieves 4 Å (2.56 g) in 1,2-dichloroethane
(33.8 ml) was added diacetoxyiodobenzene (3.297 g, 10.24 mmol).
After stirring for 15 min at room temperature, the reaction mixture
was heated at 60 ꢁC for 10.5 h. After quenching with saturated
aqueous sodium bicarbonate and saturated aqueous sodium thio-
sulfate, the resulting mixture was filtered through a Celite pad, and
washed with saturated aqueous sodium bicarbonate. The aqueous
layer was extracted with ethyl acetate, and the combined organic
extracts were washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl acetate/
CDCl3):
d
6.80 (1H, s), 5.89 (1H, m), 5.63 (1H, d, J¼8.7 Hz), 5.28
(1H, br d, J¼17.2 Hz), 5.19 (1H, d, J¼10.3 Hz), 4.65–4.45 (1H, m),
4.54 (2H, br s), 4.20 (2H, q, J¼7.1 Hz), 3.94 (1H, m), 3.87 (1H, m),
3.77 (1H, m), 3.41 (1H, quintet, J¼5.5 Hz), 2.75 (1H, dd, J¼18.3,
8.3 Hz), 2.34 (1H, dd, J¼18.3, 8.3 Hz), 1.55 (4H, dq, J¼7.3, 5.5 Hz),
1.42 (9H, s), 1.28 (3H, t, J¼7.3 Hz), 0.91 (6H, t, J¼7.3 Hz). 13C NMR
(100 MHz, CDCl3):
d 166.0, 156.3, 137.2, 132.8, 129.3, 117.2, 82.5,
79.5, 75.5, 65.4, 60.8, 54.9, 50.0, 30.6, 28.2, 26.2, 25.9, 14.1, 9.3. IR
(neat, cmꢀ1): 3335, 2978, 1716, 1685, 1541, 1283, 1243, 1173, 1058.
Anal. Calcd for C23H38N2O7: C, 60.77; H, 8.43; N, 6.16. Found: C,
60.49; H, 8.41; N, 6.09.
hexane¼1:1) to give 27 (2.233 g, 4.490 mmol, 87.7%) as a white
23
amorphous solid. [
a
]
ꢀ2.7 (c 1.04, CHCl3). 1H NMR (400 MHz,
D
4.10. (3S,4S,5S)-4-Acetamido-5-allyloxycarbonylamino-1-
ethoxycarbonyl-3-(3-pentyloxy)cyclohex-2-ene (36)
CDCl3):
d
5.91 (1H, m), 5.32 (1H, dd, J¼17.4, 1.4 Hz), 5.29–5.22 (1H,
br s), 5.24 (1H, d, J¼10.8 Hz), 4.97 (1H, s), 4.59 (2H, d, J¼5.7 Hz), 4.25
(1H, m), 4.22 (1H, dd, J¼2.8, 1.4 Hz), 3.19 (3H, s), 3.00 (1H, m), 2.76
(1H, m), 1.64 (1H, m), 1.56 (9H, s). 13C NMR (100 MHz, CDCl3):
To a stirred solution of 34 (341.0 mg, 0.750 mmol) in dichloro-
methane (5.0 ml) was added trifluoroacetic acid (1.11 ml,
15.0 mmol) at 0 ꢁC, and the resulting solution was allowed to warm
to room temperature. After stirring for 3 h, the reaction mixture
was cooled to 0 ꢁC, quenched with saturated aqueous sodium bi-
carbonate, and warmed to room temperature. The aqueous phase
was saturated with sodium chloride and extracted with dichloro-
methane three times. The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated under reduced
pressure to give a crude amine (257.5 mg) as a pale yellow amor-
phous solid, which was used for the next acetylation without fur-
ther purification.
To a stirred solution of the amine (257.5 mg, 0.727 mmol) in
pyridine (2.6 ml) was added acetic anhydride (1.3 ml) at room
temperature. After stirring for an hour, and the reaction mixture
was concentrated under reduced pressure. The crude product
was recrystallized from isopropyl alcohol–water to give 36
(215.2 mg, 0.543 mmol, 72.4% over two steps) as off-white
crystals. The mother liquid was purified by preparative TLC
d
167.0, 155.3, 148.8, 132.4, 118.2, 85.2, 84.0, 66.1, 54.7, 47.9, 46.5,
45.9, 38.5, 31.3, 27.9. IR (neat, cmꢀ1): 1781, 1747, 1731, 1710, 1521,
1370, 1294, 1237, 1177, 1148. Anal. Calcd for C17H25BrN2O8S:
497.0593 (MþHþ). Found: 497.0592.
4.8. (1S,5S,6R)-5-Allyloxycarbonylamino-7-t-butoxycarbonyl-
3-ethoxycarbonyl-7-azabicyclo[4,1,0]heptan-2-ene (30)
To a stirred solution of 27 (2.233 g, 4.490 mmol) in ethanol
(8.98 ml) was added portionwise a 1.0 M solution of sodium
ethoxide in ethanol (9.05 ml, 9.05 mmol) at 0 ꢁC until TLC (ethyl
acetate/hexane¼1:2) indicated complete reaction. The resulting
solution was diluted with dichloromethane, quenched with acetic
acid, and neutralized with aqueous saturated sodium bicarbonate.
After the reaction mixture was filtered through a Celite pad,
aqueous saturated sodium bicarbonate was added. The aqueous
phase was saturated with sodium chloride and extracted with
dichloromethane three times. The combined organic extracts were
dried over sodium sulfate and concentrated under reduced pres-
sure. The crude product was purified by silica gel column chro-
(dichloromethane/hexane¼1:1) to give 36 (45.2 mg, 0.114 mmol,
23
15.2%) as a white solid. [
a
]
ꢀ70.3 (c 1.21, CHCl3). Mp 153.0–
D
154.3 ꢁC (ethanol). 1H NMR (400 MHz, CDCl3):
d 6.81 (1H, s), 5.89
matography (ethyl acetate/hexane¼1:2) to give 30 (1.438 g,
(1H, m), 5.56 (1H, d, J¼11.3 Hz), 5.53 (1H, d, J¼26.0 Hz), 5.28 (1H,
br d, J¼17.2 Hz), 5.20 (1H, d, J¼10.3 Hz), 4.54 (2H, m), 4.21 (2H, q,
J¼7.1 Hz), 4.11 (1H, q, J¼8.7 Hz), 3.99 (1H, br d, J¼7.1 Hz), 3.86
(1H, m), 3.38 (1H, quintet, J¼5.7 Hz), 2.77 (1H, dd, J¼18.1,
4.8 Hz), 2.36 (1H, dd, J¼18.1, 9.0 Hz), 1.98 (s, 3H), 1.52 (4H, m),
1.29 (3H, t, J¼7.1 Hz), 0.90 (6H, dt, J¼8.8, 7.2 Hz). 13C NMR
23
3.924 mmol, 87.4%) as an off-white amorphous solid. [
a]
ꢀ68.7 (c
D
1.81, CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.21 (1H, dd, J¼4.6,
3.2 Hz), 5.90 (1H, m), 5.30 (1H, d, J¼17.4 Hz), 5.22 (1H, d, J¼10.5 Hz),
4.70–4.50 (1H, br s), 4.61 (2H, s), 4.56 (1H, br d, J¼4.8 Hz), 4.20 (2H,
q, J¼7.3 Hz), 3.12 (1H, d, J¼5.6 Hz), 2.99 (1H, dd, J¼5.6, 4.8 Hz), 2.73
(1H, d, J¼17.1 Hz), 2.39 (1H, d, J¼17.1 Hz), 1.45 (9H, s), 1.29 (1H, t,
(100 MHz, CDCl3):
d 171.0, 165.9, 156.6, 137.3, 132.7, 129.2, 117.4,
J¼7.3 Hz). 13C NMR (100 MHz, CDCl3):
d
165.8, 160.5, 155.4, 134.0,
82.1, 75.3, 65.4, 60.9, 54.0, 49.9, 30.6, 26.1, 25.7, 23.2, 14.1, 9.4,
9.2. IR (neat, cmꢀ1): 3299, 3278, 1729, 1685, 1643, 1549, 1248,
1055. Anal. Calcd for C20H32N2O6: C, 60.59; H, 8.14; N, 7.07.
Found: C, 60.36; H, 8.18; N, 7.04.
132.5, 130.2, 118.0, 82.2, 65.7, 61.0, 42.4, 41.8, 32.4, 27.8, 26.8, 14.1. IR
(neat, cmꢀ1): 3330, 2980, 1715, 1530, 1369, 1259, 1156, 1096, 1058.
HRMS Calcd for C18H26N2O6: 366.1791. Found: 366.1788.

N. Satoh et al. / Tetrahedron 65 (2009) 3239–3245
3245
4.11. (L)-Oseltamivir phosphate (1$H3PO4)
Compound 13: [
a
]
D
23 70.2 (c 1.09, CHCl3). 1H NMR (400 MHz, CDCl3):
d
7.33 (5H, m), 6.37 (2H, m), 5.11 (2H, m), 4.90 ((3/5)1H, br s), 4.84
A stirred mixture of 36 (566.2 mg, 1.428 mmol), 1,3-dime-
thylbarbituric acid (272.1 mg, 1.743 mmol), triphenylphosphine
(15.0 mg, 0.0571 mmol), and 5% Pd/C (E3, 50% wet, provided by
Degussa, 64.0 mg, 0.0143 mmol) in ethanol (11.3 ml) was heated at
80 ꢁC for an hour. The reaction mixture was then filtered and
concentrated under reduced pressure. To the solution of the crude
product in ethanol (5.80 ml) was added a 1.0 M solution of phos-
phoric acid in ethanol (1.70 ml, 1.70 mmol). The resulting solution
was warmed to 50 ꢁC and seed crystals of 1$H3PO4 were added to
initiate the crystallization. The mixture was slowly cooled to room
temperature and stirred overnight. The resulting suspension was
cooled to ꢀ18 ꢁC, stirred for an additional 3 h, filtered and washed
successively with acetone (seven times) and hexane (three times)
((2/5)1H, br s), 3.28 (2H, m), 3.18 (1H, m), 3.02 (1H, m), 2.73 (1H, m),
2.36 (1H, m), 1.76 (1H, m), 0.83 (1H, m). 13C NMR (100 MHz, CDCl3):
d
155.2, 154.8, 137.0, 136.9, 135.0, 134.6, 130.5, 130.0, 128.4, 128.4,
127.8, 127.7, 127.7, 127.7, 66.7, 66.7, 65.6, 65.5, 47.3, 47.2, 46.9, 46.8,
41.6, 41.6, 30.8, 30.6, 26.1, 26.1. IR (neat, cmꢀ1): 3429, 2935, 2873,
1695, 1419, 1344, 1300, 1113, 1053. HRMS Calcd for C6H19NO3:
23
274.1443 (MþHþ); Found: 274.1441. Compound 14: [
a
]
ꢀ141 (c
D
1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
d 7.35 (5H, m), 5.99 (1H, dd,
J¼9.4, 5.2 Hz), 5.85 (1H, d, J¼4.4 Hz), 5.64 (1H, dd, J¼9.4, 5.6 Hz),
5.12 (2H, m), 4.98 (1H, br s), 4.06 (2H, s), 3.21 (1H, m), 3.12 (1H, m),
2.46 (1H, m), 2.31 (1H, m), 2.23 (2H, m). 13C NMR (100 MHz, CDCl3):
d
157.0, 137.1, 136.4, 128.5, 128.1, 128.1, 126.7, 125.5, 119.2, 66.8, 66.0,
42.9, 33.9, 26.6. IR (neat, cmꢀ1): 3334, 3033, 2925, 2864, 1699, 1537,
1454, 1259, 1140, 997. Anal. Calcd for C6H19NO3: C, 70.31; H, 7.01; N,
5.12. Found: C, 70.01; H, 6.90; N, 5.08.
to give 1$H3PO4 (445.1 mg, 1.085 mmol, 76.0%) as white crystals.
23
[
a]
ꢀ31.2 (c 1.00, H2O). Mp 184.0–186.2 ꢁC (ethanol). 1H NMR
D
(400 MHz, D2O):
d
6.83 (1H, d, J¼2.1 Hz), 4.32 (1H, m), 4.23 (2H, m),
4.04 (1H, m), 3.55 (2H, m), 2.95 (1H, m), 2.51 (1H, m), 2.07 (3H, s),
Acknowledgements
1.54 (4H, m), 1.45 (2H, m), 1.37 (1H, ddt, J¼14.0, 2.3, 1.6 Hz), 0.87
(3H, m), 0.82 (3H, m). 13C NMR (100 MHz, D2O):
d 175.2, 167.3, 137.8,
84.2, 75.0, 62.3, 52.5, 49.1, 28.1, 25.4, 25.0, 22.3, 13.2, 8.5, 8.4. 31P
NMR (162 MHz, D2O):
0.6. IR (KBr, cmꢀ1): 3352, 1718, 1660, 1552,
This work was financially supported in part by a Grant for the
21st Century COE Program and Grant-in-Aid (15109001 and
16073205) from the Ministry of Education, Culture, Sports, Science
and Technology of Japan. We are indebted to Dr. Kunisuke Izawa of
d
1375, 1296, 1246, 1128, 1066, 1028, 947. Anal. Calcd for
C16H31N2O8P: C, 46.83; H, 7.61; N, 6.83. Found: C, 46.55; H, 7.36; N,
6.86.
Ajinomoto Co., Inc., for an ample supply of D-phenylalanine.
4.12. (1S,4S,7S)-2-Benzyloxycarbonyl-7-hydroxymethyl-2-
azabicyclo[2,2,2]octan-7-ene (13) and benzyl 5-(5-
References and notes
(hydroxymethyl)cyclohexa-2,4-dienyl)methylcarbamate (14)
1. 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.
To a stirred solution of pyridine (10) (5.00 g, 63.2 mmol) in
methanol (50 ml) was added sodium borohydride (2.63 g,
69.5 mmol) at ꢀ78 ꢁC. To this was added benzyl chloroformate
(10.24 g, 60.0 mmol) dropwise over a period of 90 min at such
a rate that inner temperature was maintained under ꢀ69 ꢁC. After
stirring for 100 min, water (50 ml) and diethyl ether (50 ml) were
added to the reaction mixture. The resulting mixture was warmed
to room temperature, and the organic layer was separated. The
aqueous layer was extracted with ether (50 ml), and the combined
organic extracts were washed with 1 N HCl (50 ml), 1 N NaOH
(50 ml), water (20 ml), and brine (20 ml), respectively, dried over
sodium sulfate, filtered, and concentrated under reduced pressure
to give the crude dihydropyridine 11 (9.84 g) as a pale yellow oil,
which was used for the next step without further purification. To
a stirred solution of 11 (3.00 g) in acetonitrile (14.2 ml) and water
(0.75 ml) were added the MacMillan’s catalyst 12 (0.36 g, 1.4 mmol)
and acrolein (2.8 ml, 42 mmol) at room temperature. After stirring
for 16 h, the reaction mixture was diluted with diethyl ether
(50 ml), and washed with water (50 ml). The aqueous layer was
extracted with diethyl ether (50 ml). The combined organic extracts
were washed with brine (50 ml), dried over sodium sulfate, filtered,
and concentrated under reduced pressure to give aldehyde 16
(7.77 g) as a pale yellow oil, which was used for the next step
without further purification. To a stirred solution of aldehyde 16
(5.00 g) in ethanol (25 ml) was added sodium borohydride (1.40 g,
37.0 mmol). After stirring for 30 min, the reaction was quenched
with aqueous HCl (100 ml). The reaction mixture was extracted
twice with ethyl acetate, and the combined organic extracts were
washed with brine, filtered, and concentrated under reduced
pressure to give the crude product (2.42 g). One gram of the crude
product was purified by silica gel column chromatography to give
13 (284 mg, 28.1% over three steps) as a colorless viscous oil and 14
(79 mg, 7.8% over three steps) as a white amorphous solid.
2. (a) Rohloff, J. C.; Kent, K. M.; Postich, 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; (b) Federspiel, M.; Fischer, R.; Hennig, M.;
Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.; Estermann, H.;
Gandert, C.; Go¨ckel, V.; Go¨tzo¨, S.; Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper,
S.; Ro¨ckel-Sta¨bler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res. Dev. 1999, 3,
266; (c) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044; (d) Harrington, P. J.;
Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res. Dev. 2004, 8, 86; (e)
Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310; (f) Fukuta, Y.;
Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312; (g)
Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365; (h) Farina, V.; Brown, J. D. Angew.
Chem., Int. Ed. 2006, 45, 7330; (i) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.;
Shibasaki, M. Org. Lett. 2007, 9, 259; (j) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 1403; (k) Bromfield, K. M.; Graden,
H.; Hagberg, D. P.; Olsson, T.; Kann, N. Chem. Commun. 2007, 3183; (l) 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; (m) Trost, B. M.; Zhang, T.
Angew. Chem., Int. Ed. 2008, 47, 3759; (n) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B.
J. Org. Chem. 2008, 73, 4895; (o) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2008, 47, 5788; (p) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
3. Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46,
5734.
4. Examples for asymmetric Diels–Alder reactions using dihydropyridine. Enan-
tioselective Diels–Alder reactions: (a) Takenaka, N.; Huang, Y.; Rawal, V. H.
Tetrahedron 2002, 58, 8299; (b) Nakano, H.; Tsugawa, N.; Fujita, R. Tetrahedron
Lett. 2005, 46, 5677. Diastereoselective reactions using chiral dihydropyridines:
(c) Mehmandoust, M.; Mrazano, C.; Singh, R.; Gillet, B.; Cesario, M.; Fourrey, J.-L.;
Das, B. C. Tetrahedron Lett. 1988, 29, 4423; (d) Marazano, C.; Yannic, S.; Genisson,
Y.; Mehmandoust, M.; Das, B. C. Tetrahedron Lett. 1990, 31, 1995; (e) Matsumura,
Y.; Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron Lett. 2000, 41, 7685 Dia-
stereoselective Diels–Alder reactions using chiral acrylic acid derivatives: (f)
Kouklovsky, C.; Pouilhe´s, A.; Langlois, Y. J. Am. Chem. Soc. 1990, 112, 6672; (g)
Campbell, M. M.; Sainsbury, M.; Searle, P. A. Tetrahedron Lett. 1992, 33, 3181.
5. (a) Fowler, F. W. J. Org. Chem. 1972, 37, 1321; (b) Sundberg, R. J.; Bloom, J. D. J. Org.
Chem. 1981, 46, 4836.
6. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243; (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79.
7. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888; (b) Kraus, G. A.;
Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
8. Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29, 2983.
9. Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org.
Chem. 1993, 58, 2478.