Thiol-free synthesis of oseltamivir and its analogues via organocatalytic michael additions of oxyacetaldehydes to 2-acylaminonitroalkenes

Article abstract of DOI:10.1055/s-0031-1290396

The organocatalytic addition of substituted oxyacetaldehydes to 2-acylaminonitroethenes proceeded with good to high diastereoselectivities and enantioselectivities. The resulting adducts reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly functionalized cyclohexenes. A thiol-free protocol for cyclization has been developed that leads to a separable mixture of two diastereoisomers. The unwanted diastereoisomer can be efficiently epimerized. The resulting cyclohexenes are precursors to oseltamivir and its analogues. The synthesis of the key reagent, 3-pentyloxyaldehyde, was also improved. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290396

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PAPER
paper
Thiol-Free Synthesis of Oseltamivir and Its Analogues via Organocatalytic
Michael Additions of Oxyacetaldehydes to 2-Acylaminonitroalkenes
Thiol-Free Synthesis of Oseltamivir
Juraj Rehák,a Martin Huťka,b Attila Latika,a Henrich Brath,a Ambroz Almássy,b Viktória Hajzer,a Július Durmis,*a
Štefan Toma,b Radovan Šebesta*b
a
Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
b
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, 84215 Bratislava,
Slovak Republic
Fax +421(2)60296337; E-mail: radovan.sebesta@fns.uniba.sk
Received: 30.03.2012; Accepted after revision: 09.05.2012
ecules.8 Already a large number of bioactive compounds
Abstract: The organocatalytic addition of substituted oxyacetalde-
have been synthesized through the use of organocatalytic
hydes to 2-acylaminonitroethenes proceeded with good to high dia-
reactions.9 It was recognized that conjugate addition is
stereoselectivities and enantioselectivities. The resulting adducts
reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly
also a useful transformation in the synthesis of the antivi-
functionalized cyclohexenes. A thiol-free protocol for cyclization ral agent oseltamivir.10 Hayashi and co-workers used the
has been developed that leads to a separable mixture of two diaste-
reoisomers. The unwanted diastereoisomer can be efficiently
addition of pentyloxyacetaldehyde to tert-butyl nitroacry-
late as the key step in a one-pot synthesis of oseltamivir.11
epimerized. The resulting cyclohexenes are precursors to oseltami-
We envisaged a more direct approach based on the use of
vir and its analogues. The synthesis of the key reagent, 3-pentyloxy-
2-acylaminonitroethenes. Recently, Ma and co-workers
aldehyde, was also improved.
demonstrated the viability of this approach.12 In this pa-
Key words: enantioselectivity, Michael addition, cyclization, ami-
per, we present results of our studies on Michael additions
nonitroethene, organocatalysis
of a range of oxyacetaldehydes to 2-acylaminonitroeth-
enes. This reaction is the first step in an organocatalytic
synthesis of oseltamivir. Access to its analogues, through
Asymmetric organocatalytic Michael addition is one of
structural variations of reaction partners, may become im-
the most versatile transformations for enantioselective
portant in view of emerging resistance towards oseltami-
formation of C–C and C–heteroatom bonds.1 Organocata-
vir itself.13
lysts has proved to be useful for additions of a range of do-
First, we investigated the possibility of an organocatalytic
nors such as enolizable aldehydes and ketones, diketones,
Michael addition of oxyacetaldehydes to N-protected 2-
ketoesters, and nitroalkanes. In addition, a large variety of
aminonitroethenes. As the second partner for the Michael
Michael acceptors have been utilized such as unsaturated
ketones, aldehydes, esters or sulfones.2 Particular atten-
tion has been devoted to nitroalkenes, because the result-
ing functionalized nitro-derivatives are useful building
blocks for the synthesis of many biologically relevant
compounds. Successful additions of both aldehydes3 and
ketones4 to nitroalkenes have already been demonstrated.
Interestingly, the simplest enolizable aldehyde, acetalde-
hyde, poses a special challenge because of its high reac-
tivity. List and co-workers solved the problem by slow
addition of an acetaldehyde solution to nitroalkenes.3a,5
On the other hand, Michael additions of functionalized al-
dehydes are also challenging. Although, functional
groups within the aldehyde offer interesting possibilities
for subsequent target-oriented synthesis, only a few exam-
ples of functionalized aldehyde additions are known.6 We
showed that alkoxy and aryloxyacetaldehydes can be en-
antioselectively added to a range of nitroalkenes.7
addition we chose 3-pentyloxyacetaldehyde (2a), because
a 3-pentyloxy group is present in oseltamivir. The starting
material 2a can be prepared by Hayashi’s procedure based
on osmium tetraoxide cleavage of an alkene. We have de-
veloped an alternative method involving sodium peri-
odate cleavage of a protected diol, which results from an
opening of glycidol 1 (Scheme 1). The resulting aldehyde
2a is unstable and decomposes rapidly within a few hours,
however, this decomposition can be slowed down by ad-
dition of 1% hydroquinone. N-Acyl nitroalkene deriva-
tives 3, which are readily available by a two-step
procedure,14 were selected as suitable candidates for
Michael addition. An interesting feature is their propensity
to form Z-configured double bonds, due to intramolecular
hydrogen bonding.
O
Et
Et
1. DIBAL-H
O
Et
+
HO
HO
The organocatalytic Michael addition also serves as an
initiating reaction for domino transformations, which lead
to a number of structurally or functionally interesting mol-
2. NaIO4, SiO2
CH2Cl2
O
Et
2a, 51%
1
Scheme 1
SYNTHESIS 2012, 44, 2424–2430
Advanced online publication: 13.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
The Michael addition of 2a with 3a and 3b afforded com-
pounds 4a and 4b, respectively (Scheme 2). The former
DOI: 10.1055/s-0031-1290396; Art ID: SS-2012-T0323-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiol-Free Synthesis of Oseltamivir
2425
product 4a, as a key intermediate for oseltamivir synthe- alkene 3a (Scheme 3). Interestingly, the best solvent for
sis, has also been prepared by Ma,12 and, using an alterna- the addition of aldehyde 2a was not the most suitable for
tive route from diethyl tartrate, by Lu.15
addition of other aldehydes. After testing the addition of
aldehyde 2c in several solvents and solvent mixtures, we
established that DMSO was effective; the results are sum-
marized in Table 2.
Catalyst screening in the reaction of nitroalkenes 3 with
aldehyde 2a revealed that Jørgensen–Hayashi catalyst I16
was the most selective. Similarly to Ma’s work,12 we have
found that 4a can be obtained in high enantiomeric purity
through the use of I (97% ee). Ma and co-workers used
benzoic acid as an additive in chloroform, but we obtained
the best results with chloroacetic acid in a mixture of chlo-
roform and water. At 0 °C, the product 4a was obtained in
88% yield and in high enantiomeric purity [98% ee (syn)].
The results of catalyst and initial conditions screening are
collected in Table 1.
O
NHAc
O
I (10 mol%)
AcHN
NO2
R2O
+
ClCH2CO2H
solvent
r.t., 24 h
NO2
OR2
4c–g
3a
2b, R2 = Ph
2c, R2 = PhCH2
2d, R2 = t-BuMe2Si
2e, R2 = CF3CH2
2f, R2 = 4-MeOC6H4CH2
Scheme 3
O
O
catalyst I–III
O
Table 2 Addition of Aldehydes 2 to 2-Aminonitroethenes 3a
O
HN
R1
(10 mol%)
R1
N
Et
O
NO2
+
R2
Product Solvent
Yield syn
ee syn
/antib
H
ClCH2CO2H
(20 mol%)
solvent, r.t.
NO2
(%) /antia
Et
3a, R1 = Me
O
Et
2a
3b, R1 = i-Pr
Ph
4c
4d
4d
4d
4d
4d
4d
4d
4e
4f
DMSO
NMP
70
55
38
81
61:39 74/30
56:44 45/45
53:47 30/29
56:44 53/58
56:44 53/56
56:44 53/63
53:47 20/21
50:50 55/35
60:40 75/76
67:33 31/30
50:50 58/39
Et 4a,b
Ph
Ph
Ph
OMe
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
t-BuMe2Si
CF3CH2
Ph
OSiMe3
N
N
N
H
H
H
MeOH
DMSO
OMe
II
I
III
Scheme 2
DMSO–H2O 68
CHCl3
50
40
55
60c
48
80
Table 1 Addition of Aldehyde 2a to 2-Aminonitroethenes 3b and
3ba
CHCl3/H2O
THF–H2O
CH2Cl2
R1
Catalyst Solvent
Yield syn
(%)
ee syn
/antic
/antib
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
I
MeOH
95
38
38
53
75
77
88
30
76
77
45:55
35:65
56:44
73:27
76:23
74:26
81:19
81:19
70:30
76:24
12/9
DMSO
I
DMSO
17/21
53/24
86/55
92/38
91/58
97/56
46/65
86/77
71/22
4-MeOC6H4CH2 4g
DMSO
I
THF–brine
CH2Cl2/brine
CHCl3/brine
CHCl3/H2O
CHCl3/H2Od
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
a Determined by 1H NMR spectroscopic analysis.
b Determined by enantioselective HPLC after derivatization with
9-fluorenylidenetriphenylphosphorane.
c Reaction time: 72 h.
I
I
I
Based on the model of Seebach and Golinski,17 the prop-
osition of Ma,12 and on our own recent calculations7 of en-
amines formed from oxyacetaldehydes, the formation of
product 4 can be explained by the transition state model
depicted on Figure 1. Here the anti-product (R,R)-4 results
from the E-enamine and the syn-product (S,R)-4 results
from the Z-enamine, as a result of Si-attack of the Z-con-
figured alkene 3a.
I
II
III
I
a Reaction conditions: aldehyde 2a (3 mmol), catalyst (0.2 mmol), al-
kene 3 (2 mmol), ClCH2CO2H (0.4 mmol), CHCl3–H2O (1:1, 32 mL).
b Determined by 1H NMR spectroscopic analysis.
The usefulness of the described conjugate addition prod-
ucts 4 was shown by synthesizing oseltamivir and its ana-
logues. Cyclization was performed by modifying
Hayashi’s procedure.11 Hayashi used p-toluenethiol with
Cs2CO3 to obtain the desired diastereoisomer. The thiol is
required for efficient epimerization of predominantly
formed R,R,R-isomer to the desired R,R,S-isomer, on the
other hand, use of stoichiometric amounts of thiol makes
c Determined by enantioselective HPLC after derivatization with
9-fluorenylidenetriphenylphosphorane.
d The reaction was performed at 0 °C for 5 h.
In order to prepare analogues of oseltamivir, we have fur-
ther explored the scope of this transformation by evaluat-
ing a range of alkyloxyacetaldehydes 2 in the addition to
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2424–2430

2426
J. Rehák et al.
PAPER
Although diastereoselectivities of the cyclization are low,
the diastereoisomers can be efficiently separated by col-
umn chromatography. The isomer (R,R,R)-6a can be
epimerized to the desired isomer (R,R,S)-6a by treatment
with K2CO3 followed by crystallization, resulting in an
enrichment of (R,R,S)-6a/(R,R,R)-6a to between 96:4 and
98:2 (96% yield). Relative configurations of (R,R,S) and
(R,R,R)-6a and 6b were confirmed by 2D NMR experi-
ments.
‡
‡
TMSO
Ph
Ph
TMSO
Ph
N
NHAc
N
NHAc
Ph
O
R
NO2
O
NO2
R
Re
Si
O
NHAc
O
NHAc
The synthesis of oseltamivir (7a) was then finished by re-
duction of the nitro group by treatment with zinc in acetic
acid.18 Two derivatives (7b and 7c) were synthesized in a
similar way (Scheme 5).
NO2
NO2
H
H
(R,R)-4
(S,R)-4
OR
OR
Figure 1
R3O
CO2Et
R3O
CO2Et
Zn, HCl, EtOH
r.t., 32 h
the synthesis problematic from a practical point of view.
We have performed this reaction without intermediate ad-
dition of the thiol (Scheme 4). From the diastereoisomeric
mixture, the required diastereomer for oseltamivir synthe-
sis, (R,R,S)-6a, can be isolated in pure form. The best con-
ditions for cyclization of 4a were found to be four hours
heating under microwave irradiation in the presence of
18-crown-6 and K2CO3, which afforded 6a in 66% yield
for both diastereoisomers. Again, these conditions were
not ideal for cyclization of 4d and 4f, for which the use of
Cs2CO3 in DMSO gave better yields (Table 3).
AcHN
AcHN
NH2
(R,R,R)-7a–c
NO2
(R,R,S)-6a–c
7a, R3 = 3-pentyl, 81%
7b, R3 = Bn, 34%
7c, R3 = 4-MeOC6H4CH2, 38%
Scheme 5
The presented synthesis of oseltamivir can also be per-
formed on a gram scale. Organocatalytic Michael addition
was realized with 4.5 grams of aldehyde 2a and 3.0 grams
of alkene 3a, giving 3.2 grams of pure syn-4a. The limit-
ing step in terms of scale was cyclization in the micro-
wave reactor, which, with our apparatus, could be
performed in up to 0.5 gram batches.
R3O
CO2Et
AcHN
R3O
O
OEt
OEt
NO2
(R,R,S)-6
+
K2CO3
O
+
In summary, organocatalyzed Michael addition of substi-
tuted oxyacetaldehydes to 2-aminonitroethenes lead to
useful α-hydroxy-β-amino-γ-nitrocarbonyl structural mo-
tifs. These compounds are obtained in good yields, mod-
erate diastereoselectivity and good to high
enantioselectivities (up to 97% ee). Such compounds are
useful building blocks for the synthesis of oseltamivir and
its analogues. Cyclization can be performed without a thi-
ol by using microwave irradiation. The minor diastereo-
isomer was efficiently epimerized to the desired isomer by
using K2CO3 followed by crystallization.
18-crown-6
CH2Cl2, r.t.
24 h
AcHN
P
OEt
R3O
CO2Et
NO2
4a,d,f
O
5
AcHN
6a, R3 = 3-pentyl
6b, R3 = Bn
NO2
6c, R3 = 4-MeOC6H4CH2
(R,R,R)-6
Scheme 4
Table 3 Cyclization of Aldahydes 4 to Cyclohexenes 6
R3
Base
Solvent, conditions
dr (R,R,S)/(R,R,R)
Yield (%)
3-pentyl
3-pentyl
3-pentyl
Bn
K2CO3, 18-crown-6
K2CO3, 18-crown-6
DBU, LiCl
CH2Cl2, 70 °C
CH2Cl2, 70 °C, MW
MeCN
1:1.8
1:1.5
1.5:1
1:1.4
1:2.4
1:1
56
66
61
20
22
48
27
K2CO3, 18-crown-6
DBU, LiCl
CH2Cl2
Bn
MeCN
Bn
Cs2CO3
DMSO
4-MeOC6H4CH2
Cs2CO3
DMSO
1.2:1
Synthesis 2012, 44, 2424–2430
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Thiol-Free Synthesis of Oseltamivir
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2-Methyl-N-[(E)-2-nitroethenyl]propanamide (3b)
Solvents were dried and purified by standard methods before use.
NMR spectra were recorded with a Varian NMR System 300 instru-
1H NMR (300 MHz, CDCl3): δ = 8.49 (dd, J = 11.2, 12.1 Hz, 1 H),
7.71 (d, J = 11.2 Hz, 1 H), 7.42 (d, J = 12.1 Hz, 1 H), 2.57 (sept,
J = 7.0 Hz, 1 H), 1.25 (d, J = 7.0 Hz, 6 H).
1
ment (300 MHz for H, 75 MHz for 13C). Chemical shifts (δ) are
given in ppm relative to tetramethylsilane. Flash chromatography
was performed with Merck silica gel 60. Thin-layer chromatogra-
phy was performed with Merck TLC plates (silica gel 60, F-254).
Enantiomeric excesses were determined by HPLC analysis on Chi-
ralpak AD-H, AS-H, IC and Chiralcel OD-H (Daicel Chemical In-
dustries) columns using hexane–i-PrOH as a mobile phase and by
UV detection. HRMS analyses were performed with a LC-IT-TOF
MS (Shimadzu, Kyoto, Japan) using an Ascentis C18 column with
gradient H2O–MeCN elution over 33 min. Racemic mixtures of all
the products were prepared according to the general procedure us-
ing morpholine as catalyst.
13C NMR (75 MHz, CDCl3): δ = 176.6, 136.6, 125.0, 35.9, 18.9.
HRMS: m/z [MH]+ calcd for C6H11N2O3: 159.076; found: 159.075.
Michael Addition of Alkyloxyacetaldehydes to 3; General Pro-
cedure
To a solution of (Z)-N-(2-nitrovinyl)acetamide (3a; 70 mg, 0.538
mmol) in DMSO (1 mL) was added alkyloxyacetaldehyde 2 (0.807
mmol). To the stirred solution was added (S)-I dissolved in DMSO
(0.5 mL) and chloroacetic acid (10.3 mg, 0.107 mmol). The mixture
was stirred under a nitrogen atmosphere for 24–48 h (reaction was
monitored by TLC). Upon completion, the reaction mixture was
poured into H2O and extracted with EtOAc (3 × 15 mL). The com-
bined organic extracts were dried over Na2SO4 and the solvent was
evaporated under reduced pressure to leave a yellow oil, which was
purified by column chromatography on silica (hexane–EtOAc,
3:1→1:1) to give the corresponding Michael adduct 4c–g.
Alkyloxyacetaldehydes 2
Aldehydes 2c and 2d are commercially available. Aldehydes 2b,19
2e and 2f20 were prepared according to literature procedures.
2-(Pentan-3-yloxy)acetaldehyde (2a)
Pentan-3-ol (59 mL, 555 mmol) was added to anhydrous CH2Cl2
(270 mL) under an inert atmosphere and the resulting solution was
cooled in an ice bath. DIBAL-H (20% in toluene, 402 mL, 481
mmol) was added dropwise over 2 h, and the mixture was then
stirred for 30 min. Epoxide 1 (24.5 mL, 370 mmol) was added at
20 °C over 30 min and the reaction mixture was then stirred at r.t.
for 72 h. The reaction mixture was slowly added to a mixture of
crushed ice (500 mL) and concd HCl (100 mL) and the product was
extracted with EtOAc (3 × 100 mL). The organic layers were col-
lected, dried over Na2SO4, and concentrated. Vacuum distillation
(bp 79 °C, 56 Pa) of the residue provided 3-(pentan-3-yloxy)pro-
pane-1,2-diol.
Derivatization of Michael Adducts for HPLC Analysis; General
Procedure
The Michael adduct was dissolved in toluene (1 mL) and 9-fluore-
nylidenetriphenylphosphorane (139 mg, 0.324 mmol) was added.
The reaction mixture was heated under reflux in an atmosphere of
nitrogen for 1 h. After cooling to r.t. the toluene was evaporated un-
der reduced pressure and the residue was purified by column chro-
matography on silica (hexane–EtOAc, 3:1→1:1).
N-[1-Nitro-4-oxo-3-(pentan-3-yloxy)butan-2-yl]acetamide (4a)
Yield: 920 mg (88%); colorless oil.
Yield: 12 g (20%); colorless liquid.
HPLC for triphenylphosphoranylidene derivative (Chiralcel OD-H;
i-PrOH–hexane, 20:80; 0.75 mL/min; λ = 259 nm): tR = 8.31 (anti-
4a, major), 9.65 (anti-4a, minor), 12.04 (syn-4a, major), 19.31 (syn-
4a, minor) min.
1H NMR (300 MHz, CDCl3): δ = 3.85 (ddd, J = 4.0, 5.6, 8.0 Hz,
1 H), 3.68 (m, 2 H), 3.53 (m, 2 H), 3.17 (quint, J = 5.8 Hz, 1 H),
2.79 (br s, 2 H), 1.51 (m, 4 H), 0.90 (t, J = 7.4 Hz, 6 H).
A solution of NaIO4 (11.6 g, 54.6 mmol) in H2O (79 mL) was added
to a suspension of silica gel (90 g) in CH2Cl2 (640 mL) over 15 min,
then a solution of 3-(pentan-3-yloxy)propane-1,2-diol (6.5 g, 42
mmol) in CH2Cl2 (80 mL) was added over 20 min. After 3 h, the sil-
ica gel was filtered off and washed with CH2Cl2 (3 × 100 mL). The
organic phase was extracted with a solution of Na2S2O4 (6 g, 34.5
mmol) in H2O (150 mL). The organic layer was dried over Na2SO4
and concentrated. The crude product 2a was purified by distillation
(bp 42 °C, 1.2 kPa) to provide pure aldehyde 2a.
syn-4a
1H NMR (300 MHz, CDCl3): δ = 9.65 (t, J = 0.6 Hz, 1 H), 6.04 (br
d, J = 8.5 Hz, 1 H), 5.11–5.02 (m, 1 H), 4.58 (d, J = 6.5, 2 H), 4.08
(dd, J = 0.3, 3.3 Hz, 1 H), 3.41 (quint, J = 5.8 Hz, 1 H), 1.99 (s,
3 H), 1.62–1.49 (m, 4 H), 0.98–0.87 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 201.0, 170.6, 83.5, 79.7, 74.2, 48.1,
25.9, 24.9, 22.8.
HRMS: m/z [MH]+ calcd for C11H21N2O5: 261.144; found: 261.145.
Yield: 3.9 g (72%); colorless liquid.
anti-4a
1H NMR (300 MHz, CDCl3): δ = 9.61 (d, J = 3.1 Hz, 1 H), 6.11 (br
d, J = 8.8 Hz, 1 H), 4.85–4.50 (m, 3 H), 3.95 (dd, J = 3.1, 8.0 Hz,
1 H), 3.27 (quint, J = 5.5 Hz, 1 H), 2.00 (s, 3 H), 1.57–1.42 (m,
4 H), 0.95–0.84 (m, 6 H).
1H NMR (300 MHz, CDCl3): δ = 9.76 (t, J = 1.1 Hz, 1 H), 4.06 (d,
J = 1.1 Hz, 2 H), 3.23 (quint, J = 5.8 Hz, 1 H), 1.56 (dq, J = 3.3,
7.6 Hz, 4 H), 0.93 (t, J = 7.4 Hz, 6 H). Spectral data in agreement
with the literature.11b
13C NMR (75 MHz, CDCl3): δ = 201.1, 170.5, 83.2, 80.4, 74.1, 47.2,
Preparation of Acylaminonitroethenes 3; Typical Procedure
Acetic anhydride (3.7 mL) was added to a solution of 2-nitroeth-
enylamine (1.76 g, 20 mmol) in pyridine (24 mL) at 0–5 °C during
5 min, then the reaction mixture was stirred at r.t. for 28 h. The re-
action mixture was added to aq sat. CuSO4 (200 mL) and the ob-
tained mixture was extracted with Et2O (5 × 80 mL). The organic
layers were dried with Na2SO4 and concentrated. Column chroma-
tography of the residue (SiO2; EtOAc–hexane, 1:1) afforded pure 3.
26.0, 24.8, 23.0.
HRMS: m/z [MH]+ calcd for C11H21N2O5: 261.144; found: 261.144.
N-[1-Nitro-4-oxo-3-(pentan-3-yloxy)butan-2-yl]isobutyramide
(4b)
Yield: 290 mg (77%); colorless oil.
HPLC for triphenylphosphoranylidene derivative (Chiralcel OD-H;
i-PrOH–hexane, 15:85; 0.75 mL/min; λ = 259 nm): tR = 7.43 (anti-
4b, minor), 10.26 (anti-4b, major), 10.05 (syn-4b, minor), 31.92
(syn-4b, major) min.
N-[(Z)-2-Nitroethenyl]acetamide (3a)
Yield: 2.22 g (85%); white crystals; mp 117–119 °C.
1H NMR (300 MHz, CDCl3): δ = 10.40 (br s, 1 H), 7.59 (dd, J = 7.0,
12.3 Hz, 1 H), 6.61 (d, J = 6.7 Hz, 1 H), 2.28 (s, 3 H).
MS: m/z [MH+] calcd for C4H7N2O3: 131.11; found: 131.04.
syn-4b
1H NMR (300 MHz, CDCl3): δ = 9.64 (t, J = 0.5 Hz, 1 H), 6.06 (br
d, J = 8.5 Hz, 1 H), 5.11–5.01 (m, 1 H), 4.60 (d, J = 1.1 Hz, 1 H),
4.57 (d, J = 1.7 Hz, 1 H), 4.10 (dd, J = 0.3, 3.1 Hz, 1 H), 3.41
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2424–2430

2428
J. Rehák et al.
PAPER
(quint, J = 5.7 Hz, 1 H), 2.38–2.36 (m, 1 H), 1.64–1.45 (m, 4 H),
1.16–1.01 (m, 6 H), 0.98–0.87 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 200.8, 176.8, 83.4, 79.5, 74.1, 47.7,
35.4, 26.0, 25.0, 19.4, 19.3, 9.4, 9.3.
HPLC (Chiralpak IB; i-PrOH–hexane, 10:90; 1 mL/min; λ = 254
nm): tR = 17.18 (anti-4f, major), 24.4 (anti-4f, minor), 31.29 (syn-
4f, major), 46.68 (syn-4f, minor) min.
1H NMR (300 MHz, CDCl3): δ = 2.0 (s, 3 H), 3.81–3.91 (m, 1 H),
4.18–4.35 (m, 2 H), 4.55 (dd, J = 3.4, 13.9 Hz, 1 H), 4.62 (d,
J = 6.7 Hz, 1 H), 4.77 (dd, J = 8.8, 13.9 Hz, 1 H, CH2NO2), 5.28–
5.37 (m, 1 H, CHCHO), 5.91 (d, J = 8.9 Hz) and 6.18 (d,
J = 7.6 Hz, 1 H), 9.61 (s) and 9.65 (d, J = 1.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.8, 46.5, 68.1 and 68.6, 73.5 and
73.7, 83.8 and 83.9, 125.0 and 126.5, 170.0 and 171.2, 196.5 and
197.3.
HRMS: m/z [MH]+ calcd for C8H12F3N2O5: 273.070; found:
273.069.
HRMS: m/z [MH]+ calcd for C13H25N2O5: 289.176; found: 289.166.
anti-4b
1H NMR (300 MHz, CDCl3): δ = 9.60 (d, J = 3.1 Hz, 1 H), 6.09 (br
d, J = 8.7 Hz, 1 H), 4.82 (dd, J = 5.3, 13.3 Hz, 1 H), 4.76–4.68 (m,
1 H), 4.56 (dd, J = 3.6, 13.3 Hz, 1 H), 3.94 (dd, J = 3.1, 8.2 Hz,
1 H), 3.26 (quint, J = 5.7 Hz, 1 H), 2.38–2.36 (m, 1 H), 1.61–1.46
(m, 4 H), 1.16–1.11 (m, 6 H), 0.94–0.84 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 200.9, 177.2, 83.2, 80.4, 74.2, 46.9,
35.5, 26.1, 24.9, 19.4, 19.3, 9.5, 9.1.
HRMS: m/z [MH]+ calcd for C13H25N2O5: 289.176; found: 289.167.
N-{3-[(4-Methoxybenzyl)oxy]-1-nitro-4-oxobutan-2-yl}acet-
amide (4g)
Yield: 135 mg (80%); colorless oil.
N-(1-Nitro-4-oxo-3-phenoxybutan-2-yl)acetamide (Mixture of
syn and anti-4c)
Yield: 106 mg (70%); colorless oil.
HPLC (Chiralpak IC; i-PrOH–hexane, 18:82; 0.6 mL/min; λ = 254
nm): tR = 49.8 (anti-4g, minor), 70.83 (anti-4g, major), 65.7 (syn-
4g, minor), 121.2 (syn-4g, major) min.
1H NMR (300 MHz, CDCl3): δ = 1.92 and 1.95 (s, 3 H), 3.81 (s,
3 H), 4.48 (m, 1 H), 4.52–4.54 (m, 1 H), 4.60–4.78 (m, 2 H), 4.82
(m, 1 H), 5.17 (m, 1 H), 6.09 (d, J = 8.9 Hz) and 6.20 (d, J = 8.8 Hz,
1 H), 6.90 (m, 2 H), 7.25 (m, 2 H), 9.54 (d, J = 2.5 Hz) and 9.57 (s,
1 H).
HPLC (Chiralpak IC; i-PrOH–hexane, 18:82; 0.8 mL/min; λ = 254
nm): tR = 18.87 (anti-4c, major), 28.8 (anti-4c, minor), 25.13 (syn-
4c, minor), 48.0 (syn-4c, major) min.
1H NMR (300 MHz, CDCl3): δ = 2.02 and 2.05 (s, 3 H), 4.64–4.79
(m, 2 H), 4.87–4.94 (m, 1 H), 5.28–5.36 (m, 1 H), 6.21 (m, 1 H),
6.87–7.01 (m, 2 H), 7.28–7.36 (m, 3 H), 9.65 (d, J = 2.5 Hz) and
9.73 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.9, 47.0, 55.3, 73.3, 74.1 and
74.3, 80.6 and 81.2, 114.2, 127.9, 130.4, 160.0, 170.0 and 170.2,
199.2 and 199.8.
13C NMR (75 MHz, CDCl3): δ = 23.0, 47.4, 73.9 and 74.2, 79.9 and
80.0, 115.3, 123.2, 130.0, 156.6, 170.3 and 170.7, 198.3 and 198.8.
HRMS: m/z [MH]+ calcd for C14H19N2O6: 311.124; found: 311.143.
HRMS: m/z [MH]+ calcd for C12H15N2O5: 267.098; found: 267.096.
Ethyl 4-Acetamido-5-nitro-3-(pentan-3-yloxy)cyclohex-1-ene-
carboxylate (6a)
N-[3-(Benzyloxy)-1-nitro-4-oxobutan-2-yl]acetamide (4d)
Yield: 140 mg (81%); colorless oil.
18-Crown-6 (33 mg, 0.124 mmol) and K2CO3 (373 mg, 2.70 mmol)
were added to a solution of 4a (293 mg, 1.13 mmol) and 2-
(diethoxyphosphoryl)acrylate (5; 266 mg, 1.13 mmol) in CH2Cl2
(15 mL) at 0 °C under an Ar atmosphere. The reaction mixture was
then heated for 4 h at 70 °C in a microwave reactor before being
quenched with sat. aq NH4Cl (13 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 10 mL) and the combined organic layer
was washed with brine (10 mL), dried over Na2SO4, and concentrat-
ed under reduced pressure. Chromatography (SiO2; hexane–EtOAc,
2:1) provided (R,R,S)-6a (153 mg, 40%) and (R,R,R)-6a (102 mg,
26%) as white solids.
HPLC (Chiralpak IC; i-PrOH–hexane, 18:82; 1.2 mL/min; λ = 254
nm): tR = 21.77 (anti-4d, major), 34.80 (anti-4d, minor), 29.5 (syn-
4d, major), 54.7 (syn-4d, minor) min.
1H NMR (300 MHz, CDCl3): δ = 1.93 and 1.96 (s, 3 H), 3.93 (dd,
J = 2.6, 7.6 Hz, 1 H), 4.10–4.18 (m, 1 H), 4.48–4.60 (m, 2 H), 4.70–
4.90 (m, 2 H), 5.18–5.22 and 5.98–6.02 (m, 1 H), 7.40–7.20 (m,
5 H), 9.56 (d, J = 2.5 Hz) and 9.60 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 21.9, 45.9, 72.7, 73.0 and 73.3,
80.0–80.6, 127.5, 127.7, 127.8, 134.8, 169.1 and 169.3, 198.0 and
198.7.
HRMS: m/z [MH]+ calcd for C13H17N2O5: 281.114; found: 281.114.
Compound (R,R,S)-6a
1H NMR (300 MHz, CDCl3): δ = 6.84–6.82 (m, 1 H), 5.80 (d,
J = 6.4 Hz, 1 H), 5.62 (ddd, J = 6.0, 10.6, 11.1 Hz, 1 H), 4.85–4.81
(m, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 3.77–3.68 (m, 1 H), 3.34 (quint,
J = 5.8 Hz, 1 H), 3.16–3.08 (m, 1 H), 2.91–2.81 (m, 1 H), 1.97 (s,
3 H), 1.56–1.46 (m, 4 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.94–0.86 (m,
6 H).
N-{3-[(tert-Butyldimethylsilyl)oxy]-1-nitro-4-oxobutan-2-
yl}acetamide (4e)
Yield: 97 mg (60%); colorless oil.
HPLC (Chiralpak IC; i-PrOH–hexane, 9:91; 0.7 mL/min; λ = 226
nm): tR = 17.20 (anti-4e, major), 30.00 (anti-4e, minor), 25.6 (syn-
4e, major), 53.3 (syn-4e, minor) min.
13C NMR (75 MHz, CDCl3): δ = 171.1, 165.2, 137.9, 126.8, 82.2,
1H NMR (300 MHz, CDCl3): δ = 0.92 (s, 6 H), 0.95 (s, 9 H), 1.99
and 2.01 (s, 3 H), 4.21 (dd, J = 2.0, 6.9 Hz) and 4.35 (d, J = 3.2 Hz,
1 H), 4.49–4.57 (m, 1 H), 4.67–4.76 (m, 1 H), 5.03–5.11 (m, 1 H),
5.97 (d, J = 8.5 Hz) and 6.21 (d, J = 8.0 Hz, 1 H), 9.56 (s) and 9.58
(d, J = 2.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 18.2, 23.3, 26.0, 30.6, 46.0, 75.3
and 75.8, 79.3 and 79.6, 169.9 and 170.1, 201.2 and 202.6.
81.8, 71.5, 61.3, 56.3, 29.6, 26.2, 25.5, 23.6, 14.2, 9.6, 9.3.
HRMS: m/z [MH]+ calcd for C16H27N2O6: 343.186; found: 343.186.
Compound (R,R,R)-6a
1H NMR (300 MHz, CDCl3): δ = 6.90–6.87 (m, 1 H), 5.63 (br d,
J = 8.8 Hz, 1 H), 5.0 (dt, J = 3.3, 6.6 Hz, 1 H), 4.77 (ddd, J = 3.3,
5.1, 8.4 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.13–4.10 (m, 1 H),
3.51 (quint, J = 5.8 Hz, 1 H), 3.04 (td, J = 7.0, 1.8 Hz, 2 H), 1.99 (s,
3 H), 1.64–1.45 (m, 4 H), 1.32 (t, J = 7.1 Hz, 3 H), 0.97 (t,
J = 7.2 Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H).
HRMS: m/z [MH]+ calcd for C12H24N2O5Si: 305.153; found:
305.148.
13C NMR (75 MHz, CDCl3): δ = 170.2, 165.3, 135.3, 128.5, 82.7,
80.1, 72.3, 61.5, 50.1, 26.4, 26.3, 25.6, 23.3, 14.2, 9.9, 9.3.
HRMS: m/z [MH]+ calcd for C16H27N2O6: 343.186; found: 343.186.
N-[1-Nitro-4-oxo-3-(2,2,2-trifluoroethoxy)butan-2-yl]acet-
amide (4f)
Yield: 70 mg (48%); colorless oil.
Synthesis 2012, 44, 2424–2430
© Georg Thieme Verlag Stuttgart · New York

PAPER
Thiol-Free Synthesis of Oseltamivir
2429
Cyclization of 4d and 4f; General Procedure
action mixture was stirred for an additional 32 h at r.t., then
quenched by addition of 10% NH4OH (10 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined extracts were dried over
Na2SO4 and evaporated under reduced pressure to give a yellow oil
that was purified by column chromatography on silica (CHCl3–
MeOH, 15:1→10:1) to give the corresponding amine 7 as pale-
yellow viscous oils.
To a solution of Michael adduct 4d or 4f (0.285 mmol) dissolved in
DMSO (1.5 mL) under a nitrogen atmosphere was added ethyl 2-
(diethoxyphosphoryl)acrylate (5; 87.6 mg, 0.371 mmol). A solution
of Cs2CO3 (279 mg, 0.855 mmol) in H2O (0.5 mL) was added at r.t.
within 2 h by using a syringe pump. The reaction mixture was
stirred for an additional 1 h, quenched with sat. NH4Cl (10 mL) and
extracted with EtOAc (3 × 15 mL). The combined extracts were
dried over Na2SO4 and evaporated under reduced pressure to give a
yellow oil that was purified by column chromatography on silica
(hexane–EtOAc, 3:1→1:1) to give the corresponding cyclohexene
derivative 6b or 6c as pale-yellow viscous oils.
(3R,4R,5S)-Ethyl 4-Acetamido-5-amino-3-(pentan-3-yloxy)cy-
clohex-1-enecarboxylate (7a)
Acetic acid was used instead of HCl/EtOH.
Yield: 170 mg (81%); pale-yellow oil.
1H NMR (300 MHz, CDCl3): δ = 6.79 (t, J = 2.0 Hz, 1 H), 5.50 (d,
J = 7.9 Hz, 1 H), 4.22 (q, J = 7.3 Hz, 2 H), 4.20–4.15 (m, 1 H), 3.51
(q, J = 8.8 Hz, 1 H), 3.35 (quint, J = 5.8 Hz, 1 H), 3.24 (m, 1 H),
2.75 (dd, J = 5.5, 5.2 Hz, 1 H), 2.15 (m, 1 H), 2.04 (s, 3 H), 1.60–
1.40 (m, 4 H), 1.30 (t, J = 7.0 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H),
0.91 (t, J = 7.5 Hz, 3 H). 1H NMR data agree with those reported in
the literature.8a
Ethyl 4-Acetamido-3-benzyloxy-5-nitrocyclohex-1-enecarbox-
ylate (6b)
Yield: 50 mg (48%); pale-yellow oil.
Compound (R,R,R)-6b
1H NMR (CDCl3, 600 MHz): δ = 7.28–7.42 (m, 5 H, 5 × HPh), 7.00
[m, 1 H, H-C(2)], 5.83 (d, JNH,4 = 8.8 Hz, 1 H, NH), 4.92 [ddd,
J4,5 = 10.7 Hz, J5,6 = 8.8 Hz, J5,6 = 6.3 Hz, 1 H, H-C(5)], 4.73–4.83
[m, 1 H, H-C(4)], 4.71 [d, J = 11.5 Hz, 1 H, PhCHO-], 4.53 (d,
J = 11.5 Hz, 1 H, PhCHO-), 4.25 (q, J = 7.2 Hz, 2 H, COOCH2),
4.17 [dd, J3,4 = 6.3 Hz, J2,3 = 4.1 Hz, 1 H, H-C(3)], 3.11 [dd,
J = 17.9 Hz, J5,6 = 5.8 Hz, 1 H, H-C(6)], 3.06 [ddd, J = 17.9 Hz,
Ethyl 4-Acetamido-5-amino-3-(benzyloxy)cyclohex-1-enecar-
boxylate (7b; Mixture of Isomers)
Yield: 15 mg (34%); pale-yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.97,
1.98 and 2.01 (s, 3 H), 2.26 (m), 2.66 (m) and 2.88 (dd, J = 5.2,
18.3 Hz, 2 H), 3.14 and 3.47 (m, 1 H), 3.95 and 4.28 (m, 2 H), 4.21
(q, J = 7.14 Hz, 2 H), 4.28 and 4.50 (m, 1 H), 4.70 (m, 4 H), 5.51 (br
s, 2 H), 5.75 (d, J = 7.36 Hz) and 6.02 (t, J = 9.8, 9.8 Hz, 1 H), 6.87
and 6.97 (m, 1 H), 7.37 (m, 5 H).
J5,6 = 9.2 Hz, J2,6 = 1.6 Hz, 1 H, H-C(6)], 1.91 (s, 3 H, CH3CON),
1.32 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (CDCl3, 150 MHz): δ = 169.9 (CON), 165.0 (COOEt),
136.9 (C1), 133.6 (C2), 130.1, 128.8, 128.1, 127.7 (6 × CPh), 81.5
(C5), 72.3 (PhCH2), 70.9 (C3), 61.5 (COOCH2), 49.7 (C4), 28.9
(C6), 23.1 (CH3CON), 14.1 (OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 14.1, 23.7, 28.9, 46.6, 61.2, 65.3,
71.7, 77.2, 126.9, 127.8, 128.1, 128.4, 128.7, 137.8, 166.2, 172.3.
HRMS: m/z [MH]+ calcd for C18H25N2O4: 333.181; found: 333.185.
Compound (R,R,S)-6b
1H NMR (CDCl3, 600 MHz): δ = 7.28–7.41 (m, 5 H, HPh), 6.92
[ddd, J = 2.7, 2.6, 0.9 Hz, 1 H, H-C(2)], 5.91 (d, JNH,4 = 8.9 Hz, 1 H,
NH), 5.41 [ddd, J4,5 = 10.5 Hz, J5,6 = 10.4 Hz, J = 5.9 Hz, 1 H, H-
C(5)], 4.74–4.77 [m, 1 H, H-C(3)], 4.72 (d, J = 11.7 Hz, 1 H,
PhCHO), 4.55 (d, J = 11.7 Hz, 1 H, PhCHO), 4.24 (q, J = 7.1 Hz,
2 H, COOCH2), 4.05 [ddd, J4,5 = 11.0 Hz, JNH,4 = 8.3 Hz,
Ethyl 4-Acetamido-5-amino-3-[(4-methoxybenzyl)oxy]cyclo-
hex-1-enecarboxylate (7c; Mixture of Isomers)
Yield: 42 mg (38%); pale-yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.89,
2.02 and 2.17 (s, 3 H), 2.64 (m, 2 H), 3.17 and 3.40 (m, 1 H), 3.80
and 3.15 (s, 3 H), 4.05 (m, 2 H), 4.21 (q, J = 7.0 Hz, 2 H), 4.37 and
4.49 (m, 1 H), 4.65 (m, 2 H), 5.45 (br s, 2 H), 5.64 (d, J = 7.36 Hz)
and 5.95 (dd, J = 7.9, 14.1 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 2 H), 6.84
and 6.94 (m, 1 H), 7.28 (m, 2 H).
J3,4 = 7.6 Hz, 1 H, H-C(4)], 3.05–3.13 [m, 1 H, H-C(6)], 2.92
[dddd, J = 17.5 Hz, J5,6 = 10.1 Hz, J = 3.0 Hz, J = 3.0 Hz, 1 H, H-
C(6)], 1.88 (s, 3 H, CH3CON), 1.31 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (CDCl3, 150 MHz): δ = 170.9 (CON), 165.0 (COOEt),
137.3 (C1), 136.4 (C2), 128.6, 128.5, 128.3, 128.2 (6 × CPh), 82.0
(C5), 73.6 (C3), 72.0 (PhCH2), 61.4 (COOCH2), 54.5 (C4), 29.3
(C6), 23.4 (CH3CON), 14.2 (OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 14.2, 23.5, 30.8 and 33.7, 46.2 and
47.1, 55.2, 60.9, 68.3, 70.8, 73.3, 113.9, 129.7, 134.8, 159.4, 166.3,
170.8.
HRMS: m/z [MH]+ calcd for C18H23N2O6: 363.156; found: 363.156.
HRMS: m/z [MH]+ calcd for C19H27N2O5: 363.192; found: 393.197.
(3R, 4R, 5S)-Ethyl 4-Acetamido-3-[(4-methoxybenzyl)oxy]-5-
nitrocyclohex-1-enecarboxylate [(R,R,S) and (R,R,R)-6c, Mix-
ture of Isomers]
Acknowledgment
Yield: 230 mg (27%); pale-yellow oil.
The European Commission is gratefully acknowledged for financial
support; project FP7–201431 (CATAFLU.OR). This work was also
supported by the Slovak Research and Development Agency under
contract No. DO7RP-0017-08. HRMS measurements were suppor-
ted by the Slovak Research and Development Agency, project no.
VVCE 0070/07. NMR measurements were provided by Slovak
State Programme project no. 2003SP200280203. We also thank
Prof. P. G. Cozzi for useful suggestions at the outset of the project.
1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.89,
1.91 and 1.95 (s, 3 H), 2.86–3.50 (m, 2 H), 3.80 and 3.81 (s, 3 H),
4.20–4.28 (m, 2 H), 4.50–4.96 (m, 2 H), 4.85–4.94 (m), 5.04 (dt,
J = 3.5, 5.9, 5.9 Hz) and 5.41 (dt, J = 6.0, 10.4 Hz, 1 H), 5.57 (d,
J = 7.8 Hz), 5.71 (d, J = 7.2 Hz) and 5.85 (d, J = 8.7 Hz, 1 H), 6.87–
6.97 (m, 3 H), 7.19–7.30 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 14.2, 21.0, 23.2, 49.6, 55.3, 61.4,
71.2, 71.9 and 72.4, 80.8, 81.6, 114.1, 129.3, 129.8, 129.9, 133.8,
135.0, 159.6, 165.1, 169.9 and 170.3.
HRMS: m/z [M – H−] calcd for C19H23N2O7: 391.151; found:
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2424–2430

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