High-yielding synthesis of the anti-influenza neuraminidase inhibitor (-)-oseltamivir by two one-pot sequences

Article abstract of DOI:10.1002/chem.201001108

The efficient asymmetric total synthesis of (-)-oseltamivir, an antiviral reagent, has been accomplished by using two one-pot reaction sequences, with excellent overall yield (60%) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wadsworth-Emmons reaction combined with retro-aldol/Horner-Wadsworth-Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (-)-oseltamivir has also been established. Fighting the flu: Two one-pot and column-free asymmetric sequences are used to accomplish the synthesis of (-)-oseltamivir, known as the anti-influenza drug Tamiflu (see scheme; TMS: trimethylsilyl). This high-yielding synthesis takes advantage of a diphenylprolinol silyl ether as an organocatalyst and single-pot domino operations.

Full text of DOI:10.1002/chem.201001108

DOI: 10.1002/chem.201001108
High-Yielding Synthesis of the Anti-Influenza Neuraminidase Inhibitor
(À)-Oseltamivir by Two “One-Pot” Sequences
Hayato Ishikawa,[a] Takaki Suzuki,[a] Hideo Orita,[c] Tadafumi Uchimaru,[c] and
Yujiro Hayashi*[a, b]
Abstract: The efficient asymmetric
total synthesis of (À)-oseltamivir, an
antiviral reagent, has been accom-
plished by using two “one-pot” reac-
tion sequences, with excellent overall
yield (60%) and only one required pu-
rification by column chromatography.
The first one-pot reaction sequence
Horner–Wadsworth–Emmons reaction
combined with retro-aldol/Horner–
Wadsworth–Emmons reaction and
retro Michael reactions, a thiol Michael
reaction, and a base-catalyzed isomeri-
zation. Six reactions can be successfully
conducted in the second one-pot reac-
tion sequence; these are deprotection
of a tert-butyl ester and its conversion
into an acyl chloride then an acyl
azide, Curtius rearrangement, amide
formation, reduction of a nitro group
into an amine, and a retro Michael re-
action of a thiol moiety. A column-free
synthesis of (À)-oseltamivir has also
been established.
Keywords: asymmetric synthesis ·
domino reactions · organocatalysis ·
Tamiflu
consists of
a diphenylprolinol silyl
ether mediated asymmetric Michael re-
action,
a
domino Michael reaction/
Introduction
phosphate (Tamiflu)[2] and zanamivir (Relenza)[3] are antivi-
ral flu drugs in clinical use and are both neuraminidase in-
hibitors. Tamiflu has been extensively used worldwide for
the treatment of influenza caused by the AH1N1 virus. As a
result of the intense interest in, and need for, this life-saving
medicine, many synthetic organic chemists have investigated
its effective preparation, and a large number of syntheses
have been reported.[4] Even though Tamiflu is effective at
present, the recent emergence of Tamiflu-resistant virus
strains has prompted efforts by the chemical community to
develop medicines that are active against the mutated
virus.[5] This has led to the need for simple syntheses capable
of rapidly producing a wide and diverse range of derivatives.
We set the following objectives at the start of our project-
ed synthesis of Tamiflu because they would allow a large
quantity to be prepared in a short time: 1) The number of
reactions required should be not more than 10, and the
number of separate operations should be as few as possible.
2) The overall yield should be over 50%. 3) Only inexpen-
sive reagents should be employed. 4) Purification by column
chromatography should be avoided as much as possible.
5) The use of metal-containing reagents should be avoided
as much as possible. The preparation of a molecule of this
complexity, possessing three contiguous chiral centers, in no
more than 10 reactions and in over 50% overall yield is a
very challenging target. Even if each individual reaction of a
sequence proceeds with 90% yield, which represents an ex-
Influenza remains a major health problem, and the recent
global pandemic of AH1N1 influenza resulted in many
deaths. Moreover, a great deal of attention has been paid to
the high potential risk of a worldwide spread of the avian
H5N1 influenza virus, the death rate for which is over
50%.[1] Indeed, if this virus should acquire the ability to
spread easily and directly from human to human, it could
very possibly cause a disastrous pandemic. (À)-Oseltamivir
[a] Dr. H. Ishikawa, T. Suzuki, Prof. Dr. Y. Hayashi
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[b] Prof. Dr. Y. Hayashi
Research Institute for Science and Technology
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
[c] Dr. H. Orita, Dr. T. Uchimaru
Nanosystem Research Institute
National Institute of Advanced Industrial Science and Technology
(AIST)
Tsukuba, Ibaraki 305-8568 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001108.
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FULL PAPER
cellent yield in organic synthesis, the total yield falls to 35%
after 10 reactions (0.910 =0.35). The best yield yet achieved
for the total synthesis of Tamiflu is approximately 35%.[4b,d]
Moreover, to supply Tamiflu to developing countries where
influenza might spread, production costs should be kept low.
This requires that only inexpensive reagents be used. To
prevent metal contamination of the final drug, it is desirable
to avoid metal use as much as possible. Although many syn-
theses of Tamiflu have been reported,[4] previous methods
do not meet all of these requirements, and the development
of a method that does so remains a great challenge for the
chemical community.
cyclohexene derivative 7 to 1, proceeds in 81% yield and is
comprised of six reactions (see below).
Several modifications were made to the previous three
one-pot sequences (Scheme 2) to allow the whole sequence
to be carried out in just two pots and to increase the total
overall yield from 57 to 60%. The major modifications are
as follows: 1) In the previous synthesis, NaN3 in aqueous
acetone was employed to prepare the acyl azide. As aqueous
conditions cannot be employed in the following reaction,
they were replaced with nonaqueous conditions by using
TMSN3 in toluene. 2) Through the use of TMSN3, the ex-
traction and concentration of the acyl azide, a potential
hazard, can be omitted, which makes the synthesis safer.
3) After optimization of the solvent, loading of the organo-
catalyst could be reduced from 5 to 1 mol%, a reduction
that is synthetically useful and makes this reaction practical.
A “one-pot” reaction sequence[6] is an effective method
for carrying out several transformations and forming several
bonds in a single vessel, while at the same time cutting out
several purifications, minimizing chemical-waste generation,
and saving time. To simplify the
actual process of synthesis, we
investigated the preparation of
Tamiflu in a small number of
one-pot operations. We have al-
ready reported a synthesis of
(À)-oseltamivir (1) through
three one-pot sequences.[7] In-
tensive modification of the re-
actions has allowed us to pre-
pare
1 in a more efficient
manner, and a synthesis in two
one-pot sequences has been ac-
complished.
Our synthesis of 1 through
two one-pot sequences is sum-
marized in Scheme 1. The first
one-pot sequence starts from a-
alkoxyaldehyde 2 and nitroal-
kene 3 in the presence of the
diphenylprolinol silyl ether
4,[8–11] independently developed
by our group and Jørgensenꢁs
group. The first one-pot se-
quence is composed of five re-
actions: 1) an asymmetric Mi-
chael reaction, 2) the domino
reaction of a Michael reaction
of the nitroalkane and an intra-
molecular Horner–Wadsworth–
Emmons reaction, 3) retro Mi-
chael and retro-aldol reactions,
followed by an intramolecular
Horner–Wadsworth–Emmons
reaction, 4) a Michael reaction
with toluenethiol, and 5) iso-
merization to the 5S isomer
(see below). This sequence af-
fords the highly substituted cy-
clohexane 7 in 74% yield. The
Scheme 1. Synthesis of (À)-oseltamivir (1) through two one-pot sequences. TFA: trifluoroacetic acid; TMS: tri-
methylsilyl; Tol: tolyl.
second one-pot sequence, from Scheme 2. Previous synthesis of 1 through three one-pot sequences.
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Y. Hayashi et al.
4) No halogenated solvents are used. In particular, CH2Cl2
was replaced with toluene, which is environmentally friend-
ly. This synthesis requires nine reactions, a total of two sepa-
rate one-pot sequences, and one purification by column
chromatography. The total yield of 1 from nitroalkene 3 is
60%. Full details of the two one-pot sequences and of the
previous three one-pot sequences will be described herein.
nitro group to an amine group. If this plan could be ach-
ieved, it should result in a highly efficient method for the
synthesis of 1. The realization of each individual reaction
will be described in detail.
The first one-pot sequence for the synthesis of substituted
cyclohexane 7: In our reported procedure for the Michael
reaction of propanal and nitrostyrene, the reaction was com-
plete within 1 h when catalyzed by the diphenylprolinol silyl
ether (10 mol%) in hexane at room temperature, and it af-
forded the product in good yield (85%) with high diastereo-
selectivity (syn/anti=94:6) and excellent enantioselectivity
(99% ee) [Eq. (1)].[8a] The same reaction conditions were
applied to the reaction of 3-pentyloxyacetaldehyde (2) and
tert-butyl 3-nitropropenoate (3), with catalyst 4 derived from
d-proline. To our surprise, the reaction was very slow; only
26% yield was obtained even after 60 h, and this had a low
diastereomer ratio (Table 1, entry 1). The yield was in-
creased when CH2Cl2 was employed as the solvent, but the
diastereomer ratio decreased even further (1.7:1; Table 1,
entry 2).
Results and Discussion
The retrosynthetic analysis: Our retrosynthetic analysis is
shown in Scheme 3. In 2005, we found that the enantioselec-
tive Michael reaction of an alkyl aldehyde and a nitroal-
kene[12,13] catalyzed by a diphenylprolinol silyl ether,[8a,10]
a
catalyst developed independently in our group[8] and by Jør-
gensenꢁs group,[9] affords the product in good yield with ex-
cellent diastereo- and enantioselectivities. Enders and co-
workers have elegantly employed this process in a domino
reaction[14] with a,b-unsaturated aldehydes to prepare tetra-
substituted cyclohexenecarbaldehydes,[15] so we expected
that, by using ethyl acrylate, a substituted cyclohexenecar-
boxylate would be formed as follows: If a-alkoxyaldehyde 2
and b-alkoxycarbonyl nitroalkene 3 should undergo the Mi-
chael reaction, adduct 5 will be formed. If addition product
5 can be trapped with ethyl acrylate, then consecutive Mi-
chael addition, intramolecular aldol reaction, and dehydra-
tion reaction might occur to generate cyclohexene carboxyl-
ate 8. The configurations of the C3 and C4 atoms of cyclo-
hexene carboxylate 8 would be determined by the first Mi-
chael reaction to form 5, the diastereoselectivity of which is
predicted to be high from our previous results.[8a] We expect-
ed that the configuration of the C5 atom could be easily iso-
merized owing to its position a to the nitro group and that
the substituents at the C3, C4, and C5 positions would be
equatorial because this is the most stable conformer; in
other words, we expected that the configuration of the C5
atom would be thermodynamically controlled. Once cyclo-
hexene carboxylate 8 has been prepared, the remaining
transformations necessary are the conversion of the tert-bu-
toxycarbonyl group into an acetamide and reduction of the
As the presence of acid increases the reactivity in some
Michael reactions of aldehydes and nitroalkenes catalyzed
by organocatalyst,[13c,k,h] the addition of various acids was in-
vestigated (Table 1). The pKa value of the acid is found to
be very important, not only for the activity but also for the
diastereomer ratio of the product. With the exception of
Cl3CCO2H, a strong acid, the reaction time shortens and the
diastereomer ratio (syn/anti) increases as the acidity of the
additive increases. For instance, it takes 24, 14, and 2 h for
completion of the reaction when p-nitrophenol, benzoic
acid, and formic acid are used, with the product diastereo-
mer ratios being 1.7:1, 2.0:1,
and 4.8:1, respectively (Table 1,
entries 4–6). The best additive
is ClCH2CO2H: in the presence
of 20 mol% of ClCH2CO2H
and 5 mol% of the diphenyl-
prolinol silyl ether, the reaction
proceeded smoothly within 1 h
to afford the product quantita-
tively in a high diastereomer
ratio (syn/anti=6.3:1) and with
excellent
enantioselectivity
(96% ee, syn isomer; Table 1,
entry 7). Further optimization
of the reaction conditions re-
vealed that the loading of the
Scheme 3. The retrosynthesis of 1.
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Synthesis of (À)-Oseltamivir
FULL PAPER
Table 1. Effect of acid in the Michael reaction of 2 and 3 catalyzed by 4.[a]
hyde, the molecular weight of
which was 629 [M+Na], was
obtained. Although its structure
was not fully elucidated, we
suppose that the anion at the a
position of the nitro group does
not react with ethyl acrylate,
but rather with the formyl
moiety of a second molecule in
a Henry reaction. Ethyl acry-
late is expected to be a reactive
Michael acceptor, but a-alkoxy-
aldehyde is an even more reac-
tive electrophile. To improve
the electrophilicity of the Mi-
chael acceptor, vinylphospho-
nate derivative 6[16] was select-
ed, in which the double bond is
doubly activated by two elec-
tron-withdrawing groups, the
ethoxycarbonyl and diethyl-
phosphonyl moieties. In this
case, cyclohexene derivative 8
[b]
Entry Catalyst [mol%] Acid ([mol%])
pKa
Solvent t [h] Yield [%][c] syn/anti ee [%][d]
1
2
3
4
5
6
7
8
20
20
20
20
20
5
5
5
5
1
–
–
–
–
12.5
hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
60
60
24
24
14
2
1
28
2
26
quant.
50
quant.
quant.
quant.
quant.
0
2.5:1
1.7:1
2.3:1
1.7:1
2.0:1
4.8:1
6.3:1
–
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
96
–
n.d.
97
CF3CH2OH (40)
p-NO2PhOH (40) 7.1
PhCO2H (40)
HCO2H (20)
ClCH2CO2H (20)
Cl3CCO2H (20)
ClCH2CO2H (20)
ClCH2CO2H (20)
4.2
3.8
2.9
0.7
2.9
2.9
9
10
quant.
quant.
7.6:1
7.8:1
6
[a] Unless otherwise shown, reactions were performed by employing aldehyde 2 (0.29 mmol), nitroalkene 3
(0.19 mmol), acid, catalyst 4, and solvent (0.5 mL) at room temperature for the indicated time. [b] Value in
H2O. [c] Yield of isolated product. [d] Optical purity of the major isomer, which was determined by chiral
HPLC analysis of the corresponding ester prepared by reaction with ethyl(triphenylphosphoranylidene)ace-
tate. n.d.: not determined.
organocatalyst could be reduced to 1 mol% and CH2Cl2
could be replaced with a nonhalogenated solvent such as
toluene (syn/anti=7.8:1, 97% ee; Table 1, entry 10). These
conditions are advantageous to process chemistry. The
mechanism of this effect of the acid is currently under inves-
tigation.
should be formed by successive Michael and intramolecular
Horner–Wadsworth–Emmons reactions.
When Michael adduct 5 was treated with 6 in the pres-
ence of Cs2CO3 in CH2Cl2, several products were obtained
[Eq. (2)]. One was cyclohexene derivative 8 in 30% yield as
an inseparable 5R/S diastereomer mixture, with the unde-
sired 5R isomer predominating. Another was adduct 9,
which was formed in 30% yield by an over-reaction of the
initially generated, desired product 8 with the reactive Mi-
chael acceptor 6. The third was 10, which was formed in
30% yield. The stereochemistry of 10 has not been verified,
but it is expected that the configuration of hydroxy and di-
ethylphosphonyl groups is anti, so syn elimination cannot
occur. Preliminary attempts to optimize the reaction condi-
tions to achieve selective synthesis of 8 without the forma-
tion of 9 and 10 all failed. In some cases, other byproducts
such as 11 or 12 were generated by elimination of nitrous
acid and isomerization. At this stage, we reasoned as fol-
lows: If a retro Michael reaction occurs from 9, then 9
would be transformed back into the desired product 8. If
retro-aldol and then Horner–Wadsworth–Emmons reactions
Having optimized the first Michael reaction of aldehyde 2
and nitroalkene 3, we then considered the reaction of Mi-
chael adduct 5 and ethyl acrylate. As described in the retro-
synthesis section, the functionalized cyclohexene derivative
8 would be generated by a domino reaction sequence of the
Michael reaction of an anion at the a position of the nitro
group of 5 with ethyl acrylate, an intramolecular aldol reac-
tion, and then dehydration. However, when isolated Michael
adduct 5 was treated with ethyl acrylate under a variety of
basic conditions, neither the desired product nor even the
initial Michael product could be obtained. In some cases,
the starting materials were recovered. In other cases, those
with tetrabutylammonium fluoride (TBAF) or Cs2CO3 as a
1
base, the ethyl acrylate was inert, as evidenced by H NMR
spectroscopy experiments, whereas a dimer of the nitroalde-
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Y. Hayashi et al.
Table 2. The effect of base on the equilibration between the R and S iso-
occur, compound 10 would also be converted into 8. The
solvent was found to be crucial for the success of these
transformations. When isolated 9 and 10 were treated sepa-
rately with Cs2CO3 in EtOH, cyclohexene derivative 8 was
obtained in quantitative and 90% yields, respectively. Retro-
reactions are accelerated in a polar solvent such as EtOH
and EtOH is a particularly suitable solvent for the reaction
of 9 to give 8 because the vinylphosphonate generated, 6, is
immediately trapped with EtOH to prevent its further reac-
tion with 8.
mers.[a]
Entry
Base
Solvent
T [8C]
t [min]
(R)-8/(S)-8[b]
1
2
K2CO3
Cs2CO3
Et3N
EtOH
EtOH
EtOH
À5
À5
23
10
10
240
–
4.3:1
4.6:1
1:1
3
4[c]
SiO2
23
1:1.2
[a] Unless otherwise shown, reactions were performed by employing an
R/S mixture (R:S=1.2:1 and 4.5:1, 0.03 mmol) in solvent (0.5 mL) with
base (0.15 mmol) at the indicated temperature. [b] The diastereomer
ratio was determined by 1H NMR spectroscopy. [c] See the reaction con-
ditions in the Supporting Information.
The reaction proceeded well both in CH2Cl2 and toluene.
Toluene is more suitable in terms of the industrial process.
Whereas Cs2CO3 in toluene was employed in the first reac-
tion of the Michael adduct 5 and vinylphosphonate deriva-
tive 6, the reaction conditions in the retro Michael reaction
of 9 and the retro-aldol and Horner–Wadsworth–Emmons
reactions of 10 involved Cs2CO3 in EtOH. When the first re-
action was examined in EtOH, the desired product 8 was
obtained in only 20% yield and the Michael addition prod-
uct of the vinylphosphonate with EtOH was the major prod-
uct. These reactions are therefore performed in one pot as
follows: First, the reaction of 5 with 6 is performed with
Cs2CO3 in toluene at room temperature for 2 h, affording
several spots on the TLC plate, then EtOH is added to the
same reaction vessel and the reaction mixture is stirred for
15 min, during which time the several spots on the TLC
plate converge into a single spot as the cyclohexene deriva-
tive 8 is formed in 71% yield [Eq. (3)].
entry 3), and this ratio did not change even with longer reac-
tion times, which indicated that equilibrium had been
reached. This result indicates that the R and S isomers have
similar thermodynamic stability. When the mixture was
loaded onto silica, equal amounts of the R and S isomers
were generated (Table 2, entry 4).
To understand these results relating to thermodynamic
stability, stable conformations of the R and S isomers were
investigated[17] by calculation (B3LYP/6-31G(d)[18]), and the
respective results for the R and S isomers, conformations A
and B, are shown in Figure 1. These conformations are
nearly the same as those in solution as determined by
1H NMR spectroscopy (Scheme 4). It was found that the dif-
ference in energy between these two conformers is small
(0.11 kcalmolÀ1; Table 3). This result is in good agreement
with the experimental result that the R and S isomers are
obtained in nearly 1:1 ratio. It can be seen that the 3-pentyl-
oxy moiety and tert-butoxycarbonyl group occupy axial po-
sitions in conformer A and that their relative configuration
is antiperiplanar (Figure 1). As this is a cyclohexene ring,
the 1,3 steric repulsion is not as large as it would be in a cy-
clohexane ring system, so the diaxial arrangement of these
two substituents in A is slightly more stable than the diequa-
torial positioning in B, in which a 1,2-gauche repulsion
would occur.
If the cyclohexene were to be converted into a cyclohex-
ane framework, the epimerizable substituents would be ori-
ented to be equatorial where possible under equilibration.
To achieve this, the thiol Michael reaction was examined,
because thiol groups are good Michael donors and could be
removed by the retro Michael reaction under mild condi-
tions at the last stage of the synthesis. When derivative 8
was treated with toluenethiol in the presence of base, the
Michael reaction proceeded and isomerization occurred as
expected to afford the cyclohexane derivative 7 with the de-
sired 5S stereochemistry. The stereochemistry was deter-
mined by the coupling constants and NOESY spectra. The
base and temperature are crucial for this transformation
(Table 4). When K2CO3 was employed at À58C, the desired
With the cyclohexene derivative 8 in hand, the next prob-
lem was isomerization of the R isomer into the desired S
isomer, which was found to be difficult (Table 2). When the
inseparable mixture was treated with a base such as K2CO3
or Cs2CO3, both of which are only partially soluble in
EtOH, at À58C for 10 min, the same diastereomer ratio of
products was formed with the R isomer predominating
(Table 2, entries 1 and 2). When the reaction was performed
for a longer reaction time or at a higher temperature, aro-
matization proceeded to generate a tert-butyl ethyl tereph-
thalate as a side product. Equal amounts of the R and S iso-
mers were generated with Et3N as the base (Table 2,
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Synthesis of (À)-Oseltamivir
FULL PAPER
compound 7 was obtained in good yield (85%; Table 4,
entry 3). As Cs2CO3 was used in the previous reactions, it
would be preferable to conduct this Michael/isomerization
reaction with the same base to enable a one-pot operation.
When 8 was treated with Cs2CO3 at À58C, the desired prod-
uct 7 was obtained in only 35% yield and the major product
was the aromatized compound, the tert-butyl ethyl tereph-
thalate (Table 4, entry 4). Cs2CO3 is a stronger base than
K2CO3, which led to this over-reaction. To suppress genera-
tion of this side product, the reaction conditions were
screened in detail, and temperature was found to be impor-
tant. A good result (90% yield) was obtained when the re-
action was carried out at À158C (Table 4, entry 5).
To summarize, cyclohexane derivative 7 was prepared in
one pot from 3-pentyloxyacetaldehyde (2) and tert-butyl 3-
nitropropenoate (3) as follows (Scheme 5): After a mixture
of a-alkoxyaldehyde 2 and nitroalkene 3 had been treated
with diphenylprolinol silyl ether
4
(1 mol%) and
ClCH2CO2H (20 mol%) in toluene for 6 h, vinylphospho-
nate derivative 6 and Cs2CO3 were added, and the reaction
mixture was stirred for 4 h at 08C to room temperature.
After evaporation of the toluene, EtOH was added, then
after 10 min, the reaction mixture was cooled to À158C and
toluenethiol was added. After isolation and purification by
silica-gel column chromatography, highly substituted cyclo-
hexane derivative 7 of the required configuration was ob-
tained in 74% yield as a single isomer.
Figure 1. The stable conformations of the R (A) and S isomers (B).
It should be noted that the same reagent was employed in
several reactions in one pot with control of the reactivity by
solvent and temperature. Cs2CO3 acts as a base in five dif-
ferent ways: 1) It acts as a base for the Michael reaction of
nitroalkane 5 and vinylphosphonate 6 in toluene. 2) It also
acts as a base for the intramolecular Horner–Wadsworth–
Emmons reaction. 3) In EtOH, it acts as a base for the retro
Michael reaction from 9 into 8 and the retro-aldol/Horner–
Wadsworth–Emmons reaction from 10 into 8. 4) It acts as a
base for the Michael reaction of the thiol compound and 8.
5) It acts as a base for the isomerization at the C5 atom,
with the reaction performed at lower temperature (À158C)
to suppress over-reaction.
The successful realization of the synthesis of highly substi-
tuted cyclohexane 7 through the one-pot sequence can be
summarized as follows: 1) The organocatalyst does not inter-
fere with the remaining reactions. 2) As equimolar amounts
of 2 and 3 are employed in the first reaction, no starting ma-
terials remain and, hence, they have no effect on subsequent
reactions. 3) As each reaction proceeds in excellent yield,
there are no significant side products. 4) As described
above, the same base (Cs2CO3) acts in five different ways.
Scheme 4. The stable conformations of 8 showing the coupling constants
(J) between protons: A: R isomer; B: S isomer.
The second one-pot sequence from 7 to 1: With an efficient
route to highly substituted cyclohexane derivative 7 estab-
lished, the remaining transformations necessary are conver-
sion of the tert-butyl ester into an acetylamino group, con-
version of the nitro group into an amino group, and the
retro Michael reaction of the thiol moiety. We next investi-
gated the first of these. As shown in Scheme 6, carboxylic
Table 3. Energies of the R and S conformers of 8.
[b]
Entry
Substrate
E [au][a]
DE [kcalmolÀ1
]
1
2
R isomer (A)
S isomer (B)
À1323.944735
À1323.944568
0.00
0.11
[a] Total energy. [b] Relative energy. 1 kcal=4.184 kJ.
Chem. Eur. J. 2010, 16, 12616 – 12626
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Y. Hayashi et al.
Table 4. The effect of base and temperature on the reaction of 8 and toluenethiol.[a]
Curtius rearrangement of
acyl azide 15 proceeded slowly
at room temperature in ben-
zene to afford isocyanate 16
quantitatively [Eq. (4)]. Usually
a higher temperature is neces-
sary for the Curtius rearrange-
ment, but it proceeds at room
temperature for this particular
substrate, which is a synthetic
advantage because it suppresses
the risk of explosion. When iso-
cyanate 16 was treated with
AcOH and Ac2O at room tem-
perature under the conditions
described by Barnum and Ham-
ilton,[19b] the acetylamino group
was formed in 95% yield.
Entry
Base
T [8C]
t [h]
Yield [%]
Other isomers[c]
7[b]
1
2
3
4
5
Et3N
23
23
12
24
24
13
36
71
78
29
8
15
<5
<5
NaHCO3
K2CO3
Cs2CO3
Cs2CO3
À5
85
À5
35[d]
90
À15
[a] Unless otherwise shown, reactions were performed by employing ethyl ester 8 (0.04 mmol), toluenethiol
(0.2 mmol), base (0.12 mmol), and EtOH (0.5 mL) at the indicated temperature. [b] Yield of isolated product.
[c] Yield of a mixture of other isomers. [d] tert-Butyl ethyl terephthalate was generated in 65% yield.
acid 13 was obtained quantitatively by treatment of tert-
butyl ester 7 with CF3CO2H and subsequent evaporation of
the volatile CF3CO2H. Acid chloride 14 was obtained by the
reaction of the carboxylic acid with oxalyl chloride in the
presence of a catalytic amount of DMF. After removal of
the excess oxalyl chloride, addition of NaN3 to an aqueous
acetone solution of 14 gave acyl azide derivative 15. As the
NMR spectrum of crude acyl azide 15 indicated that it was
rather pure, and it may be an explosively unstable com-
pound, we used it directly without purification. It should be
noted that crude acyl azide 15 was obtained in a single-pot
reaction from tert-butyl ester derivative 7.
These two reactions, the Curtius rearrangement and acetyla-
mino formation, can be performed in a single pot. On treat-
ment of acyl azide 15 with AcOH and Ac2O, they proceed
Scheme 5. The one-pot synthesis of cyclohexane 7 from aldehyde 2 and nitroalkene 3.
12622
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Chem. Eur. J. 2010, 16, 12616 – 12626

Synthesis of (À)-Oseltamivir
FULL PAPER
Zn and TMSCl in EtOH was
employed to generate HCl in
situ [Eq. (6)]. After reduction of
the nitro group, K2CO3 was
added into the reaction mixture
to promote the retro Michael
reaction. In contrast to the suc-
cess of the stepwise process, no
reaction occurred even at
a
higher temperature (808C),
probably because the ZnII spe-
cies present may chelate the
amine moieties and prevent the
Scheme 6. The conversion of tert-butyl ester 7 into acyl azide 15.
retro Michael reaction. To cap-
ture the ZnII species, NH3 was
bubbled through the reaction
mixture, after which treatment
with K2CO3 promoted a clean
retro Michael reaction to pro-
vide 1 in 81% yield from nitro
derivative 17 over 2 steps.
As each individual process
had been optimized, they were
now combined to investigate
the synthesis of 1 from the
highly substituted cyclohexane
derivative 7 in a one-pot se-
quence (Scheme 1). All of the
reactions can be conducted in
the same reaction vessel, with
together to generate acetylamino derivative 17 quantitative-
ly.
no isolation of the intermediates. As the final compound is
an amine, it could be isolated in excellent purity by a simple
acid–base extraction with no need for purification by
In this sequence, in the conversion of the tert-butoxycar-
bonyl moiety into an acetylamino group, aqueous NaN3 was
employed. The product, acyl azide 15, has to be extracted
because aqueous conditions were used in this step. It would
be synthetically desirable not to have to isolate and concen-
trate this potentially hazardous compound. Moreover, if
aqueous conditions could be avoided, it might be possible to
perform the synthesis of 1 from 7 in a one-pot sequence
without any isolation of the intermediates. Instead of aque-
ous NaN3, TMSN3 and pyridine in toluene were found to
convert acyl chloride 14 into acyl azide 15 quantitatively.
The use of pyridine is advantageous because other bases,
such as Et3N, gave substantial amounts of the addition prod-
uct of the azide with isocyanate 16. Without concentration
of the reaction mixture, direct addition of Ac2O and AcOH
provided acetylamino derivative 17 in 92% yield over 2
steps [Eq. (5)].
The next transformation required is reduction of the nitro
group to form an amine, which at first was performed by
treatment with Zn and aqueous 2n HCl solution to afford
amine 18 in 86% yield. Compound 1 was obtained in 91%
yield by retro Michael reaction of the thiol when 18 was
treated with K2CO3 in EtOH. We then investigated how to
achieve these two steps in a single pot. As the aqueous con-
ditions of the first reduction do not permit this, the use of
1
column chromatography. The H NMR spectra of our syn-
thetic material and of an authentic sample are shown in Fig-
ure S1 of the Supporting Information. In this way, com-
pound 1 was synthesized in 81% yield from 7.
Synthesis without column chromatography: In the two one-
pot sequences, we purified tert-butyl ester 7 by column chro-
matography, the only column necessary in the whole synthe-
sis. This process should be avoided in a large-scale synthesis.
The next reaction after formation of 7 is the transformation
of the tert-butyl ester into carboxylic acid 13 upon treatment
with CF3CO2H (Scheme 6). As 13 is an acid, it might be pos-
sible to purify it by acid–base extraction without any purifi-
cation at the stage of 7. When we looked at this, we found
that carboxylic acid 13 and phosphoric acid diethyl ester,
(EtO)2P(O)OH, which is generated by the Horner–Wads-
worth–Emmons reaction in the first one-pot reaction,
cannot be separated at this stage. However (EtO)2P(O)OH
can be removed in the previous step by an acid–base extrac-
tion; that is, tert-butyl ester
7 was separated from
(EtO)2P(O)OH by washing the organic phase twice with
NH4OH solution. Crude 7, which is then free from
(EtO)2P(O)OH, was treated with CF3CO2H to afford crude
carboxylic acid 13, and acid–base extraction of 13 followed
Chem. Eur. J. 2010, 16, 12616 – 12626
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12623

Y. Hayashi et al.
by filtration through a short silica pad gave a good purity of
13. By using this acid–base extraction technique, we can es-
tablish a column-free synthesis of 1.
Acknowledgements
This work was partially supported by Nagase Science and Technology
Foundation, Japan.
Conclusion
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An efficient, enantioselective, total synthesis of 1 through
two one-pot sequences has been accomplished. The present
synthesis has several noteworthy features: 1) Only two pots
are needed for the synthesis of the rather complex 1. 2) A
highly functionalized chiral cyclohexane framework of the
correct relative and absolute configuration can be synthe-
sized in the first one-pot sequence, which consists of a se-
quence of reactions made up of a diphenylprolinol silyl
ether mediated asymmetric Michael reaction as developed
in our group, a domino Michael reaction/Horner–Wads-
worth–Emmons reaction combined with retro-aldol/Horner–
Wadsworth–Emmons and retro Michael reactions, a thiol
Michael reaction, and a base-catalyzed isomerization. 3) Six
transformations can be successfully conducted in the second
one-pot sequence, including deprotection of a tert-butyl
ester and its conversion into an acid chloride then an acid
azide, Curtius rearrangement, amide formation, reduction of
a nitro group into an amine, and the retro Michael reaction
of a thiol. 4) The Curtius rearrangement proceeds at room
temperature without heating, which decreases potential haz-
ards. 5) The domino reaction of a Curtius rearrangement
and amide formation is a direct method for the synthesis of
12. 6) Only 1 mol% loading of the diphenylprolinol silyl
ether, which was developed in our group as an efficient or-
ganocatalyst, is needed to promote the asymmetric direct
Michael reaction, which is suitable for large-scale synthesis.
7) No halogenated solvents are used. 8) Isolation and con-
centration of the potentially hazardous acyl azide 15 can be
avoided, which makes the synthesis safer. 9) The intermedi-
ate can be purified by an acid–base extraction process. Effi-
cient purification of 1 was achieved by a simple acid–base
extraction at the final stage. Thus, the synthesis is free from
column chromatography.
This synthesis requires nine transformations in a total of
two separate reaction pots. The total yield of 1 from nitroal-
kene 3 is 60%. All of the reagents are inexpensive. The
metals employed in the present total synthesis are alkali
metals (Na, K, and Cs) and relatively nontoxic zinc. No spe-
cial care needs be taken to exclude water or air. We have
performed the first one-pot sequence with 1.13 g of alde-
hyde 2 and 1.0 g of nitroalkene 3 to afford 2.18 g of cyclo-
hexane 7. In the second one-pot sequence, 3.0 g of cyclohex-
ane 7 can be successfully converted into 1.49 g of 1. Thus,
we believe that the present procedure can be scaled up. The
synthetic route itself is completely different from those pre-
viously described and should enable the synthesis of a wide
variety of novel derivatives. This will be valuable in the
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Synthesis of (À)-Oseltamivir
FULL PAPER
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