One-pot synthesis of (-)-oseltamivir and mechanistic insights into the organocatalyzed Michael reaction

Article abstract of DOI:10.1002/chem.201302371

The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO₂H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2- nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone. (-)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E-Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine. Copyright

Full text of DOI:10.1002/chem.201302371

FULL PAPER
DOI: 10.1002/chem.201302371
One-Pot Synthesis of (À)-Oseltamivir and Mechanistic Insights into the
Organocatalyzed Michael Reaction
Takasuke Mukaiyama,[a, b] Hayato Ishikawa,[b, c] Hiroyuki Koshino,[d] and
Yujiro Hayashi*[a, b]
Abstract: The one-pot sequential syn-
thesis of (À)-oseltamivir has been ach-
ieved without evaporation or solvent
exchange in 36% yield over seven re-
actions. The key step was the asymmet-
ric Michael reaction of pentan-3-ylox-
yacetaldehyde with (Z)-N-2-nitroeth-
in both excellent yield and excellent di-
astereo- and enantioselectivity. Investi-
gation into the effect of acid demon-
strated that an acid additive accelerates
not only the E–Z isomerization of the
enamines derived from pentan-3-ylox-
yacetaldehyde with diphenylprolinol
silyl ether, but also ring opening of the
cyclobutane intermediate and the addi-
tion reaction of the enamine to
(Z)-N-2-nitroethenylacetamide.
The
transition-state model for the Michael
reaction of pentan-3-yloxyacetaldehyde
with
(Z)-N-2-nitroethenylacetamide
was proposed by consideration of the
absolute configuration of the major
and minor isomers of the Michael
product with the results of the Michael
reaction of pentan-3-yloxyacetaldehyde
with phenylmaleimide and naphthoqui-
none.
ACHTUNGTRENNUNG
Keywords: asymmetric synthesis ·
Michael addition · one-pot reaction ·
organocatalysis · Tamiflu
catalyst, chlorobenzene as a solvent,
and HCO2H as an acid additive, were
key to produce the first Michael adduct
Introduction
aration and a large number of synthetic methods have been
reported.[1] However, a robust and efficient preparation
method is still required to produce sufficient quantity of
1 for worldwide use.
(À)-Oseltamivir phosphate (1; Tamiflu), a neuraminidase in-
hibitor, is one of the most effective drugs for the treatment
of influenza and has been used extensively. For this reason,
many synthetic chemists have investigated its effective prep-
On the other hand, the development of environmentally
benign methods is a current key topic in chemistry and we
have recently designated the importance of “pot-econo-
my”[2] in the multistep synthesis of molecules. A one-pot re-
action is an effective method to conduct several transforma-
tions in a single vessel. Several transformations and bond
formations can be achieved in a single vessel, which elimi-
nates several purification operations and minimizes chemical
waste to enable a shorter total production time. Over the
last five years, we have applied the concept of pot-economy
to the synthesis of several biologically active compounds. In
2009, we reported a sequential synthesis of 1 by three one-
pot stages,[3a] which was modified into two one-pot sequen-
ces in 2010.[3b] We also reported the one-pot synthesis of
ABT-341[4] and the synthesis of prostaglandin E1 methyl
ester in three one-pot stages.[2c]
[a] T. Mukaiyama, Prof. Dr. Y. Hayashi
Department of Chemistry
Graduate School of Science
Tohoku University
6-3 Aramaki-Aza Aoba
Aoba-ku, Sendai 980-8578 (Japan)
Fax : (+81)22-795-6566
E-mail: yhayashi@m.tohoku.ac.jp
[b] T. Mukaiyama, Dr. H. Ishikawa, Prof. Dr. Y. Hayashi
Previous address (before 30thJune 2012)
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku
Tokyo 162-8601 (Japan)
In our reported synthesis of 1 by two one-pot sequen-
ces,[3b] the first sequence starts with Michael reaction of
pentan-3-yloxyacetaldehyde (2) and trans-nitroalkene 3, cat-
alyzed by (R)-diphenylprolinol silyl ether 4 (Scheme 1),
a catalyst that has been developed independently by our
group[5] and that of Jørgensen.[6] Without isolation, the Mi-
chael product 5 was treated with ethyl acrylate derivative 6.
After evaporation, the addition of toluenethiol afforded cy-
clohexane 7 with control of five consecutive chiral centers.
The second one-pot sequence commenced with trifluoroace-
tic acid hydrolysis of the tert-butylester moiety. Subsequent-
[c] Dr. H. Ishikawa
Department of Chemistry
Graduate School of Science and Technology
Kumamoto University
2-39-1, Kurokami, Chuo-ku
Kumamoto, 860-8555 (Japan)
[d] Dr. H. Koshino
Global Research Cluster, RIKEN
2-1 Hirosawa, Wako
Saitama, 351-0198 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302371.
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Scheme 1. Previous synthesis of 1 by two one-pot sequences. TFA=trifluoroacetic acid, Tol=tolyl, Ac=acetyl.
ly, acid chloride 8 was generated, which was followed by
Curtius rearrangement via acyl azide 9 to generate acet-
amide 10. The nitro group was reduced to a primary amine,
and retro-Michael reaction of the toluenethiol group fur-
nished 1. Solvent exchange was employed three times in the
second one-pot sequence, even though the reaction sequen-
ces were carried out in the same vessel. Clearly, it would be
more ideal, synthetically and operationally, if solvent ex-
change could be omitted in the one-pot operation. This
would enable a reduction in solvent waste, production time,
and cost.
those between a-alkoxylaldehydes and cis-nitroalkenes,[11]
we found that an acid additive is important to improve both
selectivity and reactivity issues, which prompted us to inves-
tigate the effect of acid. In this paper, we disclose the suc-
cessful realization of a complete one-pot synthesis of 1 with-
out any solvent exchange, along with several new findings
about the effect of acid and the course of the Michael reac-
tion.
Results and Discussion
Recently, the groups of Ma,[7] Sebesta,[8a] and Lu[9] have
independently reported the synthesis of 1 in a short number
of steps by similar routes to ours.[3] The key change from
our original route is that they all employed (Z)-N-2-nitro-
Michael reaction of a-alkoxyaldehyde with cis-nitroalkene:
First, we examined the Michael reaction of 2 and 14 mediat-
ed by (S)-diphenylprolinol silyl ether 13 (Table 1), which is
the key step in the synthesis of 1. The reason for the use of
the Z isomer as a Michael acceptor will be described later.
Ma et al. obtained the products 15/16 in approximately 80%
yield with good diastereoselectivity (15/16=5:1) by using
PhCO2H as an additive and CHCl3 as the solvent.[7] Sebesta
et al. used CHCl3/H2O as the solvent system and chloroace-
tic acid as an additive to obtain good yield (88%) and dia-
stereoselectivity (15/16=81:19).[8a] Recently, the addition of
rac-mandelic acid and 2,4-dinitrophenol was also found to
be effective.[8b] Lu et al. employed CH2Cl2 as the solvent and
chloroacetic acid as an additive, which afforded good yield
and selectivity (15/16=4:1).[9] When we performed the reac-
tion in CHCl3 in the presence of PhCO2H, the NMR spectra
of the crude mixture were not clean and the yield and dia-
stereoselectivity were low. The first step of a one-pot multi-
step reaction sequence needs to be supremely clean with
high yield and selectivity. Halogenated solvents should be
substituted with non-halogenated ones for scaleup. Although
ACHTUNGTRENNUNGethenylacetamide (14) as a starting material instead of a
(E)-tert-butyl-3-nitropropenoate (3). The former more con-
veniently possesses an aminoacetyl group and, importantly,
avoids a potentially explosive Curtius rearrangement of acyl
azide intermediate 9. When we repeated the key Michael re-
action between a-alkoxyaldehyde 2 and 14 in CHCl3 in the
presence of PhCO2H, catalyzed by diphenylprolinol silyl
ether 4, the yield and diastereoselectivity was low. The sol-
vents used were CHCl3 and CH2Cl2. Given the unsatisfacto-
ry results, and to avoid the use of environmentally unfriend-
ly chlorinated solvents for large-scale production, we set out
to determine reliable conditions under which the desired al-
dehyde–nitroalkene Michael adduct should be obtained in
good yield with excellent diastereo- and enantioselectivity.
Moreover, we aimed to realize a one-pot sequential synthe-
sis of 1 without any evaporation or solvent exchange by op-
timization of all subsequent reactions.[3,7–9] During our inves-
tigation into organocatalyzed Michael reactions,[10] including
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Synthesis of (À)-Oseltamivir
FULL PAPER
velopment with two one-pot synthesis[3b] we found that tolu-
ene gave a good result for both yield and selectivity. Nitro-
alkenes were scarcely soluble in toluene, but chlorobenzene
and CH3CN were suitable solvent candidates and both are
acceptable solvents for large-scale production. We know
that acid is an effective additive in this type of Michael reac-
tion,[10] therefore we investigated the reaction in the pres-
ence of several acids in either CH3CN or chlorobenzene
(Table 1).
Table 1. Asymmetric Michael reaction of 2 and 14 catalyzed by diphenyl-
prolinol silyl ether 13.[a]
Solvent Acid
Time [h] Yield [%][b] 15/16[c] ee [%][d]
Although the reaction proceeds in CH3CN, the reaction
was slow, even in the presence of acid, and afforded the
product with low diastereoselectivity (Table 1, entries 1 and
2). Contrary to CH3CN, chlorobenzene was found to be the
solvent of choice. In the presence of PhCO2H the reaction
was fast but resulted in low diastereoselectivity (Table 1,
entry 3). The reaction was relatively slow in the presence of
chloroacetic acid, the optimal acid in our previous synthesis
of 1 in chlorinated solvents,[3a,b] although excellent diastereo-
selectivity was obtained when chlorobenzene was used as
the solvent (Table 1, entry 4). The best result was obtained
with HCO2H in chlorobenzene (Table 1, entry 5). The reac-
tion was complete within 45 min, to afford the product in
good yield with excellent diastereo- and enantioselectivity.
The reaction also proceeded in the presence of 5 mol% of
the organocatalyst (Table 1, entry 6). The gram-scale synthe-
sis was realized with good yield and diastereoselectivity
(Table 1, entry 7). The key points for scaleup are: 1) slow
addition of a-alkoxyaldehyde 2 to suppress self-condensa-
tion, 2) control of the reaction temperature at 208C to main-
tain high diastereoselectivity. Better diastereoselectivity was
observed at 0 and 108C, but the yield was lower. On the
other hand, better yield was observed at 288C but the dia-
stereoselectivity was 5:1 (15/16). It should be noted that ni-
troalkene 14 partially dissolves in chlorobenzene and the in-
itial heterogeneous solution gradually becomes clear as the
reaction proceeds to completion.
1
2
3
4
5
CH3CN PhCO2H
CH3CN ClCH2CO2H 16
2
90
90
80
80
90
85
80
1.3:1
3.6:1
2.7:1
9:1
9:1
9:1
–
–
–
–
99
–
–
C6H5Cl PhCO2H
C6H5Cl ClCH2CO2H
C6H5Cl HCO2H
0.5
2
0.75
4
6[e] C6H5Cl HCO2H
7[f] C6H5Cl HCO2H
1.5
7.1:1
[a] Unless stated otherwise, reactions were performed as follows:
2
(0.60 mmol), 14 (0.30 mmol), acid additive (30 mol%), 13 (10 mol%),
and solvent (1 mL) at rt for the indicated time. [b] Yield calculated from
the 1H NMR spectra of the reaction mixture. [c] Ratio determined by
1H NMR spectroscopic analysis of reaction mixture. [d] The enantiomeric
excess (ee) of the major isomer was determined by chiral HPLC analysis
of the corresponding p-nitrobenzoyl ester derivative. The p-nitrobenzoyl
ester was obtained by reduction of 15 to the alcohol, followed by forma-
tion of the ester. [e] Catalyst 13 (5 mol%) was employed. [f] a-Alkoxyal-
dehyde
2 (2.25 g, 17.3 mmol) in ClC6H5 (5 mL) was slowly added
(60 min) to a mixture of nitroalkene 14 (1.5 g, 11.5 mmol), formic acid
(0.17 mL, 4.6 mmol, 40 mol%), and 13 (517 mg, 1.15 mmol, 10 mol%) in
ClC6H5 (42 mL) at 208C. The internal temperature of the reaction mix-
ture was kept at 208C. The conversion was 46% and the ratio of 15/16
was 9:1 after 30 min.
a relatively dirty reaction was observed by crude NMR spec-
troscopy of the reaction mixture obtained when diphenyl-
prolinol trimethylsilyl (TMS) ether 11 was used, the corre-
sponding bulky silyl ether diphenylmethylsilyl (DPMS)
ether 13, developed by Seebach,[12] proceeded in a clean
manner, determined by NMR spectroscopy. The catalyst
adduct 12 was observed in the stoichiometric reaction be-
tween the TMS catalyst 11 and 3 (Scheme 2),[11] therefore
The stability of the Michael product 15 is noteworthy. Ep-
imerization can readily occur because the a-alkoxyaldehyde
Michael adduct possesses an acidic a-proton. For instance,
the diastereomeric ratio was observed to decrease during
evaporation and chromatographic (silica gel) operations.
Thus, it is a great advantage to carry out the reaction in
a one-pot process. Operations such as evaporation, solvent
exchange, and isolation tend to reduce the overall diastereo-
selectivity.
Scheme 2. Formation of catalyst adduct 12
The absolute configuration of the major stereoisomer 15
of the Michael reaction of 2 with 14 catalyzed by (S)-diphe-
nylprolinol silyl ether was (2S, 3R), which was determined
after conversion to 1 (see below). This is consistent with the
observations of the groups of Ma,[7] Sebesta,[8a] and Lu.[9]
The absolute configuration of the minor isomer 16, however,
was not known. This identification would be important to
understand the reaction mechanism. To obtain the minor
isomer 16 in sufficient amounts, the reaction was performed
without an acid additive to decrease the diastereoselectivity
(Scheme 3). Compounds (2S, 3R)-17 and 18 were obtained
in 33 and 8% yield, respectively, after reduction with
a similar addition reaction is possible between TMS catalyst
11 and cis-nitroalkene 14. This unproductive side reaction
could be responsible for the unfavorable results. By employ-
ing the bulky DPMS catalyst 13 instead of the TMS catalyst
11, this side reaction would be suppressed to afford a clean
reaction.
Next, an environmentally friendly solvent system was
screened. In our first three one-pot synthesis of 1[3a] we em-
ployed a halogenated solvent system (CH2Cl2), which is un-
suitable for process chemistry objectives. In our second de-
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Y. Hayashi et al.
Scheme 3. Determination of the absolute configuration of the minor isomer 18 derived from Michael reaction of 2 and 14.
NaBH4. The enantiomeric excess (ee) of these isomers was
determined to be 80 and 60% ee, respectively. This result in-
dicates that an acid additive increases not only the yield and
diastereoselectivity, but also the enantioselectivity. Alcohol
18 was oxidized with Dess–Martin periodinane to give alde-
hyde 16, which was isomerized with pyrrolidine in the pres-
ence of p-nitrophenol and reduced with NaBH4 to afford 17
and 18 in 24 and 20% yield, respectively. Next, chiral HPLC
analysis was performed. Compound 17, generated after iso-
merization, showed the same retention time as (2S, 3R)-17,
generated from 2 and 14. Thus, the absolute configuration of
18 was determined to be (2R, 3R), therefore the absolute
configuration of 16 was determined to be (2R, 3R). The
(2S)-butanol derivative 17 was obtained, whereas the (2R)
isomer 18 was generated. Transition-state models to ration-
alize the stereochemical results are discussed later.
does not occur. Compound 22 could be generated by further
Michael reaction of the initially generated desired product
20 with acrylate derivative.[3b] The latter two compounds
were successfully converted into 20 by the addition of
EtOH. Between 15 and 20, several reactions proceed: 1) Mi-
chael reaction of nitroalkane 15 with 6 and intramolecular
Horner–Wadsworth–Emmons reaction; 2) retro-aldol reac-
tion of 21, followed by intramolecular Horner–Wadsworth–
Emmons reaction; 3) retro-Michael reaction of 22. The Mi-
chael reaction of toluenethiol, followed by epimerization at
the a-position of the nitro group, afforded the thiol Michael
adduct 10 with the desired stereochemical configuration. By
addition of Zn and TMSCl to the same vessel, reduction of
the nitro group to give the amine 23 occurred, from which
a retro-Michael reaction of the thiol group proceeded by
treatment with base to afford 1 in a single pot and without
the need to exchange or evaporate solvents. The highest
total yield of this one-pot procedure was 36% on 40 mg
scale. The one-pot procedure was applicable for scale-up
synthesis. The gram-scale synthesis was demonstrated in
28% total yield, to afford 1 (1.02 g) from cis-nitroalkene 14
(1.5 g) in a one-pot procedure. The procedure has potential
for further scale up to provide a greater amount of 1.
One-pot sequential synthesis of 1: With the best reaction
conditions for the first Michael reaction determined, the
complete one-pot sequential synthesis of 1 was examined
next (Scheme 4). The Michael reaction of a-alkoxyaldehyde
2 and cis-nitroalkene 14, catalyzed by (S)-diphenylprolinol
silyl ether 13, proceeded in the presence of HCO2H in
chloro
yield with excellent diastereo- and enantioselectivity. Ethyl
acrylate derivative 6 and Cs2CO3 were added to the same
pot. This generated multiple spots upon TLC analysis. Some
compounds present were identified as 20, 21, and 22. The
configuration of the hydroxyl and diethylphosphonyl groups
in 21 is assumed to be anti although the stereochemistry of
21 has not been determined.[3b] Therefore, syn elimination
benzene to afford the Michael product 15 in good
It should be emphasized that removal of volatile materials
from the reaction mixture, by evaporation or solvent ex-
change, which were necessary in our previous two- and
three-pot syntheses,[3a,b] were not required in this one-pot
process. Although strictly not the ideal solvent for each sub-
sequent reaction, chlorobenzene did not interfere with the
desired reaction course. This is key for the successful reali-
zation of a one-pot synthesis without solvent exchange.
ACHTUNGTRENNUNG
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Synthesis of (À)-Oseltamivir
FULL PAPER
Scheme 4. One-pot synthesis of 1.
Here, we simply add each reagent and co-solvent successive-
ly, which is synthetically and operationally simple and ideal.
As we described in our previous work,[3a,b] the cyclohex-
ane intermediate 10 is crystalline. Thus, the diastereo- and
enantiomerically pure highly substituted cyclohexane deriva-
tive 10 could be easily obtained by a single crystallization in
51% yield when we quenched the reaction at this stage. We
believe this procedure to be one of the most efficient and
practical methods for the preparation of 1.
line) to afford cyclobutane 25 (Figure 1; green line). A small
amount of nitro-enamine 26 was also observed (Figure 1;
light-blue line). Next, acid was added to the mixture at
t=13 min; ClCH2CO2H was selected as the optimal acid ad-
ditive for the catalytic Michael reaction due to our previous
results in the reaction between a-alkoxyaldehyde 2 and
trans-nitroalkene 3.[3a,b] The E/Z enamine ratio dramatically
changed from 7:1 to 2:1 immediately upon addition of
ClCH2CO2H. These results indicate two main aspects of the
reaction: 1) acid accelerates E–Z enamine isomerization,
2) the E enamine reacts faster than the Z enamine toward
trans-nitroalkene 3.
Next, the reaction of E and Z enamine with 14 was inves-
tigated in the same manner described above for the trans-ni-
troalkene 3. When cis-nitroalkene 14 (1.3 equiv) was added
to the preformed enamine solution only the Z enamine re-
acted to afford cyclobutane 27. However, the reaction was
slow. When 14 (3.3 equiv) was employed, the reaction was
faster and the same phenomenon was observed (Figure 2).
Therefore, cis-nitroalkene 14 (3.3 equiv) was used for this
study. Only one stereoisomer of cyclobutane 27 was ob-
served when cis-nitroalkene 14 was used. Also, the Z enam-
ine reacted faster than the E enamine towards 14. However,
even in the presence of both E and Z enamines the reaction
of cis-nitroalkene 14 did not progress further (or faster)
before the addition of acid. HCO2H (the best acid additive
for the catalyzed reaction of a-alkoxyaldehyde 2 and cis-ni-
troalkene 14) was added after 21 min. Although the NMR
spectra became rapidly complicated, a few points are note-
worthy. Not only the E and Z enamines, but also cyclobu-
The effect of acid additives: In our recent publication,[11] we
investigated the key Michael reaction of 2 with 3 or 14, cata-
lyzed by diphenylprolinol silyl ethers, in which the enamine
generated from the a-alkoxyaldehyde reacts with the nitro-
alkene to generate cyclobutane intermediates. The E/Z ratio
of the enamine was found to be 1.0:1.6 and the E enamine
preferentially reacts with (E)-3, whereas the Z enamine
reacts faster with (Z)-14. The effectiveness of acid additive
in the Michael reaction of a-alkoxyaldehydes and nitro-
ACHTUNGTRENNUNGalkenes prompted us to investigate the effect of acid in this
Michael reaction by comparison with the Michael reaction
of 3.
First, the effect of acid in the reaction of the trans-nitro-
ACHTUNGTRENNUNGalkene 3 was examined. We used less (1.3 equiv) of 3 than
the E and Z enamine (2.9 equiv, 1:1.9 E/Z) to investigate
which enamine reacts faster with 3. When trans-nitroalkene
3 was added to a solution of preformed enamine, the E en-
amine was consumed almost immediately (Figure 1; red
line) to afford cyclobutane 24 (Figure 1; orange line), where-
as the Z enamine was consumed more slowly (Figure 1; blue
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Y. Hayashi et al.
Figure 1. Reactivity of E and Z enamines with trans-nitroalkene 3 and
the effect of acid to promote E–Z enamine isomerization.[a,b] a) Trans-ni-
troalkene 3 (0.1m solution in C6D6, 0.015 mmol, 0.15 mL) was added to
a preformed solution of E and Z enamine (0.033 mmol, E/Z=1:1.9) in
C6D6 (0.73 mL) with toluene as an internal standard (0.5m solution in
C6D6, 0.02 mmol, 40 ml) in the presence of 4 ꢁ molecular sieves (200 mg).
Without molecular sieves, an aliquot (0.6 mL) of this reaction mixture
was transferred to an NMR tube and ClCH2COOH (0.5m solution in
C6D6, 0.015 mmol, 30 ml) was subsequently added to the NMR tube after
13 min. The reaction was monitored by 1H NMR spectroscopy. The con-
centration of each product was calculated by integration of selected
1
peaks in the H NMR spectra and plotted on the graph. b) The structures
of 24, 25, and 26 were elucidated by 2D NMR spectroscopic analysis
(COSY, HSQC, and HMBC). The relative stereochemistry of 24 and 25
was determined by NOESY.
Figure 2. Reactivity of E and Z enamines with cis-nitroalkene 14 and
effect of acid to accelerate Michael reaction.[a,b] a) Cis-nitroalkene 14
(0.05m solution in C6D6, 0.05 mmol, 1.0 mL) was added to a preformed
solution of the E and Z enamines (0.0372 mmol, E/Z=1:1.7) in C6D6
(0.73 mL) with toluene (0.5m solution in C6D6, 0.02 mmol, 40 ml) as an in-
ternal standard in the presence of 4 ꢁ molecular sieves (200 mg). With-
out molecular sieves, an aliqout (0.6 mL) of this reaction mixture was
transferred to an NMR tube and HCO2H (0.5m solution in C6D6, 62 ml)
was added to the NMR tube after 21 min. The reaction was monitored
by 1H NMR spectroscopy. The concentration of each product was calcu-
tane 27, were rapidly consumed within 10 min of the addi-
tion of HCO2H. With their disappearance, the amount of
Michael product 15 (Figure 2; black line) and nitro-enamine
28 (Figure 2; light-blue line) increased. This infers two main
roles for the acid (e.g. HCO2H): 1) to facilitate cyclobutane
ring opening, 2) to accelerate Michael addition of the enam-
ine onto the cis-nitroalkene 14.
Thus, this investigation provides strong evidence that acid
additives accelerate three main aspects of the Michael reac-
tion: 1) the E–Z enamine isomerization, 2) the ring opening
1
lated by integration of suitable peaks in the H NMR spectra and plotted
on the graph. b) The structures of 27 and 28 were elucidated by 2D
NMR analysis (COSY, HSQC, and HMBC). c) The relative configuration
of 27 was determined by NOESY. The Michael product 15 of reaction be-
tween a-alkoxyaldehyde 2 and cis-nitroalkene 14, catalyzed by 13, was
converted to (–)-Oseltamivir, which indicates the stated stereochemical
configuration of 27 to be highly probable.
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Synthesis of (À)-Oseltamivir
FULL PAPER
of cyclobutane intermediates, 3) the carbon–carbon bond-
forming addition of enamines to nitroalkenes. Although the
optimal acid additive differs according to the particular
characteristics of the Michael acceptor, the stereoselectivity
and yield in the Michael reactions of a-alkoxyaldehydes are
generally improved by screening for an appropriate acid ad-
ditive.
maleimide 30. Cordova et al. reported that the Michael reac-
tion of maleimides and aliphatic aldehydes catalyzed by
(S)-diphenylprolinol silyl ether gives the (2R, 3S)-isomer.[13]
We conducted the asymmetric Michael reaction of 2 and 30
catalyzed by 13. This generated the Michael adducts as
a mixture of diastereomers (31/32=1.1:1; Scheme 6). The re-
action was not optimized. The Michael products generated
were not stable enough for isolation so they were converted
to the respective carboxylic acids without purification. The
diastereomers were separated at this stage. The enantiose-
lectivity of each isomer was determined by chiral HPLC
after conversion to the corresponding methyl ester. The
enantiopurity of (2S, 3S)-33 was 87%ee, and that of (2R,
3S)-34 was 77% ee. These results indicate that the enantio-
facial selectivity of the chiral enamine intermediate is rela-
tively low.
The relative and absolute configurations of carboxylic
acids 33 and 34 were determined as follows (Scheme 7). The
carboxylic acid 33 was condensed with phenylglycine methyl
esters [PGME] (S)-35 and (R)-35 to give the (S)-PGME
amide 36 and (R)-PGME amide 37, respectively. The car-
boxylic acid 34 was also condensed with (S)-35 and (R)-35
to give the (S)-PGME amide 38 and (R)-PGME amide 39,
respectively. Key signals in the 1H NMR spectra of com-
pounds of 36 and 38 are more easily resolved than those of
33 and 34, therefore the relative configuration was deter-
mined by a NMR spectroscopic study according to the
J-based configuration analysis (JBCA) method.[14] In this
way, 33 and 34 were found to possess (2S*, 3S*) and (2R*,
3S*) configurations, respectively. The absolute configuration
at C2 of 33 was then determined by the PGME method of
Kusumi.[15] The chemical shift difference between
(S)-PGME amide 36 and (R)-PGME amide 37 was calculat-
ed and the absolute configuration at C2 in 36 and 37 was de-
termined to be (2S). Therefore, the absolute configuration
of 33 was determined to be (2S, 3S). The absolute configura-
tion of 34 was similarly determined to be (2R, 3S). The tran-
sition states of the reaction will be discussed later.
Michael reaction of a-alkoxyaldehyde with other cis-Mi-
chael acceptors: The proposed transition-state models for
the Michael reaction of 2 with 3 and 14, catalyzed by diphe-
nylprolinol silyl ethers, are described in Scheme 5; these
models have also been discussed in detail in our recent
mechanistic studies.[11] When the trans-nitroalkene 3 is com-
bined with a mixture of E and Z enamine, the E enamine
reacts with 3 to generate cyclobutane 24 through the pro-
posed transition-state model TS-1. The ring opening of 24
and subsequent hydrolysis generates the Michael product
29. On the other hand, when cis alkene 14 was used as a Mi-
chael acceptor, the Z enamine reacted with 14 to generate
the cyclobutane 27. In this case, ring opening of 27 and hy-
drolysis gives 15, which has a (2S)-configuration, opposite to
that of the (2R)-aldehyde 29. The transition-state model TS-
2, which was independently proposed by the group of Ma[7]
and Lu,[9] is consistent with this absolute configuration.
Although the transition-state model TS-2 may also ex-
plain the diastereo- and enantioselectivities achieved,
a more complicated sequence might exist during the reac-
tion course. For example, we found that 14 exists as its cis
isomer in CDCl3 (cis/trans= >99:1), whereas the trans
isomer prevails in DMSO (cis/trans=7:93).[11] The isomeri-
zation from cis to trans isomer might need to be considered.
Therefore, we selected to study a cis alkene Michael accept-
or that is known not to isomerize to its trans form. This
would allow for unambiguous investigation of the transition-
state models of the Michael reaction between a-alkoxyalde-
hydes and cis alkenes.
The first reaction we studied was the Michael addition of
a-alkoxyaldehyde 2 to cis-alkenyl Michael acceptor phenyl-
Scheme 5. Reactivity of the E and Z enamines toward trans-nitroalkene 3 and cis-nitroalkene 14. The E enamine reacts with 3 to give cyclobutane 24,
whereas the Z enamine reacts with 14 to give cyclobutane 27.
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Y. Hayashi et al.
Scheme 6. Asymmetric Michael reaction of 30 and a-alkoxyaldehyde 2.
Scheme 7. Synthesis of S amides 36 and 38 and R amides 37 and 39. EDC=Nꢂ-(3-dimethylaminopropyl)-N-ethylcarbodiimide, HOBt=1-hydroxybenzo-
triazole, NMM=N-methylmorpholine N-oxide.
Naphthoquinone (40) was selected as another cis alkene
for investigation (Scheme 8). Jørgensen et al demonstrated
the organocatalyzed Michael reaction of 40 with several ali-
phatic aldehydes, which generated primary alcohols in excel-
lent ee upon reduction.[16] We performed the Michael reac-
tion of a-alkoxyaldehyde 2 and 40 to generate the hemiace-
tal 41. The ee was determined after reduction of the hemi-
trast to the excellent values obtained in the reactions of ali-
phatic aldehydes reported by Jørgensen.[16] The absolute
configuration of 42 was determined to be R after conversion
of 42 into the PGME amide.[15] The transition-state models
for these reactions will be discussed next.
Transition-state models: We have already reported that al-
dehyde 2 generates both E and Z enamines, whereas ali-
phatic aldehydes generate the E enamine preferentially,
ACHTUNGTRENNUNGacetal 41 to its corresponding alcohol 42. The enantiomeric
excess of 42 was determined to be 38%. This is low in con-
Scheme 8. Asymmetric Michael reaction of 40 and a-alkoxyaldehyde 2.
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Synthesis of (À)-Oseltamivir
FULL PAPER
reaction of aliphatic aldehydes and phenylmaleimides in the
presence of (S)-diphenylprolinol silyl ether to give the Mi-
chael product (2R, 3S)-43 in excellent diastereo- and enan-
tioselectivity.[13] The Cordova group reasoned the observed
selectivity by proposition of the transition-state model TS-3
between the E enamine and phenylmaleimide (Scheme 9a).
In spite of the high enantioselectivity, the diastereoselectiv-
ity of the Michael reaction of 2 and 30 was low (Scheme 6).
From our results, we propose the transition-state models for
the Michael reaction of 2 and 30 shown in Scheme 9b–e.
Three transition-state models, TS-4, TS-5, and TS-6,
should be considered in the reaction of the E enamine. TS-4
is a similar model to that proposed by Cordova. TS-4 has
the least steric hindrance but does not agree with the acyclic
synclinal transition state proposed by Seebach and Golin-
ski.[17] Although TS-6, which affords a wrong isomer, would
provide better charge interactions than TS-5, it is sterically
encumbered. TS-5 is preferable in terms of both steric hin-
drance and electrostatic interactions. Thus, the reaction of
the E enamine would likely proceed via TS-5 (Scheme 9c).
According to the same considerations of steric and elec-
trostatic interactions, the reaction of the Z enamine would
proceed via TS-7 to provide the observed (2S, 3S) isomer 31
(Scheme 9e).
As mentioned previously, Jørgensen reported the Michael
reaction of aliphatic aldehydes with 40, catalyzed by (S)-di-
phenylprolinol silyl ethers, to afford chiral adducts in excel-
lent enantioselectivity.[16] Herein, we propose a plausible
transition-state model (Scheme 10). The naphthoquinone
approaches from the Si face of the E enamine in alignment
with optimal electrostatic interactions, as described in See-
bachꢂs model[17] (TS-8; Scheme 10a). This would generate
the Michael product 45, which converts to 46 after aromati-
zation. In contrast to the excellent enantioselectivity in the
reaction of aliphatic aldehydes, the Michael reaction of a-al-
koxyaldehydes gave low enantioselectivity (38% ee;
Scheme 8). This can be explained as follows: both the E and
Z enamines would react with 40. The E enamine would gen-
erate 47 through TS-9 (Scheme 10b), followed by aromatiza-
tion to afford the R isomer 41. The Z enamine would gener-
ate the S isomer 49 through TS-10 (Scheme 10c). The resul-
tant enantioselectivities are low because the E and Z enam-
ine each afford the opposite enantiomer and the reaction
proceeds through both enamine species.
Scheme 9. Transition-state models of prolinol-derived enamines with 30.
upon treatment with diphenylprolinol silyl ether organocata-
lysts.[11] Herein, we propose transition-state models for 30
(Scheme 9) and 40 (Scheme 10) as Michael acceptors. As
mentioned previously, Cordova et al. reported the Michael
As mentioned earlier, the absolute configuration of the
Michael product 16 was determined to be (2R, 3R) and that
of 15 as (2S, 3R) [Scheme 11]. In both products, the absolute
configuration of the a-position of the AcNH group in 15
and 16 is the same. The configuration at the a-position of
the alkoxy group in 15 and 16 is opposite, which would be
determined by geometry of the enamine. By analogy, these
results are consistent with the transition-state models pro-
posed for the cis-Michael acceptors 30 and 40. Specifically,
the major isomer 15 would result from transition-state
model TS-2 (Scheme 11a), whereas the minor isomer 16
would be derived from the reaction of the E enamine via
TS-10 (Scheme 11b).
Scheme 10. Transition-state models of enamines with 40.
Chem. Eur. J. 2013, 19, 17789 – 17800
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17797

Y. Hayashi et al.
enantioselectivity, even though both the E and Z enamine
were generated. A similar result was obtained for the reac-
tion of 3 and 2 catalysed by (R)-diphenylprolinol silyl ether
4: the Michael product 5 was obtained in good yield with ex-
cellent diastereo- and enantioselectivity, although both the
E and Z enamine were generated. These results can be ex-
plained as follows (Scheme 13): the Z enamine reacts with
14 faster than the E enamine (Figure 2) and the addition re-
action of the Z enamine is facilitated by the acid additive
(Figure 2). There is a rapid equilibrium between the E and
Z enamine in the presence of acid (Figure 1). Thus, the Z
enamine reacts preferentially and the remaining E enamine
isomerizes to the Z form, which then reacts with Michael ac-
ceptor 14 to afford the product 15. Similar phenomena are
also observed with 3, but the E enamine preferentially
reacts with (E)-3 (Figure 1) and the remaining Z enamine
readily isomerizes to its E form before reaction with the Mi-
chael acceptor (E)-3 to afford the product 5. It is notewor-
thy that excellent diastereo- and enantioselectivity are ob-
tained with good yield in the reactions of both (Z)-14 and
(E)-3. This would be possible when the following three rela-
tive rates are orchestrated correctly: 1) the speed of genera-
tion of the E and Z enamines from 2 and the diphenylproli-
nol silyl ether, 2) the reaction rate of the E and Z enamines
toward each Michael acceptor 3 and 14, 3) the isomerization
rate between the E and Z enamine. Because the reactive
enantioface of the E and Z enamine is opposite we have to
Scheme 11. Transition-state models of enamine with 14.
Isomerization and reactivity of the E and Z enamines: In
the case of phenylmaleimide 30, both the E and Z enamines
generated from 2 and 13 react with 30 to furnish a 1:1.1 mix-
ture of aldehydes 32 and 31 (Scheme 12). Both the E and Z
enamine also react with 40 to afford a 2.2:1 mixture of hem-
iacetal 41 and 49. These results indicate that both the E and
Z enamine react with each Michael acceptor.
Contrary to substrates 30 and 40, the reactions of 14 and
3 exhibit a different profile. The reaction of 14 and 2 cata-
lyzed by (S)-diphenylprolinol silyl ether 13 afforded the Mi-
chael product 15 in good yield with excellent diastereo- and
employ
(S)-diphenylprolinol
silyl ether 13 as a catalyst with
the Z enamine, whereas (R)-di-
phenylprolinol silyl ether 4 is
employed for the E enamine.
Conclusion
We have achieved a complete
one-pot sequential synthesis of
1 without solvent evaporation
or exchange on a gram-scale.
On the basis of our original
route[3] and advancements by
others[7,8a,9] we have critically
modified the first key asymmet-
ric Michael reaction of 2 with
14 to proceed in good yield and
with excellent diastereo- and
enantioselectivity. Key to the
success of this transformation
are: 1) use of a bulky silyl sub-
stitution in the diphenylprolinol
silyl ether organocatalyst, 2) use
of HCO2H as an acid additive
to accelerate the reaction and
increase
stereoselectivities,
3) use of chlorobenzene as sol-
vent to allow for all subsequent
Scheme 12. Reaction of E and Z enamines with 30 and 40.
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Synthesis of (À)-Oseltamivir
FULL PAPER
ready acid-promoted isomeriza-
tion between the E and Z en-
amine.
Collectively, the synthesis
presented herein is the first ex-
ample of a one-pot synthesis of
a drug of this stereochemical
complexity, in significant yield,
without the need to evaporate
or exchange solvents, on a gram
scale. We believe the present
synthesis of 1 to be not only ef-
ficient, but also applicable for
larger preparative scales.
Acknowledgements
We would like to thank Prof. Dieter
Seebach for significant discussions re-
garding the mechanistic study of the
Michael reaction of a-alkoxyaldehydes
with nitroalkenes. Some of the experi-
ments discussed in the section “the
effect of acid additives” were conduct-
ed by T.M. during a three-month stay
at ETH Zurich (August–October
2012; financed by Tokyo University of
Science) under the supervision of Prof.
Seebach. This work was supported by
a Grant-in-Aid for Scientific Research
on Innovative Areas (Advanced Mo-
lecular Transformations by Organoca-
talysts) from The Ministry of Educa-
tion, Culture, Sports, Science and
Technology, Japan.
Scheme 13. Isomerization and reaction of E and Z enamines with 3 and 14 in the presence of acid.
transformations and permit large-scale production, 4) con-
trol of the internal reaction temperature at 208C to increase
diastereoselectivity, 5) slow addition of 2 to suppress self-
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The transition-state model TS-2 of the Michael reaction
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Michael reaction can be effectively carried out by the cor-
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of generation of the E and Z enamines from 2 and diphenyl-
prolinol silyl ether, 2) the relative reactivity of the E and Z
enamines toward the Michael acceptors 3 and 14, 3) the
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Received: June 20, 2013
Published online: November 18, 2013
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