Two approaches toward the formal total synthesis of oseltamivir phosphate (Tamiflu): Catalytic enantioselective three-component reaction strategy and l-glutamic acid strategy

Article abstract of DOI:10.1021/jo400360j

Two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized l-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies used Dieckmann condensation to construct a six-membered ring core, after which manipulation of the functional groups and protecting groups accessed Corey's intermediate for the synthesis of oseltamivir phosphate. While the first synthesis was accomplished via four purification steps in 25.7% overall yield, albeit with moderate optical purity (76% ee), the second strategy achieved the synthesis via six purification steps in 19.8% overall yield with perfect enantiocontrol.

Full text of DOI:10.1021/jo400360j

Article
pubs.acs.org/joc
Two Approaches toward the Formal Total Synthesis of Oseltamivir
Phosphate (Tamiflu): Catalytic Enantioselective Three-Component
Reaction Strategy and L‑Glutamic Acid Strategy
Kaliyamoorthy Alagiri,† Makoto Furutachi,†,‡ Kenzo Yamatsugu,† Naoya Kumagai,† Takumi Watanabe,*,†
and Masakatsu Shibasaki*,†
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Two independent formal total syntheses of
oseltamivir phosphate were successfully achieved: the first
utilized a copper-catalyzed asymmetric three-component
reaction strategy, and the second utilized L-glutamic acid γ-
ester as a chiral source to install the correct stereochemistry.
Both strategies used Dieckmann condensation to construct a
six-membered ring core, after which manipulation of the
functional groups and protecting groups accessed Corey’s
intermediate for the synthesis of oseltamivir phosphate. While
the first synthesis was accomplished via four purification steps
in 25.7% overall yield, albeit with moderate optical purity (76%
ee), the second strategy achieved the synthesis via six
purification steps in 19.8% overall yield with perfect enantiocontrol.
as Relenza),5 the best-in-class compound, oseltamivir phos-
INTRODUCTION
Despite long-standing preventive efforts, influenza continues to
be one of the most serious threats to public health. Strains of
■
phate (Tamiflu), developed by Gilead Science and Roche,6 was
approved as a clinical medicine against influenza A and B
viruses by the FDA in 1999. Notably, Tamiflu has
demonstrated positive effects against the H5N1 and H1N1
subtypes and is in clinical use. A huge global stockpile of
oseltamivir phosphate is needed, however, to prepare for an
outbreak of influenza virus, especially newly discovered
hazardous strains that can cause serious mortality.
The process of manufacturing Tamiflu used by Roche
involves a chemical synthesis beginning with (−)-shikimic
acid,7 which can be isolated from the seeds of Chinese star
anise (plant of Illicium family). Because the supply of shikimic
acid from the plant is susceptible to climate fluctuations, a
variety of complementary methods have been developed to
secure shikimic acid reserves.8
the influenza virus easily mutate to escape host defense systems
(such as the case of the H1N1 subtype in 2009),1,2 and avian
influenza strains sometimes newly acquire infectivity between
humans resulting in very high mortality rate. Although
immunization is a reliable and established method to prevent
human from being infected by the seasonal viruses, the
preparation of vaccines against novel strains usually lags behind
their detection, allowing for flu outbreaks. Possibilities that
highly lethal strains, such as the H5N1 subtype discovered in
1997,3 will acquire infectivity between humans are of particular
concern because of the lack of immunologic warheads. An
alternative and powerful means to combat influenza is the use
of antivirals, such as viral neuraminidase inhibitors.4
Step-economic synthetic routes employing inexpensive
starting materials as well as less costly reaction and purification
conditions would be valuable alternative solutions to the supply
problem. Since the first reports of asymmetric total syntheses of
oseltamivir phosphate in 2006,9,10 a myriad of synthetic studies
have been published.11,12 Unfortunately, none of these
synthetic methods have been developed to the commercial
scale due to the high total cost (too many steps, low conversion
rates, and costly reagents), impracticality (harsh conditions,
Neuraminidase is a viral enzyme that catalyzes the cleavage of
the sialic acid residue from glycoproteins to liberate proliferated
viruses from infected cells. Six years after the report of the first-
in-class neuraminidase inhibitor, zanamivir (currently marketed
Received: February 18, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
malodorous reagents, demands for special equipment, high
dilutions, and excessive wastes), and safety issues (flammable or
explosive reagents and intermediates). In our continuing efforts
toward the development of more practical preparative routes,
our group reported several catalytic asymmetric syntheses of
oseltamivir phosphate using a yttrium-catalyzed asymmetric
ring-opening reaction of meso-aziridines with TMSN3 or
HOMO-raising barium-catalyzed asymmetric Diels−Alder
reaction as key transformations to manipulate the stereo-
chemistry.13 Despite the improved step-economy, the most
recent synthetic route13d still requires a potentially explosive
azide intermediate, which hinders its technical transfer to
industry.
Scheme 1. Retrosynthesis of Corey’s intermediate 2
Herein we disclose a formal total synthesis of oseltamivir
phosphate by two novel strategies: one using a catalytic
asymmetric reaction and the other using enantiopure starting
material to install the requisite stereochemistry. Both syntheses
were accomplished via the Dieckmann condensation to form
the six-membered ring skeleton, after which the identical
protocols led to patent-free Corey’s synthetic intermediate of
oseltamivir phosphate, 2.10 The original method reported by
Corey takes seven steps to access to 2 and uses the starting
material of low boiling point. For other approaches to
synthesize Corey’s intermediate, Kann et al. produced 2
through a diene-iron carbonyl intermediate and reported its
optical resolution,11a and Okamura et al. synthesized Corey’s
intermediate 2 using a Diels−Alder reaction of hydroxy
pyridone and ethyl acrylate in a racemic manner.11e Trost et
al. also produced an intermediate that is different from 2 only in
the protective group on the nitrogen atom (phthaloyl group) in
an elegant manner using an enantioselective palladium-
catalyzed allylic amination reaction as a key transformation.11f
However, this method includes a step that needs microwave
irradiation. Our approaches provide two alternative strategies to
access Corey’s intermediate in practical manners in terms of
total yield and stereocontrol.
According to Knochel’s report, the influence of the
substituents of each substrate on the enantioselectivity of the
three-component reaction can be summarized as follows: (1)
trimethylsilylacetylene is the most preferable, aryl-substituted
acetylene decreases the selectivity (never exceeding 90% ee),
(2) bisbenzylamine gives excellent selectivity, but simple
diallylamine substantially lowers the enantioselectivity, (3)
aliphatic aldehydes provide better selectivity compared to aryl
congeners, and α-alkyl-branched aliphatic aldehydes are the
most preferable. The choice of the secondary amine is
important not only because it is a determinant of the selectivity;
the substituents should act as a protecting group of the primary
amine and must be removed without damaging other
functionalities upon exchange with a Boc group. Because
removal of the benzyl group was expected to be problematic in
the presence of a double bond, which always exists on the
intermediates later than 4 bis(4-methoxybenzyl)amine was
examined in a preliminary study. Unfortunately, oxidative
deprotection did not work. We then decided to use
diallylamine, which is removable via allylic substitution using
Pd(0) as a catalyst. In addition, the absence of examples of
propiolate ester such as 6 in the original reports led us to
optimize reaction conditions (Table 1).
RESULTS AND DISCUSSION
■
The two novel approaches to our formal total synthesis of
oseltamivir are summarized in Scheme 1. Retrosynthetically, the
conjugated diene system of 2 precedes a cyclohexene-derived β-
ketoester 3 that can be disconnected to 4 by Dieckmann
condensation. The route then branches off to one of two
pathways, a catalytic asymmetric synthesis and a chiral pool
method. The catalytic asymmetric synthesis takes advantage of
a copper-catalyzed enantioselective three-component reaction
to give optically active propargylic amines. As reported by
Knochel et al.,14 the reaction proceeds via several events in a
stepwise manner. The first step is in situ generation of an
enamine from aldehyde 7 and secondary amine 8. Then, the
copper(I) catalyst activates the enamine as a Lewis acid,
accompanied by concomitant tautomerization into the iminium
form, which is followed by copper(I) acetylide formation en
route to its nucleophilic addition to the iminium resulting in
propargylic amine 5. Subsequent partial reduction of the triple
bond affords 4.
The chiral pool method utilizes the preinstalled chirality of L-
glutamic acid as the origin of the stereochemistry of the target
compound 2. An α-amino aldehyde 9 is readily prepared from a
commercially available L-glutamic acid γ-ester, which is followed
by a Z-selective Horner−Wadsworth−Emmons (HWE)
reaction to afford 4.
Initially, a reaction with 6, 7, and 8a was conducted under the
standard conditions reported by Knochel with slight
modification: with the catalyst system comprising 5 mol % of
CuBr and 5.5 mol % of (R)-Quinap,15 the reactions were
B
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
co-workers,17 affected the asymmetric induction (entry 10, 89%
yield, the antipode of 43% ee). Further tuning of the electronic
and steric characteristics of the aryl groups located at oxazoline
moieties had almost no beneficial effects on the enantiose-
lectivity (entries 11−13). Notably, a catalyst system comprising
Cu(II) and Ph-Pybox ligand (10 mol % of CuBr2 and 20 mol %
of (S,S)-Ph-Pybox) was slightly more effective compared with
the Cu(I) system (entries 14 and 15). Indeed, an improved
enantioselectivity up to 59% ee was observed at lower
temperature at 0 °C, although an increased loading of the
ligand and an extended reaction time (24 h) were required to
fulfill reasonable conversions (entry 16, 78%). Encouraged by
this result, the effects of a secondary amine were then
examined.
Knochel reported that the use of a secondary amine with
additional steric bulk, bis(2-phenylallyl)amine 8b, improved
enantioselectivity in many cases.18 This embellished allyl
functionality can be uneventfully removed by Pd(0)-mediated
allylic substitution. Accordingly, 8b was tested under the
conditions optimized for our system, as discussed above,
resulting in better chemical yield and stereoselectivity (entry
17, 91% yield, 64% ee). Eventually, 84% yield with 76% ee was
attained at a reaction temperature of −15 °C, as demonstrated
in entry 18. Further modifications of the conditions, however,
failed to improve the enantioselectivity.
The overall process according to the catalytic asymmetric
three-component reaction strategy is summarized in Scheme 2.
With the optically active propargylamine products in hand, the
succeeding partial reduction of the triple bond was examined.
When adduct 5a was subjected to the conditions with poisoned
Pd-mediated hydrogenation, such as Lindlar’s catalyst, reduc-
tion of the allyl group afforded Z-olefin 4a as an inseparable
mixture of products. The highest chemoselectivity was realized
by the siloxane-based reduction method reported by Trost
((Me2HSi)2O, AcOH, 2.5 mol % of Pd2(dba)3·CHCl3, and 10
mol % of P(o-tol)3),19 but the reaction continued to suffer from
a substantial undesired reduction of allyl groups. The same
reaction conditions as above with the phenyl-substituted
substrate 5b, however, escaped the overreduction to give Z-
olefin 4b in 84% yield without any trace of reduction of the 2-
phenylallyl groups, presumably because of the increased steric
bulk.
Table 1. Screening for Chiral Ligand in the Catalytic
Asymmetric Three-Component Reaction
yield
ee
e
f
entry
1
ligand
(R)-Quinap
R
X
Y
(%)
(%)
H
H
H
H
H
H
H
H
H
H
H
5.5
4
70
43
73
88
6
7
3
1
7
3
4
7
2
ac
,
2
3
4
5
6
7
8
9
L1
20
5.5
11
11
5.5
12
3
L2
(R)-Monophos
(R)-MOP
12
12
12
14
14
3
(R)-Segphos
(R,R)-i-Pr-DuPhos
(S,S)-Ph-BPE
(R,R)-Ph-Box
(R,R)-Ph-Pybox
21
17
25
88
89
91
5.5
5.5
5.5
5.5
5.5
g
2
43
33
g
10
11
12
14
(S,S)-4-MeO-C6H4-
Pybox
g
g
12
13
14
15
16
17
18
(R,R)-4-F-C6H4-Pybox
(R,R)-2-naphthyl-Pybox
(S,S)-Ph-Pybox
H
5.5
5.5
12
14
12
12
24
24
24
87
94
83
76
78
91
84
46
42
38
47
59
64
76
H
a
b
H
11
(S,S)-Ph-Pybox
H
11
20
20
20
bc
,
(S,S)-Ph-Pybox
H
bc
,
(S,S)-Ph-Pybox
Ph
Ph
bd
,
(S,S)-Ph-Pybox
a
b
c
10 mol % of CuBr was used. 10 mol % of CuBr2 was used. The
d
reaction was performed at 0 °C. The reaction was performed at −15
e
°C. NMR yield using 2-methoxynaphthalene as an internal standard.
f
g
Determined by HPLC. (R)-Isomer predominated.
The stage was set for the second key transformation of the
synthesis, Dieckmann condensation. Preliminarily, several bases
to promote this reaction were screened with 4a as the substrate.
Use of 3 equiv of LHMDS at −40 °C led to substantially better
conversion (ca. 90% yield) compared to the cases using KOt-
Bu (31%) and NaH (no reaction). The transformation
completed in 30 min at a higher temperature (−10 °C)
without affecting the reaction course to give cyclization product
3a (see Scheme 3 also). The same protocol was effective for the
synthesis via 4b to afford 3b, which was subjected to a 1,2-
reduction of the enone moiety employing NaBH4 to give 13.
The two 2-phenylallyl groups of 13 were removed by allylic
substitution in the presence of a catalytic amount of Pd(PPh3)4
and N,N-dimethylbarbituric acid as a nucleophile,20 which was
followed by introduction of the Boc group to give 14 as a
mixture of diastereomers in 58% yield over four steps. Further
efforts to shorten the reaction sequence by introducing the Boc
group prior to Dieckmann condensation failed: anion species
derived from 4 by deprotonation of carbamate NH attacked at
the carbonyl group of ester to give rise to a dead-end
byproduct. At the end of the synthesis, mesylation of the
performed in toluene in the presence of MS 4Å for 3 h at room
temperature. The product was obtained in good yield (70%),
but the enantioselectivity was as low as 7% ee. This outcome
forced us to refine the catalyst system in an ad hoc manner to
fit it to our particular system. Toward this end, we performed a
broad screening for chiral ligands. Another P,N-ligand
structurally closely related to Quinap reported by Carreira et
al.16 (L1) also afforded similarly unsatisfactory selectivity (entry
2), whereas a different type of P,N-ligand, L2, afforded an
almost racemic adduct, albeit with clean conversion (entry 3,
73% yield, 1% ee). Next, testing of a variety of chiral
monodentate and bidentate phosphorus-based ligands (phos-
phine- and phosphoramidite-based) revealed very poor
enantioselectivity (entries 4−8, 6−88% yield, 2−7% ee). We
then turned our attention to the use of Box ligands, which are
well recognized as privileged chiral ligands containing two
oxazoline rings and are commonly used in Lewis acidic copper-
catalyzed asymmetric reactions. While a simple (R,R)-Ph-Box
gave rise to the almost racemic product (entry 9), the tridentate
variant (R,R)-Ph-Pybox, originally developed by Nishiyama and
C
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 2. Formal Total Synthesis of Oseltamivir Phosphate
via a Catalytic Asymmetric Three-Component Reaction
Scheme 3. Formal Total Synthesis of Oseltamivir Phosphate
via the Glutamic Acid Route
a
a
a
Conditions: (a) 60% HClO4 (1.1 equiv), t-BuOAc (excess), rt, 2 d,
77%; (b) allyl bromide (6 equiv), NaHCO3 (4 equiv), EtOH, reflux,
24 h, yield 84%; (c) HCO2H (excess), 80 °C, 1 h; ClCO2Et (3 equiv),
Et3N (5 equiv), THF, −10 °C, 15 min, then NaBH4 (6 equiv), MeOH,
0 °C, 30 min, yield 80% for 2 steps; (d) SO3·pyridine (4 equiv), Et3N
(3.6 equiv), DMSO, 0 °C, 2 h; (CF3CH2O)2P(O)CH2CO2Et (1.1
equiv), 18-crown-6 (5 equiv), KHMDS (1.2 equiv), THF, −78 °C, 2
h, yield 80% for 2 steps; (e) LHMDS (3 equiv), THF, −40 °C, 1 h;
NaBH4 (2 equiv), MeOH, −20 °C, 30 min; Pd(PPh3)4 (10 mol %),
N,N-dimethylbarbituric acid (6 equiv), CH2Cl2, rt, 1 h; Boc2O (5
equiv), CH3CN, rt, 1 h, yield 55% for 4 steps; (f) MsCl (1.1 equiv),
Et3N (2 equiv), CH2Cl2, 4 °C, 10 min; DBU (3 equiv), rt, 1 h, 87% for
2 steps.
a
Conditions: (a) See Table 1 (runs 16−18), CuBr2 (10 mol %), (S,S)-
Ph-Pybox (20 mol %), 6 (2 equiv), 7 (1 equiv), 8a or 8b (2 equiv),
MS 4Å, toluene, −15 or 0 °C, 24 h; (b) Pd2(dba)3·CHCl3 (2.5 mol
%), P(o-tol)3 (10 mol %), (Me2HSi)2O (1 equiv), AcOH (1 equiv),
toluene, 45 or 40 °C, 19 or 24 h, yield 36% for 4a, 84% for 4b; (c)
LHMDS (3 equiv), THF, −40 °C, 1 h; NaBH4 (2 equiv), MeOH, −20
°C, 30 min; Pd(PPh3)4 (10 mol %), N,N-dimethylbarbituric acid (6
equiv), CH2Cl2, rt, 1 h; Boc2O (5 equiv), NaHCO3 aq, CH3CN, rt, 1
h, yield 55% for 4 steps; (d) MsCl (1.1 equiv), Et3N (2 equiv),
CH2Cl2, 4 °C, 10 min; DBU (3.1 equiv), CH2Cl2, rt, 1 h, 87% for 2
steps.
stereochemistry.11z In our approach, the α-carbon of L-glutamic
acid is the sole determinant of the stereochemistry of
oseltamivir phosphate, which made the overall process more
concise and efficient.
hydroxyl group and subsequent β-elimination afforded the
target compound of this study, Corey’s intermediate 2, in good
yield (87%).
Synthesis along this line commenced with commercially
available L-glutamic acid γ-ethyl ester 11 (>99% ee) as shown in
Scheme 3. The α-carboxyl group of 11 was masked as tert-butyl
ester 15 under acidic conditions with HClO4 in the presence of
t-BuOAc (77%).21 Then, the allyl groups were uneventfully
introduced to the amino group of 15 to give a fully protected L-
glutamic acid derivative 16 in 84% yield. Subsequent treatment
of HCO2H with 16 unveiled the α-carboxyl group, which was
converted to the corresponding primary alcohol 17 via the
formation of mixed anhydride followed by reduction with
NaBH4 in 80% yield over two steps.22 After thorough
investigation of the conditions for the subsequent oxidation
of the hydroxyl group (e.g., DMP, Swern, TEMPO), Parikh-
Doering oxidation (SO3·pyridine, Et3N, DMSO) was found to
produce the best conversion. Because the aldehyde product 18
was labile upon purification, the crude material was directly
used in the subsequent Z-selective HWE reaction.
Despite the overall fair efficiency of the synthetic route
described above, enhancing the enantioselectivity of the
asymmetric three-component reaction would be a formidable
task. Therefore, we decided to switch our strategy to the chiral
pool method, sharing the same synthetic intermediate 4 with
the first synthetic route (Scheme 1). Historically, many
asymmetric total syntheses have been accomplished using
readily available chiral compounds, especially abundant natural
products, as their origin of chirality. Of those, natural amino
acids are inexpensive, inexhaustible chiral pools. Among the
natural amino acids, L-glutamic acid is one of the least expensive
starting materials for asymmetric syntheses. Previously, Saicic
and co-workers achieved the synthesis of oseltamivir phosphate
by taking advantage of L-glutamic acid as a chiral source, but the
synthesis also made use of the Evans oxazolidinone-based
diastereoselective aldol reaction to furnish the requisite
D
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol, 2 equiv) were successively added at 0 °C, and the mixture was
stirred for 24 h at the same temperature. The reaction mixture was
quenched with 1.0 M aqueous HCl. The resulting biphasic mixture was
extracted with EtOAc, and the combined organic extract was washed
with brine and dried over Na2SO4. Evaporation of volatiles under
reduced pressure gave the crude mixture, which was used to determine
ee (HPLC conditions are described below) and NMR yield (10 mg of
2-methoxynaphthalene was used as an internal standard). To collect
physicochemical data, a crude material was purified with silica gel
column chromatography (n-hexane/AcOEt = 8/1 to 6/1) to afford 5a
as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 5.73 (m, 2H), 5.21
(d, J = 17.0 Hz, 2H), 5.11 (d, J = 10.5 Hz, 2H), 4.21 (q, J = 7.1 Hz,
2H), 4.11 (q, J = 7.0 Hz, 2H), 3.71 (dd, J = 7.8 Hz, 7.1 Hz, 1H), 3.28
(m, 2H), 2.87 (dd, J = 14.0 Hz, 7.8 Hz, 2H), 2.42 (m, 2H), 1.99 (m,
2H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 172.9, 153.6, 135.9, 117.7, 85.9, 77.6, 62.0, 60.5,
53.7, 51.3, 30.9, 27.9, 14.3, 14.0; IR (neat, cm−1) 3081, 2981, 2819,
2225, 1740, 1712; ESI-HRMS calcd for C17H25NO4Na [M + Na]+
330.1676, found 330.1674; [α]22D = −40.1 (34% ee, a sample obtained
under different conditions, c 0.97, CHCl3); HPLC (n-hexane/2-
propanol = 50/1, CHIRALPAK IC, 0.5 mL/min, 254 nm) tR = 17.8
min (minor), 19.6 min (major).
Toward this end, two well-known Z-selective HWE reactions
were tested. While Ando’s protocol23 with (o-tol)2P(
O)CH2CO2Et, NaI, and DBU gave the Z-olefin in 62% yield,
accompanied by a substantial amount of the E-isomer (Z/E
ratio; 80/20), the procedure reported by Still and Gennari24
using (CF3CH2O)2P(O)CH2CO2Et, KHMDS, and 18-
crown-6 achieved good reactivity (80% over 2 steps) and
excellent Z/E selectivity (98/2) to give 4a. Subsequently,
essentially the same reaction scheme developed for the first
strategy led to the desired Corey’s intermediate 2. In fact, the
four-step procedure to 20 in 55% yield was followed by the
two-step transformation into 2 in 87% yield as shown in
Scheme 2. The optical purity of the final product 2 obtained by
this method was 99% ee, confirming that no racemization
occurred during the synthesis.
CONCLUSION
■
In summary, we developed two independent synthetic methods
to access the synthetic precursor (2) of oseltamivir phosphate
reported by Corey. In the first strategy, we took advantage of
the copper-catalyzed asymmetric three-component reaction of
terminal alkyne, aldehyde, and secondary amine to afford the
propargylic amine product from which a substrate for
Dieckmann condensation, Z-olefin 4b, was derived. The second
strategy used the chirality of a readily available, optically pure L-
glutamic acid derivative as the origin of the stereochemistry of
target compound 2 and accessed the substrate of Dieckmann
condensation 4a via a Z-selective HWE reaction of 18. The first
synthesis was accomplished via five purification steps in 25.7%
overall yield albeit with moderate optical purity (76% ee), and
the second synthesis was achieved via six purification steps in
19.8% overall yield in optical pure form. Studies to further
refine the glutamic acid route to make it more cost-effective by
reducing the purification steps and tuning the reaction
conditions are underway.
(S)-Diethyl 4-(Bis(2-phenylallyl)amino)hept-2-ynedioate (5b,
Table 1, entry 18). Substrates 6 (40.5 μL, 0.400 mmol, 2 equiv), 7
(25.0 μL, 0.200 mmol, 1 equiv), and bis(2-phenylallyl)amine 8b (94.1
μL, 0.400 mmol, 2 equiv) were used in the presence of catalyst
comprising CuBr2 (4.5 mg, 20 μmol, 10 mol %) and (S,S)-Ph-Pybox
(14.8 mg, 40 μmol, 20 mol %). After stirring for 24 h at −15 °C, the
reaction mixture was quenched with 1.0 M aqueous HCl. The resulting
biphasic mixture was extracted with EtOAc, and the combined organic
extract was washed with brine and dried over Na2SO4. Evaporation of
volatiles under reduced pressure gave the crude mixture, which was
used to determine NMR yield and ee (HPLC conditions are described
below), then was purified by silica gel column chromatography (n-
hexane/AcOEt = 12/1 to 8/1) to give 5b (86.4 mg, 94%, 76% ee) as a
1
pale yellow oil. H NMR (CDCl3, 400 MHz) δ 7.28−7.11 (m, 10H),
5.43 (s, 2H), 5.27 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.07−3.90 (m,
2H), 3.86 (d, J = 13.8 Hz, 2H), 3.72−3.60 (m, 1H), 3.18 (d, J = 13.8
Hz, 2H), 2.00−1.82 (m, 3H), 1.82−1.68 (m, 1H), 1.32 (dd, J = 7.1
Hz, 7.1 Hz, 3H), 1.16 (dd, J = 7.1 Hz, 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 172.8, 153.5, 144.8, 139.3, 128.0, 127.5, 126.6, 116.5,
85.3, 78.0, 62.0, 60.2, 55.4, 50.6, 30.2, 27.5, 14.1, 14.0; IR (neat, cm−1)
EXPERIMENTAL SECTION
■
2222, 1733, 1711, 1244, 1182, 908, 779, 752, 696, 407; ESI-HRMS
All reactions were performed in oven-dried round-bottom flasks and
test tubes with a Teflon-coated magnetic stirring bar under Ar
atmosphere unless otherwise noted. Air- and moisture-sensitive liquids
were transferred via a gastight syringe and a stainless steel needle. All
workup and purification procedures were carried out with reagent
grade solvents under ambient atmosphere. Flash chromatography was
performed using silica gel 60 (230−400 mesh). Infrared (IR) spectra
were recorded on a Fourier transform IR spectrophotometer. NMR
was recorded on a 400 MHz spectrometer. For 1H NMR (400 MHz),
chemical shifts of protons are reported in parts per million downfield
from tetramethylsilane and are referenced to residual protium in the
NMR solvent (CDCl3, δ 7.26 ppm). For 13C NMR (100 MHz),
chemical shifts are reported in the scale relative to NMR solvent
(CDCl3, δ 77.0 ppm) as an internal reference. NMR data are reported
as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd:
doublet of doublets, t: triplet, q: quartet, m: multiplet), coupling
constant (Hz), and integration. Optical rotation was measured using a
2-mL cell with a 1.0-dm path length on a polarimeter. High-resolution
mass spectra (ESI-Orbitrap) were measured on an ESIMS instrument
equipped with an Orbitrap detector. HPLC analysis was conducted on
an HPLC system equipped with chiral stationary-phase columns (0.46
cm × 25 cm).
29
calcd for C29H34NO4 [M + H]+ 460.2482, found 460.2477; [α]D
=
−38.7 (73% ee, a sample obtained under different conditions, c 1.02,
CHCl3); HPLC (n-hexane/2-propanol = 50/1, CHIRALPAK IC, 0.5
mL/min, 254 nm) tR = 22.3 min (minor), 24.5 min (major).
(S)-Diethyl 4-(Diallylamino)-(Z)-hept-2-enedioate (4a). To
Pd2(dba)3·CHCl3 (105 mg, 0.102 mmol, 2.5 mol %) and P(o-tol)3
(124 mg, 0.406 mmol, 10 mol %) dissolved in toluene (10.3 mL) were
added (Me2HSi)2O (0.718 mL, 4.06 mmol), AcOH (0.232 mL, 4.06
mmol), and toluene solution (10 mL) of 5a (1.25 g, 4.06 mmol)
successively at room temperature. The mixture was stirred at 45 °C for
19 h, then allowed to reach room temperature, and quenched with
saturated aqueous NaHCO3. The aqueous layer was extracted with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography (n-hexane/EtOAc = 9/1 to 7/1)
to afford 4a as a colorless oil (450 mg, 36%). Spectral data are shown
later (as a product of the glutamic acid route). NMR spectra are
included in Supporting Information.
(S)-Diethyl 4-(Bis(2-phenylallyl)amino)-(Z)-hept-2-enedioate
(4b). To Pd2(dba)3·CHCl3 (243 mg, 0.235 mmol, 2.5 mol %) and
P(o-tol)3 (286 mg, 0.940 mmol, 10 mol %) dissolved in toluene (23.5
mL) were added (Me2HSi)2O (1.66 mL, 9.40 mmol), AcOH (0.537
mL, 9.40 mmol), and toluene solution (23.5 mL) of 5b (4.31 g, 9.39
mmol) successively at room temperature. The mixture was stirred at
40 °C for 24 h, then allowed to reach to room temperature, and
quenched with saturated aqueous NaHCO3. The aqueous layer was
extracted with EtOAc, and the organic layers were washed with brine,
(S)-Diethyl 4-(Diallylamino)hept-2-ynedioate (5a, Table 1,
entry 16). To a tube containing CuBr2 (4.5 mg, 20 μmol, 10 mol %)
and (S,S)-Ph-Pybox (14.8 mg, 40 μmol, 20 mol %) was added toluene
(0.8 mL) with stirring at room temperature. After 30 min, MS 4Å (120
mg), ethyl propiolate 6 (40.5 μL, 0.400 mmol, 2 equiv), aldehyde 725
(25.0 μL, 0.200 mmol, 1 equiv), and diallylamine 8a (49.2 μL, 0.400
E
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
dried over Na2SO4, and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (n-hexane/EtOAc =
12/1 to 8/1) to afford 4b as a colorless oil (3.65 g, 84%). H NMR
1.99−1.87 (m, 1H), 1.43 (s, 9H), 1.27 (dd, J = 7.1 Hz, 7.1 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 174.0, 155.0, 131.0, 129.9, 79.6, 63.6,
1
60.9, 44.4, 41.6, 28.3, 27.0, 14.1; IR (neat, cm−1) 3361, 2979, 2934,
1690, 1517, 1367, 1248, 1170, 1012, 755; ESI-HRMS calcd for
C14H23NNaO5 [M + Na]+ 308.1468, found 308.1473; [α]28D = −133.3
(70% ee, c 1.02, CHCl3).
(CDCl3, 400 MHz) δ 7.29−7.23 (m, 4H), 7.21−7.16 (m, 6H), 6.27
(dd, J = 11.4 Hz, 11.4 Hz, 1H), 5.94 (d, J = 11.4 Hz, 1H), 5.32 (s, 2H),
5.17 (s, 2H), 4.46−4.32 (m, 1H), 4.14−4.04 (m, 2H), 4.03 (q, J = 7.2
Hz, 1H), 3.83 (d, J = 14.1 Hz, 2H), 3.19 (d, J = 14.1 Hz, 2H), 2.08−
1.96 (m, 1H), 1.94−1.72 (m, 2H), 1.71−1.58 (m, 1H), 1.21 (dd, J =
7.2 Hz, 7.2 Hz, 3H), 1.19 (dd, J = 7.2 Hz, 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 173.8, 165.6, 146.0, 145.7, 140.1, 127.9, 127.3,
126.6, 122.7, 115.2, 60.1, 60.0, 55.2, 54.4, 30.8, 27.2, 14.2; IR (neat,
cm−1) 2980, 2820, 1721, 1631, 1416, 1186, 1029, 906, 779, 698; ESI-
HRMS calcd for C29H36NO4 [M + H]+ 462.2639, found 462.2632;
(S)-Ethyl 5-((tert-Butoxycarbonyl)amino)cyclohexa-1,3-dien-
ecarboxylate (2). To a stirred solution of the residue were
successively added 14 (172 mg, 0.603 mmol) in CH2Cl2 (3 mL),
MsCl (51.3 μL, 0.663 mmol), and Et3N (167 μL, 1.21 mmol) at 4 °C,
and the mixture was stirred for 10 min at the same temperature. DBU
(279 μL, 1.87 mmol) was added to the mixture, and the mixture was
further stirred for 1 h at room temperature. The mixture was diluted
with CH2Cl2 and washed with H2O, and the aqueous layer was back-
extracted with CH2Cl2. The combined organic layers were washed
with 1 N HCl, saturated aqueous NaHCO3, and brine successively and
dried over Na2SO4. The mixture was concentrated to give crude
material that was purified with silica gel column chromatography (n-
hexane/Et2O = 3/1 to 2/1) to afford 2 (140 mg, 0.523 mmol, 87%
yield) as a pale yellow viscous oil. ESI-HRMS calcd for C14H21NO4Na
[M + Na]+ 290.1363, found 290.1361. Physicochemical data was
identical to those reported.10 Other spectral data are shown later (as a
product of the glutamic acid route). NMR spectra obtained by this
sample are included in Supporting Information.
[α]27 = +82.0 (73% ee, c 1.04, CHCl3).
D
(2R,5S)-Ethyl 5-(tert-Butoxycarbonylamino)-2-hydroxycyclo-
hex-3-enecarboxylate (14). To a stirred solution of diester (4b)
(3.61 g, 7.83 mmol) in THF (15.7 mL) was slowly added a 1.0 M
THF solution of LHMDS (23.5 mL, 23.5 mmol) at −40 °C. The
resultant solution was stirred at the same temperature for 1 h, diluted
with EtOAc, and quenched with saturated aqueous NH4Cl. The
biphasic mixture was extracted with EtOAc, and combined organic
extracts were washed with brine and dried over Na2SO4. After
evaporation of the organic solvent under reduced pressure, the crude
product including 3b (keto−enol mixture) was obtained as a pale
yellow oil, which was used for the next reaction without further
purification.
To a stirred solution of the crude material including 3b (maximum
7.83 mmol) in MeOH (39.2 mL) was added NaBH4 (592 mg, 15.7
mmol) at −20 °C. The resultant solution was stirred at the same
temperature for 30 min and then quenched with saturated aqueous
NH4Cl (slowly added). After warming to room temperature, MeOH
was removed under the reduced pressure. The aqueous layer was
extracted with EtOAc, and the combined organic layers were washed
with brine and dried over Na2SO4. After evaporation of the volatiles
under reduced pressure, the crude product including 13 was obtained
as pale yellow oil, which was used for the next step without further
purification.
To a stirred solution of crude ester (13, maximum 7.83 mmol) in
CH2Cl2 (39.2 mL) were successively added Pd(PPh3)4 (905 mg, 0.783
mmol, 10 mol %) and N,N-dimethylbarbituric acid (7.34 g, 47.0
mmol) at room temperature. The resulting solution was stirred at the
same temperature for 1 h, and CH2Cl2 was removed under reduced
pressure. To this mixture were successively added a 1.0 M solution of
Boc2O in CH3CN (39.2 mL, 39.2 mmol) and saturated aqueous
NaHCO3 (39.2 mL) at room temperature. The resulting solution was
vigorously stirred at the same temperature for 1 h, diluted with EtOAc,
and quenched with saturated aqueous NaHCO3. The biphasic mixture
was extracted with EtOAc, and combined organic extracts were washed
with brine and dried over Na2SO4. After evaporation of volatiles under
reduced pressure, the crude mixture was purified by silica gel column
chromatography (n-hexane/AcOEt = 1/1) to give the desired product
(14) (1.23 g, diastereomeric mixture, 55% yield over 4 steps) as a pale
yellow solid. The diastereomers could be partially separated upon
careful silica gel column chromatography. Usually, the mixture of the
isomers was used in the next step without separation.
(1R,2R,5S)-Ethyl 5-(tert-Butoxycarbonylamino)-2-hydroxycy-
clohex-3-enecarboxylate (14, less polar isomer). 1H NMR
(CDCl3, 400 MHz) δ 5.77−5.71 (m, 1H), 5.65−5.59 (m, 1H), 4.53−
4.47 (m, 1H), 4.47−4.40 (m, 1H), 4.35 (brs, 1H), 4.24−4.12 (m, 2H),
2.62−2.52 (m, 1H), 2.51−2.38 (m, 1H), 1.43 (s, 9H), 1.27 (dd, J = 4.8
Hz, 4.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 173.8, 155.2, 131.6,
130.5, 79.6, 67.7, 61.0, 48.0, 47.3, 31.7, 28.3, 14.1; IR (neat, cm−1)
3424, 3361, 2976, 1718, 1682, 1523, 1181, 1053; ESI-HRMS calcd for
C14H23NNaO5 [M + Na]+ 308.1468, found 308.1474; [α]28D = −53.4
(70% ee, c 1.04, CHCl3).
(S)-1-tert-Butyl 5-Ethyl 2-Aminopentanedioate (15). L-Gluta-
mic acid γ-ethyl ester (11, 10.0 g, 57.1 mmol) was dissolved in
aqueous 60% HClO4 (6.9 mL, 62.8 mmol) with stirring in an ice bath.
t-BuOAc (250 mL) was added, and the stirring was continued until a
homogeneous solution was obtained. The mixture was maintained at
room temperature for 2 days, then 0.1 N HCl (350 mL) was added to
the mixture, and Et2O was added. The aqueous phase was separated
from the organic phase, and the aqueous phase was adjusted to pH = 9
with aqueous Na2CO3. The aqueous phase was extracted with EtOAc,
and the organic layers were combined, washed with brine, dried over
anhydrous Na2SO4, and concentrated to afford the desired ester 15 as
a colorless oil (10.14 g, 77%). The crude product was NMR pure and
was used directly without purification in the next step. 1H NMR
(CDCl3, 400 MHz) δ 4.07 (q, J = 7.2 Hz, 2H), 3.28 (dd, J = 8.2 Hz,
5.3 Hz, 1H), 2.38 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 2.02−1.92 (m, 1H),
1.80−1.68 (m, 1H), 1.51 (s, 2H), 1.40 (s, 9H), 1.19 (dd, J = 7.1 Hz,
7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.8, 173.2, 81.1, 60.3,
54.2, 30.6, 29.8, 27.9, 14.1; IR (neat, cm−1) 3385, 2979, 2935, 1731;
ESI-HRMS calcd for C11H22NO4 [M + H]+ 232.1543, found
232.1546; [α]25 = 12.4 (c 1.04, CHCl3).
(S)-1-tert-BuDtyl 5-Ethyl-2-(diallylamino)pentanedioate (16).
Diester 15 (9.4 g, 40.6 mmol) was dissolved in EtOH (100 mL), and
powdered NaHCO3 (13.65 g, 0.163 mol) and allyl bromide (21.1 mL,
0.244 mol) were added at room temperature. The mixture was stirred
under reflux for 20 h, then cooled to room temperature, filtered
through a Celite pad using EtOAc, and concentrated to give crude
material, which was purified by silica gel column chromatography (n-
hexane/EtOAc = 32/1) to afford 16 as a colorless oil (10.59 g, 84%).
1H NMR (CDCl3, 400 MHz) δ 5.78−5.65 (m, 2H), 5.15 (d, J = 17.2
Hz, 2H), 5.07 (d, J = 10.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.38−
3.28 (m, 3H), 3.01 (dd, J = 14.4 Hz, 8.0 Hz, 2H), 2.45−2.26 (m, 2H),
2.00−1.80 (m, 2H), 1.45 (s, 9H), 1.23 (dd, J = 7.1 Hz, 7.1 Hz, 3H; 13C
NMR (CDCl3, 100 MHz) δ 173.5, 171.9, 136.7, 116.9, 80.9, 61.1, 60.2,
53.3, 30.9, 28.3, 24.6, 14.2; IR (neat, cm−1): 3078, 2978, 2819, 2934,
2841, 1734; ESI-HRMS calcd for C17H29NO4Na [M + Na]+ 334.1989,
found 334.1987; [α]25 = −55.7 (c 1.1, CHCl3).
D
(S)-Ethyl 4-(Diallylamino)-5-hydroxypentanoate (17). Diester
16 (1.4 g, 4.5 mmol) was dissolved in HCO2H (15 mL) and stirred at
80 °C for 1 h. The reaction mixture was cooled to room temperature,
and HCO2H was removed by azeotropic distillation with toluene (3
times) and CHCl3 (3 times) under reduced pressure to afford the
crude mixture. To the resultant residue in THF (30 mL) at −10 °C
was added Et3N (3.1 mL, 22.5 mmol), followed by ethyl chloroformate
(1.28 mL, 13.5 mmol). After 15 min, NaBH4 (1.02 g, 27 mmol) was
added in one portion. MeOH (30 mL) was then added dropwise to
the mixture at 0 °C. The solution was stirred for an additional 30 min
(1S,2R,5S)-Ethyl 5-(tert-Butoxycarbonylamino)-2-hydroxycy-
clohex-3-enecarboxylate (14, more polar isomer). 1H NMR
(CDCl3, 400 MHz) δ 6.00−5.91 (m, 1H), 5.86−5.76 (m, 1H), 4.54−
4.42 (m, 1H), 4.40 (dd, J = 4.1 Hz, 4.1 Hz, 1H), 4.32−4.22 (m, 1H),
4.19 (q, J = 7.1 Hz, 2H), 2.80−2.67 (m, 1H), 2.30−2.15 (m, 1H),
F
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
at the same temperature and then quenched with saturated aqueous
NH4Cl. The organic solvents were evaporated under reduced pressure,
and the product was extracted with EtOAc, washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
afford crude material, which was purified by silica gel column
chromatography (n-hexane/EtOAc = 1/4) to afford 17 as a colorless
with brine, dried over Na2SO4, filtered, and concentrated to give crude
20, which was partially purified by silica gel column chromatography
(n-hexane/EtOAc = 2/1) to afford a sample including 20 (180 mg,
0.680 mmol at maximum, diastereomeric mixture) as a pale yellow oil.
To a stirred solution of partially purified 20 (180 mg, maximum
0.680 mmol) in CH2Cl2 (3.39 mL) were successively added
Pd(PPh3)4 (78.4 mg, 67.8 μmol, 10 mol %) and N,N-dimethylbarbi-
turic acid (636 mg, 4.07 mmol) at room temperature, and the mixture
was stirred for 1 h. After removing CH2Cl2 under the reduced
pressure, a 0.82 M solution of Boc2O in CH3CN (4.13 mL, 3.39
mmol) and saturated aqueous NaHCO3 were successively added at
room temperature, and the mixture was vigorously stirred for 3 h at
the same temperature. The mixture was diluted with EtOAc and
saturated aqueous NaHCO3, and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated to give a crude mixture, which
was purified with silica gel column chromatography (n-hexane/AcOEt
= 1/1) to afford 14 (175 mg, 0.613 mmol, diastereomeric mixture,
56% yield for 4 steps) as a pale yellow solid. NMR and IR data were
identical to those described above. ESI-HRMS calcd for
C14H23NO5Na [M + Na]+ 308.1468, found 308.1468. NMR spectra
obtained by this sample (diastereomeric mixture) are included in
Supporting Information.
1
oil (869 mg, 80%). H NMR (CDCl3, 400 MHz) δ 5.80−5.67 (m,
2H), 5.21−5.05 (m, 4H), 4.10 (q, J = 7.2 Hz, 2H), 3.47 (dd, J = 10.6,
5.2 Hz, 1H), 3.34−3.21 (m, 3H), 2.96 (dd, J = 14.2 Hz, 7.8 Hz, 2H),
2.90−2.78 (m, 1H), 2.32−2.17 (m, 2H), 1.95−1.83 (m, 1H), 1.48−
1.35 (m, 1H), 1.23 (dd, J = 7.1 Hz, 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 173.1, 136.4, 117.4, 60.6, 60.5, 59.2, 52.1, 31.5, 21.0, 14.2;
IR (neat, cm−1): 3440, 2978, 2934, 2876, 1733, 1642; ESI-HRMS
calcd for C13H24NO3 [M + H]+ 242.1751, found 242.1752; [α]25
23.1 (c 1.0, CHCl3).
=
D
(S)-Ethyl 4-(Diallylamino)-5-oxopentanoate (18). Et3N (0.21
mL, 1.49 mmol) was added to 17 (100 mg, 0.41 mmol) at 0 °C. Then,
SO3·pyridine (264 mg, 1.66 mmol) in DMSO (1.5 mL) was slowly
added at 0 °C. After the addition completed, the mixture was stirred at
the same temperature for 2 h. The reaction mixture was then
quenched by the addition of cold water (1 mL) and extracted with
ether. The combined organic layers were washed with 5% citric acid
and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to afford crude 18 as a colorless oil, which was used
for the succeeding reaction without further purification. 1H NMR
(CDCl3, 400 MHz) δ 9.66 (s, 1H), 5.75−5.65 (m, 2H), 5.16−5.05 (m,
4H), 4.06 (q, J = 7.1 Hz, 2H), 3.26−3.11 (m, 5H), 2.44−2.37 (m,
1H), 2.31−2.23 (m, 1H), 1.97−1.88 (m, 1H), 1.81−1.72 (m, 1H),
1.19 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 203.6, 173.2,
136.0, 117.8, 66.9, 60.4, 53.7, 31.0, 19.9, 14.2.
(S)-Ethyl 5-((tert-Butoxycarbonyl)amino)cyclohexa-1,3-dien-
ecarboxylate (2). The same protocol described above was applied to
14 synthesized via the glutamic acid route. Physicochemical data were
identical to those reported10 as follows. 1H NMR (CDCl3, 400 MHz)
δ 7.03 (d, J = 3.9 Hz, 1H), 6.18−6.09 (m, 2H), 4.61 (m, 1H), 4.42 (m,
1H), 4.20 (q, J = 7.1 Hz, 2H), 2.76−2.61 (m, 2H), 1.42 (s, 9H), 1.29
(t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 154.9,
132.7, 131.7, 127.0, 124.8, 79.5, 60.6, 43.5, 28.8, 28.4, 14.3; IR (neat,
cm−1) 3352, 2978, 1705; ESI-HRMS calcd for C14H21NO4Na [M +
(S)-Diethyl 4-(Diallylamino)-(Z)-hept-2-enedioate (4a). A
solution of (CF3CH2O)2P(O)CH2CO2Et (151 mg, 0.455 mmol)
and 18-crown-6 (547 mg, 2.07 mmol) in THF (4 mL) was cooled to
−78 °C and treated with KHMDS (0.5 M in toluene, 0.95 mL, 0.476
mmol). The mixture was stirred at −78 °C for 45 min, and then 18
(maximum 0.414 mmol) in THF (3 mL) was slowly added at −78 °C.
After the addition was completed, the mixture was stirred at −78 °C
for 2 h. Then, the reaction mixture was quenched with saturated
aqueous NH4Cl. After the mixture was warmed to room temperature,
the solvent was evaporated under reduced pressure and extracted with
EtOAc. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
afford crude material as a colorless oil (Z/E = 98/2), which was
purified by silica gel column chromatography (n-hexane/EtOAc =
11.5/1) to afford Z-olefin 4a as a colorless oil (103 mg, 80% over 2
steps). 1H NMR (CDCl3, 400 MHz) δ 6.12 (dd, J = 11.4 Hz, 10.3 Hz,
1H), 5.89 (d, J = 11.4 Hz, 1H), 5.80−5.70 (m, 2H), 5.13−5.04 (m,
4H), 4.45 (m, 1H), 4.15−4.07 (m, 4H), 3.26 (m, 2H), 2.91 (dd, J =
14.4 Hz, 7.4 Hz, 2H), 2.46 (m, 1H), 2.30 (m, 1H), 1.93 (m, 1H), 1.73
(m, 1H), 1.28−1.21 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 173.7,
165.8, 147.4, 136.5, 122.1, 116.7, 60.2, 60.1, 56.0, 52.5, 31.1, 27.3, 14.2;
IR (neat, cm−1) 2980, 2936, 1734, 1732; ESI-HRMS calcd for
Na]+ 290.1363, found 290.1361; [α]25 = −205.5 (98.9% ee, c 1.1,
D
CHCl3), lit. [α]20 = −217 (>99% ee, c 1.1, CHCl3);14a HPLC (n-
D
hexane/2-propanol = 50/1, CHIRALPAK AD-H, 1.0 mL/min, 254
nm) tR = 16.4 min (minor), 19.3 min (major).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds and HPLC
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: twatanabe@bikaken.or.jp; mshibasa@bikaken.or.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C17H28NO4 [M + H]+ 310.2013, found 310.2015; [α]25 = 138.5 (c
M.S, K.A, and M.F. are grateful to Adaptable and Seamless
Technology Transfer Program through target-driven R&D, JST
for financial support. M.F. thanks JSPS predoctral fellowship.
The authors thank Ms. Chiharu Sakashita for her technical
assistance. The authors are thankful to Dr. Ryuichi Sawa, Ms.
Yumiko Kubota, and Ms. Yuko Takahashi for spectroscopic
analysis.
D
0.91, CHCl3).
(5S)-Ethyl 5-((tert-Butoxycarbonyl)amino)-2-hydroxycyclo-
hex-3-enecarboxylate (14). To a stirred solution of 4a (340 mg,
1.10 mmol) in THF (5.49 mL) was slowly added a 1.0 M THF
solution of LHMDS (3.30 mL, 3.30 mmol) at −40 °C, and the mixture
was stirred for 30 min at the same temperature. EtOAc and saturated
aqueousNH4Cl were added to quench the reaction, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated to
give crude 19 (keto−enol mixture) as a pale yellow oil, which was used
for the next reaction without further purification.
REFERENCES
■
(1) Neumann, G.; Chen, H.; Gao, G. F.; Shu, Y.; Kawaoka, Y. Cell
Res. 2010, 20, 51.
(2) Oseltamivir-resistant strains have been already discovered: van
der Vries, E.; Stelma, F. F.; Boucher, C. A. B. N. Engl. J. Med. 2010,
363, 1381.
(3) (a) Moscona, A. N. Engl. J. Med. 2005, 353, 1363. (b) Boltz, D.
A.; Aldridge, J. R., Jr.; Webster, R. G.; Govorkova, E. A. Drugs 2010,
70, 1349.
To a stirred solution of crude 19 (maximum 1.10 mmol) in MeOH
(5.49 mL) was added NaBH4 (83.2 mg, 2.20 mmol) at −20 °C, and
the mixture was stirred for 30 min at the same temperature. After the
addition of saturated aqueous NH4Cl, MeOH was removed under
reduced pressure. EtOAc was added, and the resulting aqueous layer
was extracted with EtOAc. The combined organic layers were washed
G
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4) (a) Dawood, F. S.; Jain, S.; Finelli, L.; Shaw, M. W.; Lindstrom,
S.; Garten, R. J.; Gubareva, L. V.; Xu, X.; Bridges, C. B.; Uyeki, T. M.
N. Engl. J. Med. 2009, 360, 2605. (b) Garten, R. J.; Davis, C. T.;
Russell, C. A.; Shu, B.; Lindstrom, S.; Balish, A.; Sessions, W. M.; Xu,
X.; Skepner, E.; Deyde, V.; Okomo-Adhiambo, M.; Gubareva, L.;
Barnes, J.; Smith, C. B.; Emery, S. L.; Hillman, M. J.; Rivailler, P.;
Smagala, J.; de Graaf, M.; Burke, D. F.; Fouchier, R. A. M.; Pappas, C.;
Alpuche-Aranda, C. M.; Lopez-Gatell, H.; Olivera, H.; Lopez, I.;
Myers, C. A.; Faix, D.; Blair, P. J.; Yu, C.; Keene, K. M.; Dotson, P. D.,
Jr.; Boxrud, D.; Sambol, A. R.; Abid, S. H.; George, K. S.; Bannerman,
T.; Moore, A. L.; Stringer, D. J.; Blevins, P.; Demmler-Harrison, G. J.;
Ginsberg, M.; Kriner, P.; Waterman, S.; Smole, S.; Guevara, H. F.;
Belongia, E. A.; Clark, P. A.; aBeatrice, S. T.; Donis, R.; Katz, J.; Finelli,
L.; Bridges, C. B.; Shaw, M.; Jernigan, D. B.; Uyeki, T. M.; Smith, D. J.;
Klimov, A. I.; Cox, N. J. Science 2009, 325, 197. (c) Smith, G. J. D.;
Vijaykrishna, D.; Bahl, J.; Lycett, S. J.; Worobey, M.; Pybus, O. G.; Ma,
S. K.; Cheung, C. L.; Raghwani, J.; Bhatt, S.; Peiris, J. S. M.; Guan, Y.;
Rambaut, A. Nature 2009, 459, 1122.
(5) (a) von Itzstein, M.; Wu, W. Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R.
C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature 1993, 363, 418.
(b) von Itzstein, M. Nat. Rev. Drug Discovery 2007, 6, 967.
(6) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H. T.; Zhang, L. J.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai,
C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681.
(b) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H. W.; Zhang, L. J.;
Chen, X. W.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R.
C. J. Med. Chem. 1998, 41, 2451.
Lu, G. J. Org. Chem. 2010, 75, 3125. (v) Kamimura, A.; Nakano, T. J.
Org. Chem. 2010, 75, 3133. (w) Ko, J. S.; Keum, J. E.; Ko, S. Y. J. Org.
Chem. 2010, 75, 7006. (x) Ishikawa, H.; Bondzic, B. P.; Hayashi, Y.
Eur. J. Org. Chem. 2011, 6020. (y) Trost, B. M.; Zhang, T. Chem.
Eur. J. 2011, 17, 3630. (z) Trajkovic, M.; Ferjancic, Z.; Saicic, R. N.
Org. Biomol. Chem. 2011, 9, 6927. (aa) Werner, L.; Machara, A.;
Sullivan, B.; Carrera, I.; Moser, M.; Adams, D. R.; Hudlicky, T.;
Andraos, J. J. Org. Chem. 2011, 76, 10050. (ab) Oh, H.-S.; Kang, H.-Y.
J. Org. Chem. 2012, 77, 8792. (ac) Rehak, J.; Hut’ka, M.; Latika, A.;
Brath, H.; Almassy, A.; Hajzer, V.; Durmis, J.; Toma, S.; Sebesta, R.
Synthesis 2012, 44, 2424. For alternative approaches using
(−)-shikimic acid as starting materials, see: (ad) Karpf, M.;
Trussardi, R. Angew. Chem., Int. Ed. 2009, 48, 5760−5762. (ae) Nie,
L.-D.; Shi, X.-X. Tetrahedron Asymmetry 2009, 20, 124−129. (af) Nie,
L.-D.; Shi, X.-X.; Ko, K. H.; Lu, W.-D. J. Org. Chem. 2009, 74, 3970−
3973.
(12) For reviews, see: (a) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem.
2008, 1839. (b) Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006,
45, 7330−7334. (c) Magano, J. Chem. Rev. 2009, 109, 4398.
(d) Andraos, J. Org. Process. Res. Dev. 2009, 13, 161. (e) Magano, J.
Tetrahedron 2011, 67, 7875.
(13) (a) Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M.
Org. Lett. 2007, 9, 259. (b) Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2007, 46, 1403. (c) Yamatsugu, K.;
Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2009, 48, 1070. (d) Yamatsugu, K.; Kanai, M.; Shibasaki, M.
Tetrahedron 2009, 65, 6017.
(14) (a) Gommermann, N.; Koradin, X.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763. (b) Gommermann, N.;
Knochel, P. Chem.Eur. J. 2006, 12, 4380. (c) Gommermann, N.;
Knochel, P. Tetrahedron 2005, 61, 11418.
(15) Valk, J. M.; Claridge, T. D. W.; Brown, J. M.; Hibbs, D.;
Hursthouse, M. B. Tetrahedron: Asymmetry 1995, 6, 2597.
(16) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971.
(17) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846. (b) Desimoni, G.;
Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119.
(18) Gommermann, N.; Knochel, P. Chem. Commun. 2005, 4175.
(19) Trost, B. M.; Braslau, R. Tetrahedron Lett. 1989, 30, 4657.
(20) Garrohelion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109.
(21) Hu, J.; Miller, M. J. J. Am. Chem. Soc. 1997, 119, 3462.
(22) Ishizumi, K.; Koga, K.; Yamada, S.-i. Chem. Pharm. Bull. 1968,
16, 492.
̌
̌
(7) (a) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044.
(b) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.;
Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.;
Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. J. Org. Chem. 1998,
63, 4545. (c) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.;
Trussardi, R.; Wirz, B.; Zutter, U. Chimia 2004, 58, 621.
(8) (a) Draths, K. M.; Knop, D. R.; Frost, J. W. J. Am. Chem. Soc.
1999, 121, 1603. (b) Ghosh, S.; Chisti, Y.; Banerjee, U. C. Biotechnol.
Adv. 2012, 30, 1425 and references therein. See also: (c) Farina, V.;
Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330.
(9) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 6312.
(10) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
6310.
(11) (a) Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.;
Kann, N. Chem.Commun. 2007, 3183. (b) Satoh, N.; Akiba, T.;
Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734.
(c) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron
2009, 65, 3239. (d) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.;
Cheng, Y.-S. E.; Yang, A.-S.; Hsiao, S.-C.; Su, C.-Y.; Wong, C.-H. J.
Am. Chem. Soc. 2007, 129, 11892. (e) Kipassa, N. T.; Okamura, H.;
Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008, 10, 815−816.
(f) Trost, B. M.; Zhang, T. Angew. Chem., Int. Ed. 2008, 47, 3759.
(g) Zutter, U.; Iding, H.; Spurr, P.; Wirz, B. J. Org. Chem. 2008, 73,
4895. (h) Shie, J.-J.; Fang, J.-M.; Wong, C.-H. Angew. Chem., Int. Ed.
2008, 47, 5788. (i) Matveenko, M.; Willis, A. C.; Banwell, M. G.
Tetrahedron Lett. 2008, 49, 7018. (j) Ishikawa, H.; Suzuki, T.; Hayashi,
Y. Angew. Chem., Int. Ed. 2009, 48, 1304. (k) Ishikawa, H.; Suzuki, T.;
Orita, H.; Uchimaru, T.; Hayashi, Y. Chem.Eur. J. 2010, 16, 12616.
(l) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49,
4656. (m) Sullivan, B.; Carrera, I.; Drouin, M.; Hudlicky, T. Angew.
Chem., Int. Ed. 2009, 48, 4229. (n) Werner, L.; Machara, A.; Hudlicky,
T. Adv. Synth. Catal. 2010, 352, 195. (o) Mandai, T.; Oshitari, T.
Synthesis 2009, 783. (p) Oshitari, T.; Mandai, T. Synlett 2009, 787.
(q) Sun, H.; Lin, Y.-J.; Wu, Y.-L.; Wu, Y. Synlett 2009, 2473. (r) Osato,
H.; Jones, I. L.; Chen, A.; Chai, C. L. L. Org. Lett. 2010, 12, 60.
(s) Wichienukul, P.; Akkarasamiyo, S.; Kongkathip, N.; Kongkathip, B.
Tetrahedron Lett. 2010, 51, 3208. (t) Ma, J.; Zhao, Y.; Ng, S.; Zhang, J.;
Zeng, J.; Than, A.; Chen, P.; Liu, X.-W. Chem.Eur. J. 2010, 16, 4533.
(u) Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.;
(23) (a) Ando, K. J. Org. Chem. 1999, 64, 8406. (b) Ando, K.; Oishi,
T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745.
(24) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(25) Izquierdo, J.; Rodriguez, S.; Gonzalez, F. V. Org. Lett. 2011, 13,
3856.
H
dx.doi.org/10.1021/jo400360j | J. Org. Chem. XXXX, XXX, XXX−XXX