Synthesis of optically active, unnatural α-substituted glutamic acid derivatives by a chiral calcium-catalyzed 1,4-addition reaction

Article abstract of DOI:10.1016/j.tetasy.2010.03.004

The first catalytic asymmetric 1,4-addition reactions of azlactones with acrylic esters have been developed. A chiral coordinative calcium catalyst was found to be effective for these reactions, and the desired 1,4-adducts were obtained in good yields and enantioselectivities. The product was converted to the corresponding α-alkylated glutamic acid by acid hydrolysis.

Full text of DOI:10.1016/j.tetasy.2010.03.004

Tetrahedron: Asymmetry 21 (2010) 1221–1225
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of optically active, unnatural
a-substituted glutamic acid
derivatives by a chiral calcium-catalyzed 1,4-addition reaction
*
ꢀ
Tetsu Tsubogo, Yuichiro Kano, Koki Ikemoto, Yasuhiro Yamashita, Shu Kobayashi
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science and
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first catalytic asymmetric 1,4-addition reactions of azlactones with acrylic esters have been devel-
oped. A chiral coordinative calcium catalyst was found to be effective for these reactions, and the desired
1,4-adducts were obtained in good yields and enantioselectivities. The product was converted to the cor-
Received 18 January 2010
Accepted 3 March 2010
Available online 21 April 2010
responding
a-alkylated glutamic acid by acid hydrolysis.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
O
1. Introduction
∗
O
O
O
Ph
N
OtBu
R3
Chiral Ca Catalysts
Ph
N
∗
+
OtBu R2
OR4
R1
∗
R2
a,a-Disubstituted amino acids have been recognized as interest-
R1
R3
ing components in both bioorganic and medicinal chemistry1 be-
cause these unnatural amino acids can modify the structures of
peptides or proteins in an unusual manner. However, the asymmet-
ric synthesis of these amino acids has not been established because
it is difficult to prepare stereogenic carbon centers with high enan-
tiomeric purity. The catalytic enantioselective synthesis of these
R4O
O
O
O
O
N
R"
R"
N
N
N
Ca
OR
Ca
OR
R'
R'
a
,
a
-disubstituted amino acids is recognized as a particularly chal-
Scheme 1. Synthesis of substituted glutamic acid derivatives using chiral calcium
catalysts.
lenging research topic. Although some methods for the synthesis
of optically active a,a-disubstituted amino acids have been investi-
gated over the last decade,2 more versatile methodologies are de-
sired. For this purpose, azlactones are attractive enolate
ity and selectivity were attained. Furthermore, we have also re-
ported that a new type of chiral calcium catalyst,6 which is
prepared using a combination of a calcium Brønsted base and a
chiral coordinative ligand, pyridinebisoxazoline (pybox),7 can be
successfully used in asymmetric carbon–carbon bond-forming
reactions with good to high enantioselectivities (ees). The new chi-
ral calcium catalyst system possesses significant potential because
several kinds of chiral neutral coordinative ligands are applicable
for the preparation of the chiral catalysts. Therefore, in our efforts
to expand upon chiral calcium chemistry, we used chiral calcium
catalyst systems for the asymmetric 1,4-addition of azlactones to
equivalents of
-protons. Although some enantioselective carbon–carbon bond-
forming reactions involving the use of azlactones have recently been
reported,3 their enantioselective 1,4-addition reaction with
,b-
unsaturated esters has not. This reaction could provide a practical
method for the synthesis of optically active -substituted glutamic
a-amino acids due to the high acidity of their active
a
a
a
acid derivatives4 by using a catalytic amount of chiral Brønsted base.
The group 2 alkaline earth metals, calcium, strontium, and bar-
ium, are of great interest because of their abundance and specific
properties such as low electronegativity and various coordination
sites. The use of alkaline earth metals in organic synthesis,5 espe-
cially as catalysts, is also beneficial from an environmental view-
point. Recently we developed chiral calcium (Box-Ca4c–e) and
acrylates, which provide optically active
a-substituted glutamic
acid derivatives with stereogenic carbon centers.
chiral strontium (sulfonamide-Sr5f–i
bond-forming reactions, which included the synthesis of optically
active glutamic acid derivatives (Scheme 1), in which high reactiv-
) catalyzed carbon–carbon
2. Results and discussion
We investigated the asymmetric 1,4-addition reaction of azlac-
tone 2a prepared from alanine with methyl acrylate 3a using chiral
alkaline earth metal catalysts. In the initial catalyst screening for
the reaction in THF, calcium, strontium, and barium alkoxides with
* Corresponding author. Tel.: +81 3 5841 4790; fax: +81 3 5684 0634.
E-mail address: shu_kobayashi@chem.s.u-tokyo.ac.jp (S. Kobayashi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.004

1222
T. Tsubogo et al. / Tetrahedron: Asymmetry 21 (2010) 1221–1225
chiral anionic ligands were employed. However, promising enanti-
oselectivity (ee) was not obtained. On the other hand, a chiral cal-
cium complex with a neutral coordinative ligand, pybox, was
found to be effective and low but significant selectivity was ob-
served when pybox 1a (R1 = iPr, Scheme 2) was used as a ligand
(Table 1, entry 1). The catalyst was prepared in THF at room tem-
perature (rt), and the solvent THF was removed under reduced
pressure to afford an active calcium complex. After considering
the effects of solvents, toluene showed the most promising results:
53% yield and 59% ee were obtained (entry 4). Other alkaline earth
metals were also investigated but it was the calcium complex that
showed the highest ee (entries 4–6). The reaction at lower temper-
ature proceeded smoothly to afford the product in moderate yield
with 76% ee (entry 7). In an effort to further improve the ee, we
optimized the conditions for the catalyst preparation. We subse-
quently found that the catalyst prepared in toluene at 50 °C gave
better yield and the same ee (entry 8). Ligand structure, especially
with regard to the substituents on the two oxazoline rings, was
then optimized (entries 9–12). Ligands with Me substituents at
the 4,40-positions gave higher selectivities and over 80% ee was ob-
served (pybox 1b–d). During optimization, it was found that the
low stability of the product obtained under acidic conditions at
the work-up stage sometimes led to low isolated yield. Procedures
for quenching the reaction and purification of the product were
therefore reoptimized. Isolated yields were improved by quench-
ing the reaction with brine and purification without any aqueous
work-up (entries 9–12).
We then investigated the substrate scope of the asymmetric
1,4-addition reaction under the optimized reaction conditions.
First, several acrylates were examined in the reaction of 2a (Table 2,
entries 2–4). When ethyl acrylate 3b was employed, the ee was
almost the same as that of the reaction with methyl acrylate 3a
(entry 2). While low yield and ee were obtained in the reaction
of tert-butyl acrylate 3c (entry 3), the reaction of benzyl acrylate
3d gave good yield with similarly good ee to that of the reaction
of 3a (entry 4). These results indicated that the steric bulkiness
of the ester part could affect the ee of the chiral calcium–azlactone
complex. Next, the effect of the R1 group on the azlactone structure
was examined. The azlactones bearing straight alkyl chains, Et (2b)
and nPr (2c), gave slightly lower ees (entries 5 and 6). Benzyl azlac-
tone 2d also gave lower ee (entry 7), but the azlactone with a
branched alkyl chain 2e (iBu) reacted with 3a to afford the product
with high ee (84% ee, entry 8).
A proposed reaction mechanism of the calcium-catalyzed asym-
metric 1,4-addition reaction using azlactone is shown in Figure 1.
The chiral calcium complex deprotonated the
a-position of the
azlactone 2 to afford a chiral calcium enolate 5. The enolate was
then reacted with an acrylic ester 3 with good enantioselection to
afford the 1,4-additon product, initially as the calcium enolate form
6. The enolate 5 was protonated by azlactone 2 to afford product 4,
along with regeneration of the reactive calcium enolate 5 (pathway
1). Alternatively, the free alcohol (iPrOH) reacted with 6 to afford
the product 4 and the active calcium complex (pathway 2).
Conversion of the product was examined (Scheme 3).8 Ring-
opening of the azlactone and cleavage of the benzoyl group
occurred simultaneously by acidic hydrolysis to afford the
corresponding
a-methyl glutamic acid hydrochloride salt in high
yield. The HCl-free form of the product was obtained by treatment
with propylene oxide in ethanol. The absolute configuration of
the product was determined to be the (S)-form by making a
comparison of the specific rotation of the compound.9
R2
R2
R2
R2
O
O
O
O
N
N
N
N
N
N
R1
R1
Me
Me
1c: R2 = Me
1d: R2 = Et
1a: R1 = iPr
1b: R1 = Me
O
O
O
O
Scheme 2. Pyboxes.
1. 1 M HCl, reflux
2. , EtOH
MeO
O
HO
OH
O
N
NH2
4aa
7aa
Ph
Table 1
Optimization of the reaction conditionsa
2 steps, 99% yield
O
O
M(OiPr)2 (10 mol%)
Pybox (10 mol%)
O
Scheme 3. Conversion of the product.
O
O
MeO
O
+
Table 2
Conditions, 24 h, 0.2 M
MS 4A
OMe
3a, 1.2 eq
N
N
Substrate scopea
2a Ph
4aa
Ph
O
O
Ca(OiPr)2 (10 mol%)
O
O
R1
Entry
M
Pybox
Conditions
Yield (%)
ee (%)
R1
Pybox (10 mol%)
Tol, −20°C, 24 h,
0.2 M, MS 4A
O
R2O
O
+
1
2
3
Ca
Ca
Ca
Ca
Sr
Ba
Ca
Ca
Ca
Ca
Ca
Ca
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
0 °C, THF
0 °C, Et2O
0 °C, DCM
0 °C, Tol
0 °C, Tol
0 °C, Tol
ꢀ20 °C, Tol
ꢀ20 °C, Tol
ꢀ20 °C, Tol
–20 °C, Tol
–20 °C, Tol
–20 °C, Tol
28
23
22
53
34
22
65
79
86
78
70
78
40
50
12
59
11
0
76
76
80
80
80
81
*
OR2
3, 1.2 eq
N
2
N
4
Ph
R1
Ph
4
Entry
R2
Pybox
Product
Yield (%)
ee (%)
5
6b
1
2
3
4
Me
Me
Me
Me
Et
Me
Et
1d
1d
1b
1b
1d
1b
1b
1b
4aa
4ab
4ac
4ad
4ba
4ca
4da
4ea
78
81
52
80
77
92
75
78
81
81
69
78
71
76
64
84
7
tBu
Bn
8c
9c,d
10c,e
11c,d
12c,d
5
Me
Me
Me
Me
6b
7b,c
8
nPr
Bn
iBu
a
The 1,4-addition reaction of 2a (0.30 mmol) with 3a (0.36 mmol) was per-
a
The 1,4-addition reaction of 2 (0.30 mmol) with 3 (0.36 mmol) was performed
formed using metal alkoxide (10 mol %) and pybox (10 mol %) for 24 h in 0.2 M in
the presence of molecular sieves 4 Å (100 mg) unless otherwise noted.
using Ca(OiPr)2 (10 mol %) and pybox 1 (10 mol %) for 24 h in 0.2 M in the presence
of molecular sieves 4 Å (100 mg) unless otherwise noted. Brine was used for
quenching the reaction. The products’ absolute configuration was tentatively
assigned in analogy to compound 4aa.
b
The reaction was performed for 0.5 h.
The catalyst was prepared by heating in toluene (50 °C, 2 h), and the catalyst
c
solution was used in reactions without removal of the solvent.
b
d
The reaction mixture was purified by silica gel column chromatography,
Brine was used for quenching the reaction.
The reaction mixture was purified by silica gel column chromatography,
e
without any aqueous work-up.
c
The reaction was performed in 0.1 M.
without any aqueous work-up.

T. Tsubogo et al. / Tetrahedron: Asymmetry 21 (2010) 1221–1225
1223
O
*
R1
O
N
O
R1
O
N
N
R2O
O
N
Ca
RO OR
*
*
Ph
N
N
2
5
Ph
4
N
N
Ca
O
*
N
O
OR
ROH
5
Pathway 2
N
N
R1
Ca
6
O
OR
N
*
N
R1
Ph
O
N
N
Ca
N
Pathway 1
Ph
O
RO
O
R1
O
R2O
O
R1
*
O
N
N
Ph
O
Ph
2
OR2
3
Figure 1. Proposed catalytic cycle.
3. Conclusion
a
b
d
We have developed the first catalytic enantioselective 1,4-addi-
tion reaction of azlactones to acrylic esters for the synthesis of chi-
HO
OH
MeO
OMe
N
N
N
N
O
O
O
O
O
ral
a-substituted glutamic acid derivatives. A chiral coordinative
calcium catalyst was found to be effective, and good yields and
enantioselectivities were obtained. The product obtained was eas-
ily converted to the a-substituted glutamic acid in high yield. Fur-
ther improvement of the catalyst system is currently in progress.
c
H2N
NH2
NC
CN
O
4. Experimental
4.1. General
e
O
O
R
R
R
N
MeO
OMe
NH
N
R
N
N
NH
Me
Me
1H and 13C NMR spectra were recorded on a JEOL ECX-400, ECA-
500, and ECX-600 spectrometers in CDCl3 unless otherwise noted.
Tetramethylsilane (TMS) served as the internal standard (d = 0) for
1H NMR, and CDCl3 was used as the internal standard (d = 77.0) for
13C NMR. IR spectra were measured with a JASCO FT/IR-610 spec-
trometer. Optical rotations were measured with a JASCO P-1010.
High-resolution mass spectrometry was carried out using a JEOL
JMS-T100TD (AccuTOF TLC). High-performance liquid chromatogra-
phy was carried out using the following apparatus: SHIMAZU LC-8A,
LC-10ATvp, LC-20AB (liquid chromatograph); SHIMAZU SPD-10A
(UV detector); SHIMADZU SPD-20A (UV/vis detector); SHIMA-
ZUSPD-M20A (diode array detector); and SHIMADZU C-R8A
(Chromatopac). SiO2 (Iatrobeads 6RS-8060) was purchased from
Mitsubishi Kagaku Iatoron, Inc. Calcium bis-iso-propoxide
(Ca(OiPr)2) was purchased from Kojundo Chemical Laboratory Co.,
Ltd. Azlactones 2 were prepared according to literature methods.3l
Acrylic acid esters were purchased from Tokyo Chemical Industry
Co., Ltd and were distilled prior to use. Amino alcohols were pre-
pared according to reported procedures.10 Molecular sieves 4 Å
(powder) were purchased from Aldrich Co., Ltd and activated
(200 °C, 1 mm Hg, six days) prior to use. THF was purchased from
Wako Junyaku Kogyo Co., Ltd as a dry solvent and distilled in the
presence of benzophenone and sodium. Toluene was purchased
from Wako Junyaku Kogyo Co., Ltd as a dry solvent and was used
without further purification. SiO2 (Silica Gel 60 N, spherical, neutral,
63–210 mm) was purchased from Kanto Chemical. Co., Inc.
Scheme 4. Synthesis of pyboxes. Reagents and conditions: (a) acetone dimethyl
acetal, concd HCl, MeOH, 100 °C, 4 h, 73%; (b) NH3 (aq), MeOH, rt, overnight, 85%;
(c) DBU, diphenyl phosphorochloride, DCM, 40 °C, 4 h, 64%; (d) Na, MeOH, rt, 36 h,
quant; (e) amino alcohol, DCM, reflux, four days, 1c: 58%, 1d: 80%.
4.2.1. Synthesis of imidate
First we synthesized dimethyl pyridine-2,6-bis(carbimidate)
using modified literature methods.11–14
4.2.1.1. Dimethyl pyridine-2,6-dicarboxylate.
Pyridine-2,6-
dicarboxylic acid (299 mmol, 50.0 g), acetone dimethyl acetal
(400 mL), and methyl alcohol (800 mL) were combined in a one-
necked flask (1 L). Concd HCl (33 mL) was added and the mixture
was heated to 100 °C for 4 h. The solution was then cooled to room
temperature and stirred overnight. A white solid was collected,
washed with methyl alcohol and ether, and dried under reduced
pressure to afford the desired product (42.5 g, 73%).12 1H NMR
(CDCl3) d: 8.29–8.28 (m, 2H), 8.01–7.99 (m, 1H), 3.99 (s, 6H). 13C
NMR (CDCl3) d: 165.0, 148.1, 138.4, 128.0, 53.2.
4.2.1.2. Pyridine-2,6-dicarboxamide.
A
1-L flask was
charged with dimethyl pyridine-2,6-dicarboxylate (218 mmol,
42.5 g). Aqueous NH3 (28%, 500 mL) and methanol (700 mL) were
added and the mixture was stirred overnight. A white solid was
collected, washed with ether, and dried under reduced pressure
to afford the desired product (30.6 g, 85%).13 1H NMR (DMSO-d6)
d: 8.26–8.25 (m, 2H), 8.20–8.17 (m, 1H), 3.91 (s, 4H). 13C NMR
(DMSO-d6) d: 164.6, 147.6, 139.3, 128.0.
4.2. Synthesis of pyboxes
4.2.1.3. Pyridine-2,6-dicarbonitrile.
amide (20 mmol, 3.3 g), DBU (120 mmol, 18.3 mL), and DCM
Pyridine-2,6-dicarbox-
Pyridinebisoxazolines (pyboxes) were synthesized according to
methods described in the literature7,10–14 (Scheme 4).

1224
T. Tsubogo et al. / Tetrahedron: Asymmetry 21 (2010) 1221–1225
(100 mL) were combined in a flame-dried three-necked flask fitted
with a reflux condenser, dripping funnel, and rubber septum. The
mixture was stirred at room temperature. After 10 min, diphenyl
phosphorochloride (80 mmol, 16.9 mL) was slowly added and the
mixture was heated to 40 °C. After 3 h, the reaction was quenched
with sat. NH4Cl (50 mL) and the organic layer was separated. The
aqueous layer was extracted with DCM (50 mL ꢁ 3). The organic
layers were combined and washed with sat. NaHCO3 (50 mL ꢁ 4)
until diphenyl phosphorochloride was removed, and finally
washed with water (50 mL). The solvent was evaporated under re-
duced pressure, and the crude product was recrystallized from
ethyl alcohol to afford the desired product (1.7 g, 64%).14 1H NMR
(CDCl3) d: 8.07–8.05 (m, 1H), 7.92–7.91 (m, 2H). 13C NMR (CDCl3)
d: 138.9, 135.2, 131.1, 115.4.
DCM (15 mL ꢁ 2). The organic layers were combined and dried
over anhydrous Na2SO4. After filtration and concentration under
reduced pressure, the crude product was purified by short column
chromatography (Iatrobead 6RS-8060 = 5.0 g, hex/EtOAc = 3/1) to
afford the desired product.
4.4. Conversion of the product
Methyl 3-(4,5-dihydro-4-methyl-5-oxo-2-phenyloxazol-4-yl)-
propanoate 4aa (0.19 mmol, 49.8 mg) and HCl solution (1 M,
10 mL) were refluxed for 12 h. After concentration of the reaction
mixture, the crude product was washed with EtOAc (10 mL ꢁ 3).
The combined aqueous layer was evaporated under reduced pres-
sure. The crude mixture was dissolved in ethanol (10 mL), refluxed
with propylene oxide (5 mL) for 30 min, and then cooled to room
temperature. The white precipitate was filtered, washed with
EtOAc, (10 mL) and dried under reduced pressure. (S)-2-Methylglu-
tamic acid (7aa, 30.7 mg, 99%) was obtained as a white solid.8 (S)-
2-Methylglutamic acid: 1H NMR (D2O) d: 2.13–2.06 (m, 2H), 1.89–
1.82 (m, 2H), 1.30 (s, 3H). 13C NMR (D2O) d: 199.7, 177.2, 61.5, 33.9,
4.2.1.4. Dimethyl pyridine-2,6-bis(carbimidate).
Pyridine-
2,6-dicarbonitrile (15.5 mmol, 2.0 g), methyl alcohol (50 mL), and
sodium metal (2.3 mmol, 53.0 mg, washed with hexane) were
combined and the mixture was stirred at room temperature. After
36 h, acetic acid (2.3 mmol, 0.13 mL) was added to quench the
reaction, and the solvent was evaporated under reduced pressure.
The solid was dried in vacuo and used without further purification.
The crude yield was quantitative.11 1H NMR (CDCl3) d: 9.16 (s, 2H),
7.85 (s, 3H), 3.96 (s, 6H). 13C NMR (CDCl3) d: 165.9, 146.8, 138.9,
122.5, 54.0.
32.9, 23.0. ½a 2D1
ꢂ
¼ ꢀ4:7 (c 0.19, H2O, 80% ee). {lit.9a
½
a 2D0
ꢂ
¼ þ10 (c
0.19, H2O, (R)-isomer)}, ½a D15
ꢂ
¼ þ3:0 (c 2.0, 6 M HCl, 81% ee); lit.9
4.5. Compound data
4.5.1. (S)-Methyl 3-(4,5-dihydro-4-methyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4aa
4.2.2. Synthesis of pyboxes7e
4.2.2.1. 2,6-Bis((S)-5,5-dimethyl-4-methyl-4,5-dihydrooxazol-
IR (cmꢀ1) 1822, 1738, 1655, 1004. 1H NMR (CDCl3) d: 7.92–7.90
(m, 2H), 7.52–7.40 (m, 1H), 7.42 (m, 2H), 3.55 (s, 3H), 2.28–2.14 (m,
4H), 1.47(s, 3H). 13C NMR (CDCl3) d: 180.3, 172.6, 160.3, 132.8,
128.8, 127.9, 125.6, 68.5, 51.8, 32.9, 28.9, 23.6. HPLC Daicel Chiral-
cel OD-H, hexane/iPrOH = 9/1, flow rate = 0.5 mL/min, detection
wavelength = 254 nm, tR = 11.8 min (minor), tR = 14.0 min (major).
DART-HRMS (m/z) calcd for C14H16NO4 ((M+H)+): 262.1079; found:
2-yl)pyridine 1c.
Dimethyl pyridine-2,6-bis(carbimidate)
(0.42 mmol, 80.2 mg) and (S)-3-amino-2-methylbutane-2-ol
(0.83 mmol, 85.3 mg) in DCM (10 mL) were heated to 45 °C, with
stirring, for four days. The reaction mixture was concentrated un-
der reduced pressure, and the crude product was purified by col-
umn chromatography (EtOAc only). The desired product was
obtained (1c, 71.9 mg, 58%) as a yellow solid. IR (cmꢀ1) 1635,
1573, 1076. 1H NMR (CDCl3) d: 7.99–7.97 (m, 2H), 7.77–7.74 (m,
1H), 3.94 (q, 2H, J = 6.9 Hz), 1.44 (s, 6H), 1.31 (s, 6H), 1.21 (s, 6H).
13C NMR (CDCl3) d: 160.9, 147.6, 137.0, 125.3, 87.4, 69.9, 28.3,
21.7, 16.4. DART–HRMS (m/z) calcd for C17H24N3O2 ((M+H)+):
262.1073. ½a 2D5
¼ þ1:4 (c 0.98, CHCl3, 80% ee).
ꢂ
4.5.2. (S)-Ethyl 3-(4,5-dihydro-4-methyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4ab
IR (cmꢀ1) 1822, 1736, 1656, 1005. 1H NMR (CDCl3) d: 7.93–7.90
(m, 2H), 7.52–7.40 (m, 3H), 4.00 (q, 2H, J = 3.2 Hz), 2.24–2.14 (m,
4H), 1.48 (s, 3H), 1.23–1.09 (m, 3H). 13C NMR (CDCl3) d: 180.3,
172.1, 160.2, 132.8, 128.8, 127.9, 125.6, 68.5, 60.6, 33.0, 29.1,
23.7, 14.0. HPLC Daicel Chiralcel OD-H, hexane/iPrOH = 9/1, flow
rate = 0.5 mL/min, detection wavelength = 254 nm, tR = 11.3 min
(minor), tR = 13.8 min (major). DART-HRMS (m/z) calcd for
302.1869; found: 302.1876. ½a D25
¼ ꢀ38:6 (c 0.5, CHCl3).
ꢂ
4.2.2.2. 2,6-Bis((S)-5,5-diethyl-4-methyl-4,5-dihydrooxazol-2-yl)-
pyridine 1d. Dimethyl pyridine-2,6-bis(carbimidate) (2.1 mmol,
395 mg) and (S)-2-amino-3-ethylpentan-3-ol (4.1 mmol, 537 mg) in
DCM (20 mL) were heated to 45 °C, with stirring, for four days. The
reaction mixture was concentrated under reduced pressure, and the
crude product was purified by column chromatography (SiO2, EtOAc
only). The desired product was obtained (1d, 583 mg, 80%) as a yellow
solid. IR (cmꢀ1) 1653, 1574, 1085. 1H NMR (CDCl3) d: 8.00–7.99 (m,
2H), 7.81–7.78 (m, 1H), 4.11 (q, 2H, J = 7.0 Hz), 1.87–1.59 (m, 8H),
1.30 (d, 6H, J = 6.8 Hz), 1.03 (t, 6H, J = 7.37 Hz), 0.89 (t, 6H,
J = 7.37 Hz). 13C NMR (CDCl3) d: 160.6, 147.2, 137.2, 125.0, 92.0, 67.9,
29.6, 24.6, 16.4, 8.3, 7.5. DART-HRMS (m/z) calcd for C21H32N3O2
C
15H18NO4 ((M+H)+): 276.1236; found: 276.1245. ½a 2D7
¼ ꢀ2:4 (c
ꢂ
1.0, CHCl3, 81% ee).
4.5.3. (S)-tert-Butyl 3-(4,5-dihydro-4-methyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4ac
IR (cmꢀ1) 1825, 1733, 1651, 1092. 1H NMR (CDCl3) d: 8.00–7.99
(m, 2H), 7.59–7.47 (m, 3H), 2.23–2.19 (m, 4H), 1.54 (s, 3H), 1.40 (s,
9H). 13C NMR (CDCl3) d: 180.4, 171.3, 160.1, 132.8, 128.7, 127.9,
125.7, 80.7, 68.5, 33.0, 30.2, 27.9, 23.7. HPLC Daicel Chiralpak
AD-H, hexane/iPrOH = 9/1, flow rate = 0.5 mL/min, detection wave-
length = 254 nm, tR = 19.1 min (major), tR = 22.8 min (minor).
DART-HRMS (m/z) calcd for C17H22NO4 ((M+H)+): 304.1549; found:
((M+H)+): 358.2495; found: 358.2490. ½a 2D5
¼ ꢀ38:6 (c 0.5, CHCl3).
ꢂ
4.3. Typical experimental procedure
At first, Ca(OiPr)2 (0.030 mmol), pybox 1d (0.030 mmol), and MS
4 Å (100 mg) were added to a flame-dried flask (30 mL) in an ar-
gon-filled glove box. Toluene (0.5 mL) was then added and the
mixture was stirred for 2 h at 50 °C. After cooling to ꢀ20 °C, azla-
cone 2a (0.30 mmol) in toluene (1.0 mL) and acrylate 3a
(0.36 mmol) were added successively. The mixture was stirred
for 24 h at ꢀ20 °C and then brine (10 mL) was added to quench
the reaction. After the addition of DCM (10 mL), the organic layer
was separated, and the aqueous layer was extracted twice with
304.1557. ½a 2D8
¼ ꢀ8:1 (c 0.5, CHCl3, 69% ee).
ꢂ
4.5.4. (S)-Benzyl 3-(4,5-dihydro-4-methyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4ad
IR (cmꢀ1) 2367, 1822, 1734, 1658, 1093. 1H NMR (CDCl3) d:
7.98–7.97 (m, 2H), 7.59–7.46 (m, 3H), 7.38–7.26 (m, 5H), 5.06
(dd, 2H, J = 22.8, 12.4 Hz), 2.43–2.22 (m, 4H), 1.54 (s, 3H). 13C
NMR (CDCl3) d: 180.2, 171.9, 160.2, 135.5, 132.8, 128.8, 128.5,
128.3, 128.2, 126.9, 125.6, 68.5, 66.5, 32.9, 29.1, 23.6. HPLC Daicel

T. Tsubogo et al. / Tetrahedron: Asymmetry 21 (2010) 1221–1225
1225
Chiralcel OD-H, hexane/iPrOH = 9/1, flow rate = 0.5 mL/min, detec-
R. Mol. Pharmacol. 1997, 51, 809; (c) Jullian, N.; Brabet, I.; Pin, J.-P.; Acher, F. C. J.
Med. Chem. 1999, 42, 1546.
2. Synthesis of a,a-disubstituted quaternary amino acid derivatives: (a) Maruoka,
tion wavelength = 254 nm, tR = 16.2 min (minor), tR = 19.8 min
(major). DART-HRMS (m/z) calcd for
C
20H20NO4 ((M+H)+):
K.; Ooi, T. Chem. Rev. 2003, 103, 3013; (b) O’Donnell, M. J. Acc. Chem. Res. 2004,
37, 506; (c) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127; (d) Nájera, C.;
Sansano, J. M. Chem. Rev. 2007, 107, 4584; (e) Hashimoto, T.; Maruoka, K. Chem.
Rev. 2007, 107, 5656; (f) Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406; (g)
Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008, 3427.
338.1392; found: 338.1386. ½a D26
¼ ꢀ3:9 (c 1.0, CHCl3, 78% ee).
ꢂ
4.5.5. (S)-Methyl 3-(4,5-dihydro-4-ethyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4ba
3. Selected examples of catalytic asymmetric reactions using azlactones. Dynamic
kinetic resolution: (a) Seebach, D.; Jaeschke, G.; Gottwald, K.; Matsuda, K.;
Formisano, R.; Chaplin, D. A. Tetrahedron 1997, 53, 7539; (b) Liang, J.; Ruble, J.
C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154; (c) Berkessel, A.; Cleemann, F.;
Mukherjee, S.; Müller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005, 44, 807; Carboxy
group transfer: (d) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532; (e)
Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368; (f)
Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006, 8, 769; (g)
Joannesse, C.; Johnston, C. P.; Concellón, C.; Simal, C.; Philp, D.; Smith, A. D.
Angew. Chem., Int. Ed. 2009, 48, 8914; 1,4-Addition reaction: (h) Alemán, J.;
Milelli, A.; Cabrera, S.; Reyes, E.; Jørgensen, K. A. Chem. Eur. J. 2008, 14, 10958;
(i) Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326, 120; Other reactions: (j)
Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. 1997, 36, 2635; (k) Trost, B. M.;
Jäkel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438; (l) Melhado, A. D.;
Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638; (m) Cabrera, S.;
Reyes, E.; Alemán, J.; Milelli, A.; Kobbelgaard, S.; Jørgen, K. A. J. Am. Chem. Soc.
2008, 130, 12031; (n) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa, H.
Chem. Asian J. 2009, 4, 246; (o) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc.
2008, 130, 14088; (p) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430; (q) Jiang, J.; Qing, J.; Gong, L.-Z. Chem. Eur. J. 2009, 15, 7031; (r)
Uraguchi, D.; Asai, Y.; Ooi, T. Angew. Chem., Int. Ed. 2009, 48, 733.
IR (cmꢀ1) 1820, 1738, 1656, 1100. 1H NMR (CDCl3) d: 7.99–7.97
(m, 2H), 7.79–7.42 (m, 3H), 3.58 (s, 3H), 2.30–1.92 (m, 4H), 1.27 (q,
2H, J = 3.5 Hz), 0.96–0.82 (m, 3H). 13C NMR (CDCl3) d: 179.9, 172.6,
160.5, 132.8, 128.8, 127.9, 126.8, 73.0, 51.7, 31.9, 30.4, 28.9, 8.02.
HPLC Daicel Chiralcel OD-H, hexane/iPrOH = 9/1, flow
rate = 0.5 mL/min, detection wavelength = 254 nm, tR = 11.7 min
(minor), tR = 13.3 min (major). DART-HRMS (m/z) calcd for
C
15H18NO4 ((M+H)+): 276.1236; found: 276.1233. ½a 2D5
¼ ꢀ2:9 (c
ꢂ
1.0, CHCl3, 70% ee).
4.5.6. (S)-Methyl 3-(4,5-dihydro-4-nor-propyl-5-oxo-2-phenyl-
oxazol-4-yl)propanoate 4ca
IR (cmꢀ1) 1815, 1739, 1655, 1102. 1H NMR (CDCl3) d: 7.93–7.91
(m, 2H), 7.54–7.41 (m, 3H), 3.54 (s, 3H), 2.27–2.14 (m, 4H), 1.84–
1.79 (m, 2H), 1.24–1.11 (m, 2H), 0.94–0.81 (m, 3H). 13C NMR
(CDCl3) d: 180.0, 172.6, 160.4, 132.8, 128.8, 127.9, 126.8, 72.5,
51.7, 39.3, 32.3, 28.8, 17.1, 13.8. HPLC Daicel Chiralpak IA, hex-
ane/iPrOH = 150/1, flow rate = 0.5 mL/min, detection wave-
length = 254 nm, tR = 28.8 min (major), tR = 36.3 min (minor).
DART-HRMS (m/z) calcd for C16H20NO4 ((M+H)+): 290.1392; found:
4. Examples of 2-methyl glutamic acid derivatives. Catalytic asymmetric reaction:
(a) Kano, T.; Kumano, T.; Maruoka, K. Org. Lett. 2009, 11, 2023;
Diastereoselective reaction: (b) Chinchilla, R.; Falvello, L. R.; Galindo, N.;
Nájera, C. Angew. Chem., Int. Ed. 1997, 36, 995; Synthesis of glutamic acid
derivatives using our catalysts: (c) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am.
Chem. Soc. 2007, 129, 5364; (d) Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita,
Y. Org. Lett. 2008, 10, 807; (e) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.
290.1398. ½a 2D4
¼ ꢀ2:7 (c 0.99, CHCl3, 76% ee).
ꢂ
5. Examples of catalytic asymmetric reaction using alkaline earth metal catalysts.
Ba: (a) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561; (b)
Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704; (c) Yamaguchi, A.;
Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387; (d)
Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew.
Chem., Int. Ed. 2009, 48, 1070; (e) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2009, 131, 10842; Sr: (f) Agostinho, M.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 2430; (g) Kobayashi, S.; Yamaguchi, M.; Agostinho, M.;
Schneider, U. Chem. Lett. 2009, 38, 296; (h) Nguyen, H. V.; Matsubara, R.;
Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 5927; (i) Matsubara, R.; Florian, B.;
Nguyen, H. V.; Kobayashi, S. Bull. Chem. Soc. Jpn. 2009, 82, 1083; Ca: (j) Yamada,
Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165; (k) Suzuki, T.; Yamagiwa,
N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R.
Tetrahedron Lett. 2001, 42, 4669; (l) Kumaraswamy, G.; Sastry, M. N. V.; Jena,
N. Tetrahedron Lett. 2001, 42, 8515; (m) Kumaraswamy, G.; Sastry, M. N. V.;
Jena, N.; Kumar, K. R.; Vairamani, M. Tetrahedron: Asymmetry 2003, 14, 3797;
(n) Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B.
Adv. Synth. Catal. 2005, 347, 867; (o) Kumaraswamy, G.; Jena, N.; Sastry, M. N.
V.; Ramakrishna, G. ARKIVOC 2005, 53.
4.5.7. (S)-Methyl 3-(4,5-dihydro-4-benzyl-5-oxo-2-phenyloxazol-4-
yl)propanoate 4da
IR (cmꢀ1) 2360, 1816, 1738, 1654, 1101. 1H NMR (CDCl3) d:
7.77–7.74 (m, 2H), 7.45–7.32 (m, 3H), 7.09–7.08 (m, 5H), 3.52 (s,
3H), 3.11 (q, 2H, J = 13.3 Hz), 2.33–2.2 (m, 4H). 13C NMR (CDCl3)
d: 179.1, 172.5, 160.3, 133.8, 132.7, 130.1, 128.7, 128.5, 128.1,
127.3, 125.4, 73.8, 51.8, 43.5, 32.1, 29.0. HPLC Daicel Chiralpak
AD-H, hexane/iPrOH = 9/1, flow rate = 0.5 mL/min, detection wave-
length = 254 nm, tR = 16.5 min (major), tR = 18.9 min (minor).
DART-HRMS (m/z) calcd for C17H22NO4 ((M+H)+): 338.1392; found:
338.1394. ½a 2D6
¼ ꢀ41:0 (c 1.0, CHCl3, 64% ee).
ꢂ
4.5.8. (S)-Methyl 3-(4,5-dihydro-4-iso-butyl-5-oxo-2-phenyloxazol-
4-yl)propanoate 4ea
6. Coordinative chiral calcium catalyzed reactions: (a) Tsubogo, T.; Yamashita,
Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 9117; (b) Poisson, T.; Tsubogo,
T.; Yamashita, Y.; Kobayashi, S. J. Org. Chem. 2010, 75, 963.
IR (cmꢀ1) 1813, 1739, 1652, 1095. 1H NMR (CDCl3) d: 7.98–7.96
(m, 2H), 7.58–7.34 (m, 3H) 3.58 (s, 3H), 2.49–2.46 (m, 1H), 2.29–
2.14 (m, 4H), 1.96–1.58 (m, 2H), 0.98–0.82 (m, 6H). 13C NMR
(CDCl3) d: 180.5, 172.5, 161.1, 132.8, 128.8, 127.9, 125.9, 72.0,
51.8, 46.0, 33.4, 28.4, 24.8, 24.0, 23.0. HPLC Daicel Chiralpak IA,
hexane/iPrOH = 100/1, flow rate = 0.5 mL/min, detection wave-
length = 254 nm, tR = 19.7 min (major), tR = 28.3 min (minor).
DART-HRMS (m/z) calcd for C17H22NO4 ((M+H)+): 304.1549; found:
7. For the synthesis of pybox: (a) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119; (b) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151; (c)
Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Organometallics 1991, 10, 500;
(d) Gupta, A. D.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50, 13725; (e)
Desimoni, G.; Faita, G.; Guala, M.; Pratelli, C. Tetrahedron: Asymmetry 2002, 13,
1651; (f) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Döbler, C.;
Spannenberg, A.; Mägerlein, W.; Hugl, H.; Beller, M. Chem. Eur. J. 2006, 12, 1855.
8. Transformation of azlactones: (a) Nájera, C.; Abellán, T.; Sansano, J. M. Eur. J.
Org. Chem. 2000, 2809; (b) Yamada, T.; Okada, T.; Sakaguchi, K.; Ohfune, Y.;
Ueki, H.; Soloshonok, V. A. Org. Lett. 2006, 8, 5625.
304.1540. ½a 2D5
¼ ꢀ11:4 (c 0.94, CHCl3, 84% ee).
ꢂ
9. Reported examples: (a) Obrecht, D.; Bohdal, U.; Daly, J.; Lehmann, C.;
Schönholzer, P.; Müller, K. Tetrahedron 1995, 51, 10883; (b) Chinchilla, R.;
Galindo, N.; Nájera, C. Synthesis 1999, 704; (c) Tang, G.; Tian, H.; Ma, D.
Tetrahedron 2004, 60, 10547.
10. Amino alcohols synthesis: Denmark, S. E.; Stavenger, R. A.; Faucher, A.-M.;
Edwards, J. P. J. Org. Chem. 1997, 62, 3375.
11. Müller, P.; Boléa, C. Helv. Chim. Acta 2001, 84, 1093.
12. Alcock, N. W.; Clarkson, G.; Glover, P. B.; Lawrance, G. A.; Moore, P.;
Napitupulu, M. Dalton Trans. 2005, 518.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), the University of Tokyo,
and MEXT (Japan). T.T. thanks the JSPS Research Fellowship for
Young Scientists.
13. 2,6-Pyridinedicarboxamide is commercially available.
14. Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.; Shia, K.-S. Chem.
Commun. 2007, 301.
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