Highly enantioselective monoalkylation of p-chlorobenzaldehyde imine of glycine tert-butyl ester under mild phase-transfer conditions

Article abstract of DOI:10.1016/j.tetasy.2006.01.019

The selective monoalkylation of glycine tert-butyl ester aldimine Schiff base 3 has been realized in high chemical yield with excellent enantioselectivity under mild liquid-liquid phase-transfer conditions by the use of binaphthyl-derived chiral quaternar

Full text of DOI:10.1016/j.tetasy.2006.01.019

Tetrahedron: Asymmetry 17 (2006) 603–606
Highly enantioselective monoalkylation of
p-chlorobenzaldehyde imine of glycine tert-butyl
ester under mild phase-transfer conditions
Takashi Ooi,a Yuichiro Arimura,a Yukihiro Hiraiwa,a Lin Ming Yuan,a Taichi Kano,a
Toru Inoue,b Jun Matsumotob and Keiji Maruokaa,*
aDepartment of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
bResearch and Development Center, Nagase & Co., Ltd, 2-2-3 Murotani, Nishi-ku, Kobe 651-2241, Japan
Received 22 November 2005; accepted 16 January 2006
Available online 28 February 2006
Abstract—The selective monoalkylation of glycine tert-butyl ester aldimine Schiff base 3 has been realized in high chemical yield
with excellent enantioselectivity under mild liquid–liquid phase-transfer conditions by the use of binaphthyl-derived chiral quater-
nary ammonium bromides 7 and 8 as catalysts. This achievement demonstrates that 3 can be used as a cost-effective substrate for the
preparation of optically active a-alkyl-a-amino acid derivatives by chiral phase-transfer catalysis.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
recent studies in this area of research, we became intri-
gued with the possibility of the enantioselective mono-
The enantioselective alkylation of the benzophenone
imine of glycine tert-butyl ester 1 using chiral phase-
transfer catalysts has been developed into a powerful
method for the synthesis of optically active a-amino acid
derivatives.1 A key feature of this extremely useful asym-
metric transformation is the selective monoalkylation of
1 due to the considerable difference in acidity of the
a-proton between the starting substrate 1 and the corre-
sponding monoalkylation product 4. This property, im-
parted by the presence of the benzophenone imine
moiety, is essential for securing the configurational sta-
bility of the newly created stereogenic center in 4 under
the basic reaction conditions. On the other hand, the p-
chlorobenzaldehyde imine of a-alkyl-a-amino acid tert-
butyl ester 2 has been employed for the preparation of
optically active a,a-dialkyl-a-amino acid derivatives by
phase-transfer-catalyzed alkylation.1,2 This is certainly
because the a-proton of 2 is acidic enough to be depro-
tonated under typical conditions in contrast to its ben-
zophenone imine counterpart 4, and hence aldimine
Schiff base 33a derived from glycine tert-butyl ester has
long been regarded as an unsuitable substrate for the
stereoselective monoalkylation. Over the course of our
alkylation of 3 under appropriate phase-transfer
conditions in view of its practical advantages such as
low cost. Herein, we report that the selective monoalkyl-
ation of 3 is indeed feasible under mild liquid–liquid
phase-transfer conditions, and our binaphthyl-derived
chiral quaternary ammonium bromides 73 and 84 act
as an efficient catalyst to achieve rigorous stereochemi-
cal control (Scheme 1).
2. Results and discussion
The requisite aldimine Schiff base 3 can be readily pre-
pared by simple imine formation between glycine tert-
butyl ester and p-chlorobenzaldehyde in MeOH at room
temperature with the aid of MgSO4. Monoalkylation of
3 was then performed by introducing a 50% KOH aque-
ous solution into a mixture of 3, benzyl bromide
(1.2 equiv), and (R,R)-7 in toluene at 0 °C under an
argon atmosphere followed by vigorous stirring at that
temperature. The reaction was found to go to completion
within 2 h and the corresponding a-benzyl-a-amino ester
6a was obtained almost quantitatively without detectable
production of the double benzylation product. Interest-
ingly, the enantiomeric excess of 6a was revealed to
be 98% ee by HPLC analysis using a chiral column
*
Corresponding author. Tel./fax: +81 75 753 4041; e-mail: maruoka@
kuchem.kyoto-u.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.019

604
T. Ooi et al. / Tetrahedron: Asymmetry 17 (2006) 603–606
cat. R*4N X
hydrolysis
R1X
Ph2C
N
CO2But
Ph2C
N
CO2But
H2N
CO2H
*
+
*
solvent—base
R1
H
R1
α-alkyl-α-amino acid
1
4
H
cat. R*4N X
R2X
hydrolysis
CO2But
p-Cl-C6H4
N
CO2But
H2N
CO2H
*
p-Cl-C6H4
p-Cl-C6H4
N
*
solvent—base
R1 R2
R1 R2
α,α-dialkyl-α-amino acid
R1
H
2 (R1 - H)
5
(R,R)-7 or (R)-8 (1 mol%)
1 M HCl
THF
CO2But
H2N
CO2But
R1X
N
+
*
toluene—50%aq KOH
H
R1
6
3
0 °C
81—99% yields
90—99% ee
F
F
F
F
F
F
F
Br
Br
Bu
N
N
Bu
F
(R,R)-7
(R)-8
F
F
F
F
Scheme 1.
(entry 1 in Table 1). Moreover, the structurally simplified
catalyst (R)-8 exhibited comparable catalytic and chiral
efficiency, giving 6a in 95% yield with 98% ee (entry 2).
3 has been accomplished by the utilization of either 7 or
8 as catalysts. The reaction proceeds smoothly at 0 °C
in toluene with 50% KOH aqueous solution as a base,
and a variety of alkyl halides are employable without
fear of substantial racemization. p-Chlorobenzaldehyde,
although inexpensive, can be recovered after acidic
hydrolysis of the alkylation product, and directly reused
for the condensation with glycine tert-butyl ester to pre-
pare Schiff base 3; this strengthens the practical aspect of
the present methodology for application in the industrial
production of various natural and unnatural a-amino
acids.
These promising results prompted us to conduct further
experiments to probe the scope of common alkyl
halides; and the selected examples listed in Table 1
demonstrate a rather surprising utility of this method.
Generally, 1 mol % of 7 or 8 with 1.2 equiv of alkyl
halide was sufficient enough for a smooth reaction. In
addition to the representative p-substituted benzylic
bromides, 1-bromomethyl naphthalene was well accom-
modated, offering practical access to a wide range of
enantiomerically pure phenyalanine analogues (entries
3–8). For the simple allylation, 8 appeared to be a suit-
able catalyst (entries 9 and 10), while higher asymmetric
induction was attained with 7 when cinnamyl bromide
was a reacting partner (entries 13 and 14). Although
significant rate retardation seemed inevitable in the
reaction with less reactive alkyl halides, such as ethyl
iodide under the present conditions (entry 15), it was
overcome by using an excess amount of the electrophile
(entries 16 and 17).
4. Experimental
A typical experimental procedure for the asymmetric
alkylation of 3 under phase-transfer conditions is as fol-
lows (entry 7 in Table 1). A long reaction tube equipped
with a cross shaped magnetic stir bar was charged with
(R,R)-7 (2.7 mg, 0.003 mmol), p-chlorobenzaldehyde
imine of glycine tert-butyl ester 3 (76.1 mg, 0.30 mmol),
1-bromomethyl naphthalene (79.6 mg, 0.36 mmol), and
toluene (2.0 mL). The flask was evacuated and filled
with argon (three times, balloon), and the mixture was
cooled to 0 °C in an ice bath. A solution of KOH
(50 wt % in water, 0.6 mL) was added via syringe and
the reaction mixture stirred vigorously under an argon
atmosphere for 2 h at 0 °C. The reaction was quenched
3. Conclusion
In conclusion, a highly enantioselective monoalkylation
of p-chlorobenzaldehyde imine of glycine tert-butyl ester

T. Ooi et al. / Tetrahedron: Asymmetry 17 (2006) 603–606
605
Table 1. Asymmetric monoalkylation of 3 under phase-transfer conditions catalyzed by chiral quaternary ammonium bromide 7 or 8a
(R,R)-7 or (R)-8 (1 mol%)
1 M HCl
THF
CO2But
H2N
CO2But
*
R1X
p-Cl-C6H4
N
+
toluene–50%aq KOH
H
R1
3
argon, 0 C
˚
6
Entry
Alkyl halide (R1X)
PhCH2Br
Catalyst
Time (h)
Yieldb (%)
eec (%) (config)d
Product
1
2
3
4
5
6
7
8
7
8
7
8
2
2
2
4.5
2
99
95
97
96
99
97
98 (S)
98 (S)
99
98
95
6a
6a
6b
6b
6c
6c
p-Me–C6H4CH2Br
p-F–C6H4CH2Br
1.5
99
Br
7
7
2
96
99 (S)
6d
8
8
7
8
7
8
7
8
7
7
8
2
2
2
2
2
3
6
10
5
6
96
84
92
99
95
82
90
43
93
81
98 (S)
92
98
98
96
94
90
97 (S)
99 (S)
90 (S)
6d
6e
6e
6f
9e
CH2@CHCH2Br
10e
11e
12e
13
CH2@C(Me)CH2Br
6f
trans-PhCH@CHCH2Br
6g
6g
6h
6h
6h
14
15e
16e,f
17e,f
EtI
a Unless otherwise noted, the reaction was carried out with 1.2 equiv of alkyl halide in the presence of 1 mol % of either (R,R)-7 or (R)-8 in toluene–
50% KOH aqueous solution at 0 °C under argon atmosphere for the given reaction time.
b Isolated yield.
c Enantiomeric excess of the amino ester 6 was determined by HPLC analysis using a chiral column. See the typical procedure.
d The absolute configuration of 6a was assigned by comparison of the specific rotation with the reported value.5 For 6d and the N-benzoate of 6h the
HPLC retention time was compared with that of the authentic sample independently synthesised via the alkylation of 1 using 7 as the catalyst.3d
e Isolated as its N-benzoate.
f With 10 equiv of EtI.
with H2O (10 mL) at 0 °C and allowed to warm to room
temperature. The mixture was separated and the aque-
ous phase extracted with Et2O. The combined organic
layer was dried over Na2SO4 and concentrated in vacuo.
The residue was diluted with THF (10 mL) and the mix-
ture was treated with 1 M HCl (10 mL) at 0 °C. After
being stirred for 30 min, the reaction was allowed to
warm to room temperature and extracted with Et2O.
The ethereal phase was back-extracted with 1 M HCl.
The combined acidic aqueous layer was neutralized with
solid NaHCO3 at 0 °C and extracted with EtOAc. The
combined organic extracts were dried over Na2SO4
and concentrated under reduced pressure. Purification
by flash column chromatography on silica gel (1:3
hexane/EtOAc eluent) afforded 6d as a clear oil
([M+H]+); HPLC analysis: Daicel Chiralcel OD-H,
hexane/2-propanol = 100:1, flow rate = 0.5 mL/min,
k = 254 nm, retention time; 53.2 min (R) and 81.1 min
(S).
The volatile amino esters were isolated as their N-benzo-
ates and subjected to HPLC analysis. The additional
procedure required for the ethylation of 3 is representa-
tive. The alkylation experiment was conducted as de-
scribed above. After its completion, H2O (10 mL) was
added at 0 °C and the whole mixture allowed to warm
to room temperature. Then, the aqueous phase was sep-
arated and extracted with Et2O. The combined organic
layer was dried over Na2SO4 and concentrated in vacuo.
The residue was diluted with THF (10 mL) and treated
with 1 M HCl (10 mL) at 0 °C. After stirring for
30 min, the mixture was allowed to warm to room tem-
perature and extracted with Et2O. The ethereal phase
was back-extracted with 1 M HCl. The combined acidic
aqueous layer was neutralized with solid NaHCO3 at
0 °C and extracted with CHCl3. The combined organic
layer was dried over Na2SO4 and filtrated without aspi-
ration. The filtrate was cooled to 0 °C, and Et3N
(84.0 lL, 0.6 mmol) and benzoyl chloride (70.0 lL, 0.6
mmol) added sequentially. The reaction mixture was
stirred for 1 h at 0 °C and evaporated in vacuo. The
residue was purified by flash column chromatography
(78.1 mg; 96% yield); Rf = 0.29 in 1:2 hexane/EtOAc;
26
½aꢀD ¼ þ33:6 (c 1.04, CHCl3, 99% ee); 1H NMR
(CDCl3, 400 MHz) d 8.10 (1H, d, J = 8.4 Hz), 7.86
(1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 8.0 Hz), 7.55–7.48
(2H, m), 7.42–7.35 (2H, m), 3.78 (1H, dd, J = 5.2,
8.8 Hz), 3.62 (1H, dd, J = 5.2, 14.0 Hz), 3.11 (1H, dd,
J = 8.8, 14.0 Hz), 1.58 (2H, br), 1.40 (9H, s); 13C NMR
(CDCl3, 100 MHz) d 174.1, 133.7, 133.7, 131.8, 128.6,
127.4, 127.3, 125.9, 125.4, 125.1, 123.5, 81.1, 55.8,
39.0, 28.0; IR (neat) 3377, 1726, 1597, 1393, 1368,
1250, 1152, 793, 775; HRMS (ESI) calcd for
C17H22NO2: 272.1645 ([M+H]+), found: 272.1649

606
T. Ooi et al. / Tetrahedron: Asymmetry 17 (2006) 603–606
on silica gel (9:1 hexane/EtOAc eluent) to give 6h as a
white solid (73.2 mg; 93% yield); Rf = 0.53 in 4:1 hex-
References
29
1
1. For recent reviews, see: (a) O’Donnell, M. J. Aldrichim. Acta
2001, 34, 3; (b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103,
3013; (c) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506; (d)
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
2. For recent examples, see: (a) Nakoji, M.; Kanayama, T.;
Okino, T.; Takemoto, Y. J. Org. Chem. 2002, 67, 7418; (b)
Belokon, Y. N.; Bhave, D.; D’Addario, D.; Groaz, E.;
North, M.; Tagliazucca, V. Tetrahedron 2004, 60, 1849; (c)
Ohshima, T.; Shibuguchi, T.; Fukuta, Y.; Shibasaki, M.
Tetrahedron 2004, 60, 7743; (d) Maeda, K.; Miller, R. A.;
Szumigala, R. H., Jr.; Shafiee, A.; Karady, S.; Armstrong,
J. D., III Tetrahedron Lett. 2005, 46, 1545.
3. (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J.
Am. Chem. Soc. 2000, 122, 5228; (b) Ooi, T.; Takeuchi, M.;
Ohara, D.; Maruoka, K. Synlett 2001, 1185; (c) Ooi, T.;
Takeuchi, M.; Maruoka, K. Synthesis 2001, 1716; (d) Ooi,
T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139.
ane/EtOAc; ½aꢀD ¼ þ42:9 (c 1.00, CHCl3, 99% ee); H
NMR (CDCl3, 400 MHz) d 7.81 (2H, m), 7.50 (1H,
m), 7.43 (2H, m), 6.76 (1H, br), 4.69 (1H, m), 2.02
(1H, m), 1.83 (1H, m), 1.50 (9H, s), 0.96 (3H, m); 13C
NMR (CDCl3, 100 MHz) d 171.6, 166.6, 134.2, 131.4,
128.4, 126.9, 82.2, 54.0, 28.1, 25.9, 9.3; IR (neat) 3335,
3062, 1732, 1641, 1365, 1253, 1152, 777, 711; HRMS
(ESI) calcd for C15H21NNaO3: 286.1414 ([M+Na]+),
found: 286.1412 ([M+Na]+); HPLC analysis: Daicel
Chiralpak AD-H, hexane/2-propanol = 20:1, flow rate =
0.5 mL/min, k = 254 nm, retention time; 16.9 min (min-
or) and 47.5 min (major).
Acknowledgments
4. Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem.,
Int. Ed. 2005, 44, 1549.
5. ½aꢀD ¼ þ14:7 (c 1.03, CHCl3, 98% ee); lit. ½aꢀD ¼ þ10:2 (c
0.90, CHCl3), Konda, Y.; Takahashi, Y.; Arima, S.; Sato,
N.; Takeda, K.; Dobashi, K.; Baba, M.; Harigaya, Y.
Tetrahedron 2001, 57, 4311.
This work was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas ‘Advanced Mole-
cular Transformation of Carbon Resources’ from the
Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
26
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