Asymmetric alkylation of glycine imine esters using solid supports preloaded with base

Article abstract of DOI:10.1016/j.tet.2004.07.002

Investigations into the use of solid supports preloaded with base for the asymmetric alkylation of a benzophenone-derived glycine-imine was described. Residual traces of water on the support dramatically accelerated the reactions to complete within a few

Full text of DOI:10.1016/j.tet.2004.07.002

Tetrahedron 60 (2004) 8405–8410
Asymmetric alkylation of glycine imine esters using solid supports
preloaded with base
*
Haitao Yu, Setsuko Takigawa and Hideko Koshima
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Received 17 May 2004; revised 1 July 2004; accepted 1 July 2004
Available online 6 August 2004
Abstract—Investigations into the use of solid supports preloaded with base for the asymmetric alkylation of a benzophenone-derived
glycine-imine was described. Residual traces of water on the support dramatically accelerated the reactions to complete within a few minutes.
The conditions employed in the present synthesis are mild, efficient and general.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
expensive, while the inexpensive KOH or NaOH has very
low surface area even in powder sate. In order to further
improve the asymmetric alkylation using these bases, it is
desirable to develop a new procedure that would have the
possibility of acceleration of the reaction with high
enantioselectivity and also allow an easy separation from
the reaction mixture once the reaction has completed.
a-Amino acids are the important naturally occurring amino
acids assembling into polypeptides with a wide range of
vital biological functions, and hence the synthesis of
optically active a-amino acids using a simple and easily
scalable procedure remains an important synthetic chal-
lenge nowadays. The asymmetric alkylation of glycine
imine esters for enantioselective synthesis of natural or
unnatural amino acids using asymmetric phase transfer
catalysis1 has certainly gained solid success through recent
extensive studies on the development of new catalysts2 and
modification of the reaction conditions.3
In our recent paper, we have developed a simple, efficient
and practical method using commercially available solid
supports preloaded with base to asymmetric alkylation of
glycine imine ester (Scheme 1).4 The alkylation product is
readily obtained after simple extractive workup. Using the
solid support with high sorptive surface area in this
asymmetric reaction can avoid the problems associated
with stirring of heterogeneous reaction mixture. The
reaction on solid support proceeded rapidly with high
yield and enantioselectivity, and moreover, it is possible for
performing the asymmetric alkylation of glycine imine ester
at lower temperatures using the inexpensive KOH. Hetero-
geneous organic reactions using inorganic solids as reaction
media have been proven useful to chemists both in academia
and in industry, because of their inexpensive nature and
special catalytic attributes under heterogeneous reaction
Generally, lower reaction temperatures provided higher
enantioselectivity. Corey group had successfully used solid
cesium hydroxide monohydrate as the basic phase in order
to allow the use of lower temperatures (K60 to K80 8C) at
which the aqueous phase of 50% aqueous KOH or NaOH
can freeze and effectively stopping reaction.2d They
achieved high asymmetric induction in the asymmetric
phase-transfer alkylation of glycine imine esters. However,
the vigorously stirring was essential to obtain rapid reaction,
and the powdery cesium hydroxide monohydrate is a little
Scheme 1.
Keywords: Asymmetric alkylation; Glycine imine esters; Solid supports; Amino acids; Chiral phase transfer catalysts.
* Corresponding author. Tel.: C81-89-927-8523; fax: C81-89-927-9923; e-mail: koshima@eng.ehime-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.002

8406
H. Yu et al. / Tetrahedron 60 (2004) 8405–8410
conditions.5 As part of our program to develop practical
method that can be used in industrial processes, we further
made more detailed studies on the method. In this work, by
extending the above study, the factors of effect on the
reaction enantioselectivity and reaction rate are explored.
commercial available.2c The catalyst 4 is derived from
cinchonine and the other three, 5, 6 and 7 are derived from
cinchonidine. The N-spiro type chiral C2-symmetric
quaternary ammonium bromide, catalyst 8 is commercially
available.2i The reaction was monitored by TLC for
disappearance of starting Schiff base 1, a following simple
workup that the solid support was washed with CH2Cl2 and
the product was isolated directly by flash chromatography
gave pure product. The enantiopurity was determined by
HPLC analysis of the alkylated imine 3 by using a chiral
column (Chiralcel OD) with hexane/2-propanol as solvent.
The absolute configuration was assigned by the relative
retention times of both enantiomers determined previously.2
2. Results and discussion
Preliminary experiments were carried out in order to
determine the effects of different catalysts on the enantio-
selectivity and the reaction rate. The enantioselective
efficiency of the catalysts was evaluated by the enantio-
selective alkylation of Schiff base 1: the catalyst was mixed
with 1 and benzyl bromide (2a) in dichloromethane. This
particular assay reaction was chosen because it was known
that the enantioselectivity of the imine 3 could be readily
assessed by HPLC, and the absolute stereochemistry of this
product was already known.2d The catalysts 4, 5 and 6 were
prepared according to the literature,2h the catalyst 7 is
As shown in Table 1, the catalysts 4, 5, 6 and 8 showed high
enantioselectivity on solid support kaolin/KOH (81–84%
ee, entries 1–3 and 5), whereas the rate of the reaction
proved to be a little slow as estimated by TLC when catalyst
6 and 8 were used. However, when the reaction was carried
out with the commercially available catalyst 7, the product 3
Table 1. Enantioselective alkylation of 1 with different catalysts and different solid supports a
Entry
Catalyst
Support
Time (h)
Yield (%)
Ee (%) (Config.)
1
2
3
4
5
6
7
8
4
5
6
Kaolin
Kaolin
Kaolin
Kaolin
Kaolin
Aluminium oxide
Montmorillonite K10
Celite
1.0
0.5
6.5
0.5
5.0
3.5
24
97
97
86
91
91
90
90
50
81 (R)
82 (S)
84 (S)
72 (S)
86 (R)
84 (S)
86 (S)
62 (S)
7
8b
5
5
5
140
a
Unless otherwise specified, the reaction was carried out in air with 1 (0.05 mmol) and benzyl bromide (0.06 mmol) on the support/KOH (0.5 g, containing
about 6 mmol of KOH per gram, no water) in the presence of the catalyst (0.005 mmol) at 20 8C. The starting materials and catalyst were dissolved in
0.1 ml of CH2Cl2.
0.001 mmol of catalyst 8 was used.
b

H. Yu et al. / Tetrahedron 60 (2004) 8405–8410
8407
Table 2. Enantioselective alkylation of 1 with different base used to treat the kaolin supportsa
Entry
Base (mmol/g)
Time (h)
Yield (%)
Ee (%)
Config.
1
2
3
4
5
6
7
KOH (2)
KOH (3)
KOH (5)
KOH (6)
KOH (7)
NaOH (6)
CsOH (6)
5.0
0.75
1.5
2.0
12
75
88
88
89
86
83
80
85
88
90
91
84
80
81
S
S
S
S
S
S
S
6.5
1.5
a
The reaction was carried out in air with 1 (0.05 mmol) and benzyl bromide (0.06 mmol) on the kaolin/base (0.5 g, no water) in the presence of the catalyst 5
(0.005 mmol) at 20 8C. The starting materials and catalyst were dissolved in 0.1 ml of PhCH3/CHCl3 (5:5).
was obtained in a little low selectivity 72% ee (Table 1,
entry 4). The preparation of (R)-3 can use pseudo-
enantiomertic catalysts 4 or 8, while 5, 6 and 7 can give
corresponding (S)-enantiomer. The easily prepared catalyst
5 was chosen for the further investigation.
KOH on solid support and changing the inorganic base from
KOH to NaOH or CsOH to measure the effect of these
factors on the enantioselectivity with benzyl bromide (2a).
The best enantioselection for the alkylated product was
obtained when the amount of KOH on solid support kaolin
was 6 mmol/g (Table 2, entry 4), while using NaOH or
CsOH at the same condition led to a decrease on the
enantioselection (Table 2, entries 6 and 7). Therefore, the
solid support kaolin/KOH (containing about 6 mmol of
KOH per gram) was used in the following reaction in this
investigation.
Further experiments involved using varying solid supports
preloaded with KOH to probe the enantioselective alkyl-
ation of 1 in our assay reaction. It was found that the
alkylation of imine 1 on solid supports preloaded with KOH,
such as kaolin, aluminium oxide and montmorillonite K10
could be effected at 20 8C, giving similar enantioselection
(82–86% ee, Table 1, entries 2, 6 and 7), while the reaction
on montmorillonite K10 proved to be a little slow (24 h).
These results showed that structural differences among the
three solid supports maybe scarcely affected the enantio-
selectivity of the reaction. However, the reaction using solid
support celite/KOH was far less effective resulting in low
yield (50%) and low level of enantioselection (62% ee) after
140 h (Table 1, entry 8). The difference between celite/KOH
and the other three solid supports maybe caused by the
difference of the surface area in addition to the surface
chemistry. The kaolin/KOH was chosen as solid support in
the following studies. The support was recovered by
washing with dichloromethane and drying to be recycled
for use in subsequent reactions without decrease in activity
over three cycles.
In our previous paper, we have reported that the presence of
CH2Cl2 in the reaction on the solid supports is crucial.4 The
amount of CH2Cl2 that can just dissolve the starting mixture
and cannot make the support to form slurry was found to be
best and yield the clean product. One of our initial aims of
this work was to develop methodology that was as
environmentally benign as possible, and so results of studies
on effects of solvents which were used to dissolve the
starting materials and catalyst on the enantioselective
alkylation of 1 are presented in this paper.
Because the catalysts in this investigation easily dissolved in
dichloromethane and chloroform, but did not dissolve very
well in toluene, we chose to use somewhat more
environmentally acceptable toluene mixed with other
organic solvents to dissolve the starting materials and
catalyst. It was found that the asymmetric alkylation could
be carried out on the solid support kaolin/KOH in which the
starting materials and catalyst dissolved in the mixture of
toluene with dichloromethane or chloroform at different
A study of the influence of base used to treat solid support
kaolin on the enantioselective alkylation of 1 was performed
using 5 as catalyst; the result being summarized in Table 2.
The experiments involved using varying the amount of
Table 3. Effect of solvent on the enantioselective alkylation of 1a
Entry
Solvent
CH2Cl2
Catalyst
Solvent (ml)
Time (h)
Yield (%)
Ee (%)
Config.
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
7
7
4
4
4
4
0.2
0.1
0.1
0.1
0.1
0.1
0.15
0.15
0.1
0.1
0.2
0.1
0.2
0.1
0.1
0.1
0.5
0.5
3.0
6.0
2.0
3.0
4.0
23
0.67
0.83
0.5
1.5
2.0
0.75
2.0
0.33
97
95
95
91
89
96
99
71
96
97
91
91
97
92
82
91
84
80
80
80
91
90
92
93
72
72
72
89
81
79
78
57
S
S
S
S
S
S
S
S
S
S
S
S
R
R
R
R
PhCH3/CH2Cl2, 3:7
PhCH3/CH2Cl2, 4:6
PhCH3/CH2Cl2, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 6:4
PhCH3/CHCl3, 6:4
PhCH3/CHCl3, 7:3
PhCH3/CH3CN, 7:3
PhCH3/CH3CN, 8:2
CH2Cl2
PhCH3/CHCl3, 5:5
CH2Cl2
PhCH3/CH2Cl2, 3:7
PhCH3/CHCl3, 5:5
PhCH3/CH3CN, 8:2
9
10
11
12
13
14
15
16
a
The reaction was carried out in air with 1 (0.05 mmol) and benzyl bromide (0.06 mmol) on the kaolin/KOH (0.5 g, containing about 6 mmol of KOH per
gram, no water) in the presence of the catalyst (0.005 mmol) at 20 8C.

8408
H. Yu et al. / Tetrahedron 60 (2004) 8405–8410
Table 4. Effects of temperature and residual water in the supports on the enantioselective alkylation of 1a
Entry
Residual
water (%)
Temp. (8C)
Solvent
Time (h)
Yield (%)
Ee (%)
Config.
1
2
3
4
5
6
25
18
16
14
12
10
7
7
2
2
2
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
K30
20
K30
20
20
K30
20
0
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CH2Cl2, 7:3
PhCH3/CHCl3, 5:5
PhCH3/CH2Cl2, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CH2Cl2, 7:3
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CHCl3, 5:5
PhCH3/CH2Cl2, 3:7
PhCH3/CH2Cl2, 3:7
PhCH3/CH2Cl2, 3:7
PhCH3/CHCl3, 7:3
PhCH3/CHCl3, 7:3
14
4.0
87
85
87
89
90
91
90
90
93
91
90
90
91
89
98
98
89
92
89
94
93
87
89
89
88
89
87
84
80
92
94
89
86
90
86
89
91
92
96
90
92
83
88
90
85
89
S
S
S
S
S
S
S
R
S
S
S
R
R
S
S
S
S
S
S
S
S
S
S
0.33
0.03
0.03
0.03
0.03
0.16
0.33
0.5
0.5
0.5
0.5
2.0
24
130
0.5
1.5
0.08
1.0
7
8b
9
10c
11c
12b
13b
14
15
16
17
18
19
20
21
22
23
2
2
0
0
0
12
12
12
12
12
1.5
0.75
23
d
—
d
—
a
Unless otherwise specified, the reaction was carried out in air with 1 (0.05 mmol) and benzyl bromide (0.1 mmol) on the kaolin/KOH (0.5 g, containing
about 6 mmol of KOH per gram) in the presence of the catalyst 5 (0.005 mmol). The starting materials and catalyst were dissolved in 0.1 ml of PhCH3/
CHCl3 (5:5).
Catalyst 8 (0.001 mmol) was used instead of 5.
0.001 mmol of catalyst 5 was used.
b
c
d
The liquid–liquid reaction was carried out in air with glycine imine (1) (0.17 mmol) and benzyl bromide (0.85 mmol) in the presence of catalyst 5
(0.0017 mmol) in 50% aqueous KOH (0.25 ml)—PhCH3/CHCl3 (7:3, 0.75 ml) without support.
ratio. The level of enantioselectivity improved when the
to 94% ee rapidly by performing the reaction using catalyst
8 on kaolin/KOH (Table 4, entry 8). It is showed that careful
optimization of the reaction conditions could lead to
significantly acceleration of the reaction with high
enantioselectivities.
mixture of toluene and chloroform were used in comparison
with those using only dichloromethane or the mixture of
toluene and dichloromethane (Table 3, entries 1–8).
Successful reaction was also possible using the mixture of
toluene and acetonitrile, the reaction proceeded rapidly with
high conversion of starting material to product, however in
these cases the obtained ee’s were lower (Table 3, entries 9
and 10). The use of a slight excess amount (0.15 ml) of a
mixture of toluene/chloroform (7/3, v/v) made the support
slurry state, leading to the prolonged reaction time (23 h) for
the alkylation of 1, but the best enantioselection (93%) was
achieved (Table 3, entry 8). Overall the variation of
enantioselectivity with solvent type was obvious, and so it
is likely that successfully making choice of suitable solvents
could result in the improvement in enantioselectivity of the
alkylation reaction.
The residual water on solid support in excess of 18% (w/w)
made the support slurry and deactivated, led to liquid–solid
two phases in the reaction system instead of all the starting
materials and catalyst absorbed on the solid support. In these
cases, the yield and enantioselection decreased with
prolonged reaction time (Table 4, entries 1 and 2).
The influence of the temperature on the enantioselectivity
and rate of the alkylation reaction was probed. Alkylation of
1 with benzyl bromide was conducted at three different
temperatures: 20, 0 and K30 8C. As expected, the best
enantioselection for the alkylation product was obtained at
the lower temperature (Table 4, entries 5 and 14–21).
If residual traces of water existed on the support, a dramatic
acceleration effect on the rate of the reaction was observed
(Table 4, entries 3–13). Particularly, the reaction was
completed within 2 min at 20 8C on the kaolin/KOH support
containing 7–14% (w/w) residual water (Table 4, entries
4–7). The similar enantioselections as the reaction on dry
solid support kaolin/KOH were obtained with significant
increase in the reaction rate (Table 4, entries 3–13 and 14).
Lowering the concentration of catalyst 5 from 10 to 2 mol%,
similar results were obtained without decrease on the
enantioselection (Table 4, entries 9–11). The enantio-
selectivity achieved with 2 mol% of catalyst 8 being similar
to that obtained with catalyst 5 (Table 4, compare entries 10,
11 with 12, 13). The enantioselectivity was further enhanced
For comparison purposes, the reaction was also carried out
using aqueous 50% KOH in a mixture of toluene/chloro-
form without solid support under the similar conditions as
for the solid support method. It was found that slight lower
enantioselections were obtained under liquid–liquid phase
transfer condition than the solid support method at 20 or
0 8C (Table 4, entries 14, 15, 22 and 23).
The effectiveness of the supports preloaded with base
appears to be due to a combination of the factors: an
increase in the effective surface area for reaction; the
presence of pores which constrain both catalyst and reactant
and thus act as microreactors. A small amount of solvent

H. Yu et al. / Tetrahedron 60 (2004) 8405–8410
Table 5. Enantioselective alkylation of 1 with different alkyl halidesa
8409
Entry
Alkyl halide
2a: PhCH2Br
Catalyst
(mol%)
Temp. (8C)
Time (h)
Yield (%)
Ee (%)
(Config.)
1
2
5 (10)
5 (2)
5 (2)
20
20
0
0
0
rt
0
0
20
20
20
20
20
20
20
20
20
20
0.03
0.03
0.1
10
0.16
18
90
89
95
95
90
68
89
79
90
88
83
82
88
85
80
78
78
76
92 (S)
92 (S)
96 (S)
97 (S)
92 (S)
91 (S)
96 (R)
99 (R)
90 (S)
89 (S)
92 (S)
90 (S)
89 (S)
87 (S)
90 (S)
86 (S)
93 (S)
93 (S)
3
4b
5
5 (1)
7 (10)
7 (10)
8 (2)
8 (1)
5 (10)
5 (2)
5 (10)
5 (2)
5 (10)
5 (2)
6c
7
0.18
2.0
8d
9
2b: 4-Cl–PhCH2Br
2c: (2-Naphthyl)CH2Br
2d: CH2]CHCH2Br
2e: CH3(CH2)2CH2I
2f: CH3(CH2)4CH2I
0.05
0.05
0.03
0.05
0.05
0.05
0.15
0.15
0.15
0.15
10
11
12
13
14
15
16
17
18
5 (10)
5 (2)
5 (10)
5 (2)
a
Unless otherwise specified, the reaction was carried out in air with 1 (0.05 mmol) and benzyl bromide (0.1 mmol) on the kaolin/KOH (0.5 g, containing
about 6 mmol of KOH per gram, 7% water) in the presence of the catalyst (0.005 or 0.001 mmol). The starting materials and catalyst were dissolved in
0.1 ml of PhCH3/CHCl3 (5:5).
b
c
d
The result of liquid–liquid reaction in Ref. 2h: the reaction was carried out in air with glycine imine (1) (0.17 mmol) and benzyl bromide (0.85 mmol) in the
presence of catalyst 5 (0.0017 mmol) in 50% aqueous KOH (0.25 ml)—PhCH3/CHCl3 (7:3, 0.75 ml) without support.
The result of liquid–liquid reaction in Ref. 2c: the reaction was carried out in air with glycine imine (1) (0.5 mmol) and benzyl bromide (0.6 mmol) in the
presence of catalyst 7 (0.05 mmol) in 50% aqueous KOH (1 ml)—PhCH3 (5 ml) without support.
The result of liquid–liquid reaction in Ref. 2i: the reaction was carried out in air with glycine imine (1) (0.5 mmol) and benzyl bromide (0.6 mmol) in the
presence of catalyst 8 (0.005 mmol) in 50% aqueous KOH (1 ml)—PhCH3 (3 ml) without support.
contained in the solid support can provide a better internal
preparation of optically active amino acids or related
derivatives. Further studies on the optimization of the
reaction conditions and the applications of this method to
other asymmetric synthesis will be reported in due course.
diffusion of the reactants inside the pores. A synergistic
interaction maybe exists between the components of solid
support, leading to the formation of active sites, which
control the reaction. In the case of commercial available
solid supports without base treatment the active sites is
absent. Further work is need, however, to elucidate the
detailed mechanism.
4. Experimental
4.1. General
With these preliminary studies completed, in order to
demonstrate the utility of this method, attention was turned
to conducting the enantioselective alkylation of 1 with other
alkyl halides and the results summarized in Table 5 clearly
demonstrate the general applicability of the present method.
Rapid reaction rates were achieved with not only substituted
benzyl bromide (2b) and 2-(bromomethyl)naphthalene (2c)
but also allylic bromide (2d) and alkyl iodides (2e, 2f). The
catalyst was reduced to 2 mol%, showing no significant
influence on the reaction rate and obtained ee’s (entries 2,
10, 12, 14, 16 and 18). The reactions carried out with benzyl
bromide (2a) using catalysts 5, 7 and 8 at 0 8C were all much
faster than the usual liquid–liquid reactions of the
literatures2c,h,i with similar enantioselections, respectively
(Table 5, entries 3–8).
HPLC was carried out using a Waters 470 apparatus
equipped with chiral columns. 1H NMR spectra were
measured on a JEOL JNM-GSX270 spectrometer with
tetramethylsilane as an internal standard. IR spectra were
recorded on a JASCO FT/IR-300E spectrophotometer. Mass
spectra were carried out with a Perkin–Elmer ELAN 600.
The solvents were of analytical grade. Catalysts 4, 5 and 6
were prepared by a published procedure.2h The catalyst 7
(Aldrich), catalyst 8 (Aldrich) and all the supports: kaolin
(Wako, cat. No. 117-00025), aluminium oxide (Merck, cat.
No. 1011097, for chromatography, 90 standardized),
montmorillonite K10 (Aldrich, cat. No. 28,1152-2, surface
area 220–270 m2/g, bulk density 300–370 g/l) and celite
(Wako, cat. No. 537-02305, No. 545), were used as
received.
3. Conclusion
4.2. General procedure for the preparation of solid
support preloaded with base
We have developed a simple, convenient and practical
method for the asymmetric alkylation of N-diphenyl-
methylene glycine t-butyl ester using solid support pre-
loaded with base. The simple experimental and product
isolation procedures combined with easy recovery and reuse
of this support is expected to contribute to the development
of clean and environmentally friendly strategy for the rapid
Kaolin clay (3 g) was added to 4 ml of 25% KOH solution,
and the mixture was sonicated for a period of 4 h then dried
in a rotary evaporator for several hours (obtaining solid
support with suitable residual water). Residual traces of
water were removed from the support by irradiating with
microwave for 15 min. The solid was ground to a powder.

8410
H. Yu et al. / Tetrahedron 60 (2004) 8405–8410
Catalysis. Sasson, Y., Neumann, R., Eds.; Blackie Academic
and Professional: London, 1997. Chaper 14. (b) Nelson, A.
Angew. Chem. Int. Ed. 1999, 38, 1583. (c) O’Donnell, M. J.
Catalytic Asymmetric Synthesis 2nd ed., Ojima, I., Ed.; Wiley,
New York, 2000. Chapter 10. (d) Shioiri, T.; Arai, S.
Stimulating Concepts in Chemistry. Vogtle, F., Stoddart, J. F.,
Shibasaki, M., Eds.; Wiley-VCH: Weinheim; 2000. p. 123. (e)
O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (f) Najera, C.
Synlett; 2002, 1388. (g) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
103, 3013.
The solid support thus prepared contains about 6 mmol of
KOH per gram.
4.3. Typical procedure for alkylation of N-diphenyl-
methylene glycine t-butyl ester on solid support
preloaded with base
A solution of N-diphenylmethylene glycine t-butyl ester (1)
(0.05 mmol), benzyl bromide (2a) (0.06 mmol) and catalyst
5 (0.005 mmol) in CH2Cl2 (0.1 ml) was slowly added
dropwise into kaolin/KOH (0.5 g, 51 equiv. KOH to 1). The
so-obtained solid was stilled at 20 8C. After completion of
the reaction (monitored by TLC), the reaction mixture was
extracted with CH2Cl2 (2!5 ml) from the support. The
extract was condensed with an evaporator and then the
residue was purified by flash chromatography on silica gel
(hexane/diethyl ether/triethylamine: 50/5/0.5) to afford the
desired product (S)-a-benzyl t-butylglycinate benzo-
phenone imine (3a) as a colorless oil. The entantiomeric
excess was determined by HPLC (Chiralcel OD, hexane/
2-propanol: 500:2.5, 1 ml/min, lZ254 nm, 23 8C). Spectral
data are in agreement with literature values.2d
2. For representative examples: (a) O’Donnell, M. J.; Bennett,
W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (b)
O’Donnell, M. J.; Wu, S.; Hoffman, C. Tetrahedron 1994, 50,
4507. (c) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997,
38, 8595. (d) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414. (e) Arai, S.; Tsuji, R.; Nishida, A.
Tetrahedron Lett. 2002, 43, 9535. (f) Shibuguchi, T.; Fukuta,
Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 9539. (g) Kita, T.; Georgieva, A.;
Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem. Int.
Ed. 2002, 41, 2832. (h) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.;
Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S.
Angew. Chem. Int. Ed. 2002, 41, 3036. (i) Ooi, T.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139.
Acknowledgements
3. (a) Ooi, T.; Tayama, E.; Doda, K.; Takeuchi, M.; Maruoka, K.
Synlett 2000, 1500. (b) Okino, T.; Takemoto, Y. Org. Lett.
2001, 3, 1515.
We are grateful to the Kurata Memorial Hitachi Science and
Technology Foundation for financial support.
4. Yu, H.; Koshima, H. Tetrahedron Lett. 2003, 44, 9209.
5. For reviews: (a) Cornelis, A.; Laszlo, P. Synthesis 1985, 909. (b)
Balogh, M.; Laszlo, P. Organic Chemistry using Clays
Springer: Berlin, 1993. (c) Varma, R. S. Tetrahedron 2002,
58, 1235.
References and notes
1. For reviews: (a) Shioiri, T. Handbook of Phase-transfer