Catalytic Stereoselective 1,4-Addition Reactions Using CsF on Alumina as a Solid Base: Continuous-Flow Synthesis of Glutamic Acid Derivatives

Article abstract of DOI:10.1002/anie.201701789

A novel methodology using CsF?Al₂O₃ as a highly efficient, environmentally benign, and reusable solid-base catalyst was developed to synthesize glutamic acid derivatives by stereoselective 1,4-addition of glycine derivatives to α,β-unsaturated esters. CsF?Al₂O₃ showed not only great selectivity toward 1,4-addtion reactions by suppressing the undesired formation of pyrrolidine derivations by [3+2] cycloadditions, but also offered high yields for the 1,4-adduct with excellent anti diastereoselectivities. The catalyst was well characterized by using XRD, ¹⁹F MAS-NMR and ¹⁹F NMR spectroscopy, FT-IR, CO₂-TPD, and XPS. And highly basic F from Cs₃AlF₆ was identified as the most probable active basic site for the 1,4-addition reactions. Continuous-flow synthesis of 3-methyl glutamic acid derivative was successfully demonstrated by using this solid-base catalysis.

Full text of DOI:10.1002/anie.201701789

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Catalytic Stereoselective 1,4-Addition Reactions Using CsF
on Alumina as Solid Base: A Heterogeneous Platform for
Continuous-Flow Synthesis of Glutamic Acid Derivatives
Authors: Parijat Borah, Yasuhiro Yamashita, and Shu Kobayashi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201701789
Angew. Chem. 10.1002/ange.201701789
Link to VoR: http://dx.doi.org/10.1002/anie.201701789
http://dx.doi.org/10.1002/ange.201701789

10.1002/anie.201701789
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Stereoselective 1,4-Addition Reactions Using CsF on
Alumina as Solid Base: A Heterogeneous Platform for
Continuous-Flow Synthesis of Glutamic Acid Derivatives
Parijat Borah, Yasuhiro Yamashita, and Shū Kobayashi*[a]
Abstract: A novel methodology using CsF·Al2O3 as a highly efficient, α,β-unsaturated carbonyl compounds or other Michael acceptors
environmentally benign and reusable solid base catalyst was
developed to synthesize glutamic acid derivatives via stereoselective
1,4-addition of glycine derivatives to α,β-unsaturated esters.
CsF·Al2O3 showed not only great selectivity toward 1,4-addtion
reactions by suppressing undesired formation of pyrrolidine
derivations via [3+2] cycloaddition, but also offered high yields for
the 1,4-adduct with excellent anti diastereoselectivities. The catalyst
was well characterized by using XRD, 19F MAS-NMR, 19F NMR, FT-
IR, CO2-TPD, and XPS, and highly basic F from the Cs3AlF6 was
identified as the most probable active basic site for the 1,4-addition
reactions. Continuous-flow synthesis of 3-methyl glutamic acid
derivative was successfully demonstrated by using the solid base-
catalyzed methodology.
is one of the effective synthetic routes for the synthesis of
glutamic acid and its β-substituted derivatives.[7] However, such
synthetic methodologies are still not adequate due to low
stereoselectivity at the β-position, especially in β-alkyl
substituted products. In addition, undesired [3+2] cycloaddition
undergoes easily when Lewis acids are employed for the
stereocontrol.[8] Soloshonok et al. reported highly stereoselective
1,4-additions for the synthesis of β-alkyl substituted derivatives
of glutamic acid, although these methodology required specially
designed chiral/achiral Ni(II) complexes of glycine Schiff bases
as substrates to achieve high selectivity.[9] While several
catalytic disastereoselective methodologies have been
developed for this purpose,[10] in most of these methods, cyclic
α,β-unsaturated carbonyl compounds[10b, 10d, 11] or β-aryl[12] and
13]
[10a, 10f, 14]
β-CF3,[10e,
β-ROCO
substituted acyclic α,β-
The generation of carbanion by using a base is one of the key
steps in numerous organic reactions, and extensive studies
have been made to investigate various base-catalyzed organic
reactions.[1] Compared with liquid bases or organometallics,
solid base catalysts possess many advantages such as less
production of waste chemicals, no requirement of neutralization
of reaction mixture, easy separation of the catalysts from
products as well as possibility of catalyst reusability, scope for
high temperature reactions, etc.[2] However, the exploration of
solid base-catalyzed organic reactions is still in an inadequate
level even after half century since the first report of solid base in
spite of various challenges associated with the replacement of
liquid bases for solids.[3] Alkali metal fluorides such as KF or CsF
on alumina are potential solid bases and have been explored
extensively in wide range of organic reactions except only a few
examples of stereoselective solid base catalysts. Surprisingly,
their basic strength as well as identification of their active
phases are still under debate.[4] Furthermore, ambiguity about
heterogeneity of the basic sites of these solid bases still prevails
according to certain reports.[5] Therefore, it is crucial to identify
actual catalytic basic sites for the development of an efficient
methodology in particular stereoselective synthesis using these
solid bases as reusable heterogeneous catalysts.
unsaturated carbonyl compounds were employed, and highly
diastereoselective 1,4-additions of conventional simple Schiff
bases of glycine esters to β-alkyl substituted α,β-unsaturated
carbonyl compounds were scarcely reported. Recently our
laboratory has reported such 1,4-addition reactions of glycine
derivatives with acyclic β-alkyl α,β-unsaturated carbonyl
compounds using chiral alkaline earth metal complexes as
catalysts in the presence of a catalytic amount of Brønsted
15]
base.[8,
In these reports, however, we were often suffered
from [3+2] cycloaddition as side reactions to afford substituted
pyrrolidine derivatives, and the selectivity for 1,4-addition
reactions over the cycloaddition has been achieved by the use
of more sterically hindered protecting groups of the amine parts
as well as by employing Lewis acidic alkaline earth metal
complexes in homogeneous catalytic systems. For the supply of
β-substituted glutamic acid derivatives, more simple and
selective systems under heterogeneous conditions are highly
demanded. Herein, we report for the first time an efficient and
environmentally benign methodology to synthesize the β-
substituted glutamic acid derivatives, via 1,4-addition of a simple
glycine Schiff base to β-substituted α,β-unsaturated esters,
using a solid base as a heterogeneous base catalyst under mild
conditions.
On the other hand, β-substituted derivatives of glutamic acid
are essential nutrients for mammals, including humans, for their
vital role as structural components of peptides and proteins, as
well as a key ingredient in numerous biochemical pathways.[6]
Catalytic stereoselective 1,4-addition of glycine derivatives to
We began our investigation of stereoselective 1,4-addition of
glycine Schiff base (1a) to methyl crotonate (2a) in
a
combination with various solid bases as shown in Table S1 in
the supporting information (SI). The initial trials indicated that
CsF•Al2O3 (pre-treated at 200 ˚C) promoted the desired catalytic
1,4-addition reaction with high diastereoselectivity for the anti-
1,4-adduct. Further optimization of the reaction conditions using
CsF·Al2O3 is summarized in Table 1 (complete table in Table S3
in the SI). The solvent screening showed that relatively polar
solvents were effective for the reaction, and that THF was found
to be the best solvent. Low catalyst loading and high
concentration were found to be favourable for 1,4-addition as
well as anti-diastereoselectivity. Under the optimal conditions,
CsF·Al2O3 offered the highest yield of 98% for the desired 3aa at
[a]
Dr. P. Borah, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201701789
Angewandte Chemie International Edition
COMMUNICATION
a catalyst loading of 2 mol% (w.r.t CsF) within a short reaction
time (1 h) (Table 1, entry 4).
significant downfall in the reactivity (Table S4). The XPS
analysis indicated that less than 40 wt% loading of CsF cannot
afford complete surface coverage by the Cs3AlF6 (XPS analysis
in the SI). On the other hand, catalyst with 60 wt% loading of
CsF on alumina contains CsF phase alongside the crystalline
Cs3AlF6 phase as indicated by XRD (Fig S12) and the additional
19F NMR analysis (Fig S14). This dispersed F on alumina from
the impregnated CsF can catalyse the reaction in homogeneous
fashion [5] resulting low selectivity (Table S4, entry 1). On the
other hand, the basicity of the best catalyst is an outcome of the
interaction of Cs+ of the crystalline phase of Cs3AlF6 with the O
atom from the support which not only generates basicity on the
O species but also lead the negative charge to be localized
more on F atom resulting strong basic F containing sites (detail
discussion in the XPS section in the SI).
Table 1. Optimization of reaction conditions for catalytic 1,4-addition reaction
using CsF·Al2O3 as solid base.
3aaa
Mol% of Time
CsF.Al2O3 (h)
Conversio
n of 1a (%)
Entry X mg
Y ml (M)
3aa:4aa
Yield (%) anti:syn
1
2
3
4
5
30
5
39.5
6.6
2.6
2.0
1.3
0.5
0.5
0.5
1
4 (0.05) 100
1 (0.2) 100
1 (0.2) 100
1 (0.2) 100
1 (0.2) 96.3
96:4
98:2
98:2
98:2
98:2
96
96
97
98
96
96:4
98:2
2
>99:1
>99:1
>99:1
1.5
1
1
a Determined by 1H NMR analysis (crude).
Several CsF·Al2O3 samples were prepared followed by the
thermal treatment under vacuum at various temperatures such
as 120, 170, 200, 300, 400 and 500˚C. CsF·Al2O3 without any
thermal treatment showed negligible catalytic activity (Table S5,
entry 1 in the SI) in spite of possessing basic sites originated
from the F of impregnated CsF (Fig S10 in the SI). This catalyst
contains surface adsorbed water and CO2 which poisoned the
basic sites.[5] Thus, increase in the catalytic activity was
observed as the thermal treatment increases from 120 ˚C to 200
˚C (Table S5, entries 2-4) and thermally treated at 200 ˚C was
found to be optimal for the catalytic 1,4-addition with strong
basicity as indicated by CO2-TPD (Fig S10). The XRD patterns
of these catalysts showed the appearance of a strong signal
Figure 1: XRD patterns of various samples of CsF·Al2O3: (a) without thermal
treatment and thermal treatment at (b) 120 ˚C, (c) 170 ˚C, (d) 200 ˚C, (e) 300
˚C, (f) 400 ˚C, (g) 500 ˚C. Indexed XRD patterns are available in the Fig S11.
Table 2. Substrate scope for catalytic 1,4-addition reaction using CsF·Al2O3 as
solid base.
centred at 2θ = 27.3˚ corresponding to Cs3AlF6 (Figure 1).[16] 19
F
MAS NMR studies also revealed that the chemical shift at -95
ppm attributed to F from CsF disappeared in the optimal
catalyst and a new signal appeared at -114 ppm attributed to
AlF63-(Fig. S1 and S2).[16] An additional 19F NMR analysis also
advocated the absence of free CsF in this catalyst (Fig S14) and
the FTIR transmittance analysis confimed the formation of
Cs3AlF6 (Fig S13). Similar high catalytic activities were also
observed for the catalysts treated at 300 and 400˚C with a
minuscule declination in the selectivity. XRD patterns of these
two catalysts also showed the presence of crystalline phase of
Cs3AlF6 along with other phases such as β-CsAlF4 and CsAl2F7.
A complete loss of basicity (Fig S10) and thereby catalytic
activity (Table S5) was observed for CsF•Al2O3 treated at 500˚C
due to the presence of less crystalline Cs3AlF6 phase resulted by
sintering. The FTIR transmittance analysis confimed signals
ascribed to CsAlF4 and AlF3 for the samples pretreated at 300˚C
and 500˚C (Fig S13). Furthermore, XRD studies also indicated a
gradually decrease of the crystalline size of Cs3AlF6 phase when
the loading of CsF was less than 40 wt% (Fig S12) resulting a
1,4 adduct
1,4-
Entry
R1 R2 R3
R4
1,4:[3+2]a
adduct
Yield (%) anti:syna
1
2
3
4
5
6
7
8
Ph Me Me
iPr Me Me
tBu Me Me
Ph iPr Me
Ph sBu Me
Ph Bu Me
Ph Me H
H
H
H
H
H
H
H
3aa
3ba
3ca
3ab
3ac
3ad
3ae
98:2
-
96
>99:1
-
0
-
0
-
97:3
98:2
98:2
99:1
-
94c
96d
95d
quant
82
>99:1
>99:1
>99:1
-
Ph Me H
Me 3af
50:50b
This article is protected by copyright. All rights reserved.

10.1002/anie.201701789
Angewandte Chemie International Edition
COMMUNICATION
results also indicated that electron withdrawing group-
substituted aryl can enhance the reactivity markedly. A similar
trend was also observed in the case of other electron
withdrawing group-substituted β-aryl-α,β-unsaturated methyl
esters (entries 19-22). Moreover, these substrates did not show
any reactivity in THF as solvent. On the other hand, the addition
9
Ph Me Et
H
H
H
H
H
H
H
H
H
3ag
3aj
98:2
95:5
95:5
90:10
95:5
82:18
93:7
98:2
95:5
91:9
98:2
97:3
97:3
97:3
97:3
86
86
86
93
88
88
83
94
91
88
92
94
92
91
92
98:2
92:8
93:7
88:12
95:5
88:12
95:5
99:1
95:5
88:12
97:3
97:3
96:4
95:5
98:2
10e
11g
12e
13g,i
14e
15g,i
16f
Ph Me Pentyl
Ph Me Octyl
Ph Me iBu
3ah
3ai
of toluene enhanced the reactivity significantly and
a
Ph Me iBu
3ai
combination of toluene and diethyl ether was found to be optimal
for these substrates. 2-Naphthyl substituted α,β-unsaturated
methyl esters also underwent 1,4-addition catalytically to offer
the desired 1,4-adduct in high yield with high selectivity (entry
23).
Ph Me Ph(CH2)2-
Ph Me Ph(CH2)2-
Ph Me MeOCO-
Ph Me Ph-
3ak
3ak
3al
CsF•Al2O3 as a heterogeneous solid base catalyst presented
a tremendous reusability towards the 1,4-addition reaction with a
consistent yield and selectivity up to four catalytic cycles (Table
S6 in the SI). The hot filtration test was also carried out, and no
detectable catalysis in the solution phase was observed
indicating the absence of metal leaching (experimental section in
the SI). The structural integrity and the regeneration of the basic
sites of the recovered catalyst were confirmed by powder XRD,
19F MAS-NMR and CO2-TPD (Fig. S5, S6 and S15 in the SI).
Furthermore, except CsF•Al2O3, few other solid bases containing
cesium, basic-alumina as well as α-alumina and few liquid bases
failed to act as base catalyst for this reaction (Table S7). As
shown in the photograph in the SI, the colour of the white
CsF•Al2O3 turned into yellow in the presence of Schiff base (Fig.
S7) whereas the solution remained colourless. It implied that the
enolate stabilized on the surface of the solid base after the
deprotonation of glycine Schiff base as shown in the plausible
mechanism. The catalysis on the surface effectively suppressed
further [3+2] cycloaddition due to the steric hindrance. On the
contrary, the entire reaction mixture turned yellow in the case of
KF•Al2O3 indicating the enolates were in the solution due to the
homogeneous nature of the active base species i.e. KF or liquid
like F anion (see the discussion of Figs. S8 and S9 in the SI).
Such homogeneous nature of the active base spices also cast a
negative impact on the selectivity towards 1,4-adduct.
Furthermore, the catalytic turnover and the reusability of
KF•Al2O3 were not achieved.
17h
18g
19g,j
20g,j
21g,j
22h,j
23h,k
3am
Ph Me p-NO2C6H4- H 3an
Ph Me p-CF3C6H4- H 3ao
Ph Me p-FC6H4-
Ph Me p-ClC6H4-
Ph Me p-BrC6H4-
Ph Me 2-naphthyl
H
H
H
H
3ap
3aq
3ar
3as
1H NMR analysis (crude). b 2,4-Syn:anti. c Reaction time: 8 h. d Reaction time:
a
5 h. e Reaction time: 12 h. f Reaction time: 3 h. g Reaction time: 24 h. hReaction
i
j
time: 48 h. Solvent: diethyl ether (0.2 M). Solvent: toluene:diethyl ether = 1:1
(0.2 M). kSolvent: toluene:diethyl ether = 2:1 (0.07 M).
With the optimal conditions in hand, the substrate scope for
the CsF•Al2O3-catalyzed stereoselective 1,4-addition of various
glycine Schiff bases with α,β-unsaturated esters were examined
(Table 2). The investigations showed no reactivity when alkane
substituted imine part of the glycine Schiff bases were used due
to the presence of less acidic α-proton as compared to 1a
(entries 2 and 3). Similarly, low reactivity was observed when
the steric bulk of the ester part of crotonate was increased (entry
4-6). For further expansion of this methodology, we investigated
a range of α,β-unsaturated methyl esters. The reactions of 1a
with both methyl acrylate (2e) and methyl methacrylate (2f)
proceeded in high yields although methyl methacrylate gave 1:1
of syn/anti-2,4 diastereomeric ratio. Further investigations
revealed that the steric bulkiness of the β-substitution of α,β-
unsaturated methyl esters had a negative influence on the
reactivity as well as the selectivity. Substrates with a linear alkyl
chain at the β-position of α,β-unsaturated methyl esters provided
reasonable selectivity for the desired 1,4-adduct with higher
diastereoselectivity (entries 9-11) as compared to those with a
branched/substituted alkyl chain (entries 12 & 14). However, an
improved selectivity was achieved by employing diethyl ether as
solvent for these substrates in an expense of longer reaction
time (entries 13 & 15). On the other hand, dimethyl fumarate
offered good reactivity to form the desired product with good
yield and selectivity (entry 16). We also investigated series of β-
aryl-α,β-unsaturated methyl esters to form the corresponding
anti 1,4-adducts. For these substrates role of solvent is
inevitable. Methyl cinnamate (entry 17) and methyl 4-
nitrocinnamate (entry 18) provided comparable reactivity in THF
as solvent, although the former offered better selectivity. These
Figure 2. The schematic diagram of the continuous-flow reactor
Recently, continuous-flow synthesis draws much attention in
the field of organic synthesis because of its several advantages
over batch systems in terms of environmental friendliness,
efficiency, and safety.[16] These advantages have inspired our
group to develop several methodologies on continuous-flow
synthesis with various heterogeneous catalysts.[17] Therefore,
next, we attempted to develop a continuous-flow synthesis of the
This article is protected by copyright. All rights reserved.

10.1002/anie.201701789
Angewandte Chemie International Edition
COMMUNICATION
[6]
M. Kotnik, J. Humljan, C. Contreras-Martel, M. Oblak, K. Kristan, M.
Hervé, D. Blanot, U. Urleb, S. Gobec, A. Dessen, T. Solmajer, J. Mol.
Biol. 2007, 370, 107-115.
derivative of 3-methylglutamic acid using our novel methodology
(Figure 2). Keeping 0.5 M as fixed concentration of 1a, a flow
rate of 0.5 mL/min was accepted as the optimal rate (Table S9 in
the SI). The results indicated that the flow system could
effectively suppress the unwanted [3+2] cycloaddition primarily
due to the short residence time of the desired 1,4-adduct on the
solid catalyst. With the optimized conditions in hand, the desired
3-methylglutamic acid derivative was continuously synthesized
for a period of 38 h with high yield (94%) and significantly high
selectivity (1,4 addition/ [3+2] cycloaddition = 99:1; anti:syn for
1,4 adduct = >99:1) (Table S10 in the SI).
[7]
[8]
[9]
a) A. S. Vadim, Curr. Org. Chem. 2002, 6, 341-364; b) C. Nájera, J. M.
Sansano, Chem. Rev. 2007, 107, 4584-4671.
S. Saito, T. Tsubogo, S. Kobayashi, J. Am. Chem. Soc. 2007, 129,
5364-5365.
a) V. A. Soloshonok, C. Cai, V. J. Hruby, L. Van Meervelt, N.
Mischenko, Tetrahedron 1999, 55, 12031-12044; b) V. A. Soloshonok,
C. Cai, V. J. Hruby, Org. Lett. 2000, 2, 747-750; c) V. A. Soloshonok, C.
Cai, T. Yamada, H. Ueki, Y. Ohfune, V. J. Hruby, J. Am. Chem. Soc.
2005, 127, 15296-15303.
[10] Phase-transfer catalysis in the presence of stoichiometric amounts of
bases, see: a) C. Alvarez-Ibarra, A. G. Csakye, M. Maroto, M. L.
Quiroga, J. Org. Chem. 1995, 60, 6700-6705; b) D. Tasheva, N.
Petkova, V. Dryanska, Synth. Commun. 2003, 33, 3661-3670; c) T. Ma,
X. Fu, C. W. Kee, L. Zong, Y. Pan, K.-W. Huang, C.-H. Tan, J. Am.
Chem. Soc. 2011, 133, 2828-2831; d) M.-Q. Hua, L. Wang, H.-F. Cui, J.
Nie, X.-L. Zhang, J.-A. Ma, Chem. Commun. 2011, 47, 1631-1633; e) A.
E. Sheshenev, E. V. Boltukhina, A. J. P. White, K. K. Hii, Angew. Chem.
Int. Ed. 2013, 52, 6988-6991; Angew. Chem. 2013, 125, 7126–7129; f)
V. I. Maleev, M. North, V. A. Larionov, I. V. Fedyanin, T. F. Savel'yeva,
M. A. Moscalenko, A. F. Smolyakov, Y. N. Belokon, Adv. Synth. Catal.
2014, 356, 1803-1810; g) M. Tiffner, J. Novacek, A. Busillo, K. Gratzer,
A. Massa, M. Waser, RSC Adv. 2015, 5, 78941-78949; h) S. Wen, X. Li,
W. Yao, A. Waheed, N. Ullah, Y. Lu, Eur. J. Org. Chem. 2016, 2016,
4298-4301; i) A. Chandra, R. Viswanathan, J. N. Johnston, Org. Lett.
2007, 9, 5027-5029.
In summary, we have developed an efficient methodology for
the synthesis of 3-substituted glutamic acid derivatives via
stereoselective 1,4-addition of glycine derivatives to α,β-
unsaturated esters in the presence of CsF·Al2O3 as a robust
recyclable solid base catalyst. Several β-substituted α,β-
unsaturated esters, notably, β-alkyl substituted α,β-unsaturated
esters gave the desired adducts in high diastereoselectivities. It
was found that CsF·Al2O3 could suppress the unwanted
formation of pyrrolidines derivations via [3+2] cycloaddition,
which was otherwise predominant over the 1,4-addtion reaction.
We recognized an interaction of Cs+ from the crystalline phase
of Cs3AlF6 with the O atom form the support is responsible for
the generation of active site in the best catalyst. We also
successfully demonstrated the continuous-flow synthesis of the
3-methyl glutamic acid derivative by using the CsF·Al2O3 catalyst.
Further investigation to apply this solid base to other reactions is
in progress.
[11] Simple metal base or non-metal base catalysis, see: a) J. Beck, L.
Vercheval, C. Bebrone, A. Herteg-Fernea, P. Lassaux, J. Marchand-
Brynaert, Bioorg. Med. Chem. Lett. 2009, 19, 3593-3597; b) J. S. Tullis,
M. J. Laufersweiler, J. C. VanRens, M. G. Natchus, R. G. Bookland, N.
G. Almstead, S. Pikul, B. De, L. C. Hsieh, M. J. Janusz, T. M. Branch, S.
X. Peng, Y. Y. Jin, T. Hudlicky, K. Oppong, Bioorg. Med. Chem. Lett.
2001, 11, 1975-1979; c) E. Domínguez, M. J. O'Donnell, W. L. Scott,
Tetrahedron Lett. 1998, 39, 2167-2170; d) B. Herradón, E. Fenude, R.
Bao, S. Valverde, J. Org. Chem. 1996, 61, 1143-1147; e) A. Shibuya, M.
Kurishita, C. Ago, T. Taguchi, Tetrahedron 1996, 52, 271-278; f) P.
Pachaly, H.-S. Kang, D. Wahl, Arch. Pharm. 1991, 324, 989-995; g) K.
Shuji, T. Akira, W. Eiji, T. Otohiko, Chem. Lett. 1989, 18, 1301-1304; h)
J. M. McIntosh, R. K. Leavitt, P. Mishra, K. C. Cassidy, J. E. Drake, R.
Chadha, J. Org. Chem. 1988, 53, 1947-1952.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS) and Ministry of Education, Culture, Sports, Science and
Technology (MEXT), and the Japan Science and Technology
Agency (JST). P.B. thanks JSPS Postdoctoral Fellowship for
Research in Japan. The authors thank Prof. Noritaka Mizuno
and Prof. Kazuya Yamaguchi from the Department of Applied
Chemistry at The University of Tokyo for the CO2-TPD analysis.
A special thanks to Dr. Yoshiyuki Ogasawara for his valuable
support on conducting the series of CO2-TPD analysis.
[12] a) E. J. Corey, M. C. Noe, F. Xu, Tetrahedron Lett. 1998, 39, 5347-
5350; b) D. Tzalis, P. Knochel, Tetrahedron Lett. 1999, 40, 3685-3688;
c) M. Strohmeier, K. Leach, M. A. Zajac, Angew. Chem. Int. Ed. 2011,
50, 12335-12338; Angew. Chem. 2011, 51, 12543-12546.
[13] a) R. Viswanathan, C. R. Smith, E. N. Prabhakaran, J. N. Johnston, J.
Org. Chem. 2008, 73, 3040-3046; b) J. S. Bandar, T. H. Lambert, J. Am.
Chem. Soc. 2012, 134, 5552-5555.
[14] a) L. Antolini, A. Forni, I. Moretti, F. Prati, E. Laurent, D. Gestmann,
Tetrahedron: Asymmetry 1996, 7, 3309-3314; b) O. Marrec, C.
Christophe, T. Billard, B. Langlois, J.-P. Vors, S. Pazenok, Adv. Synth.
Catal. 2010, 352, 2825-2830.
Keywords: alkali metal fluorides on alumina • β-Glutamic acid
derivatives • flow synthesis • solid base • stereoselective addition
reactions
[15] J. S. Bandar, A. Barthelme, A. Y. Mazori, T. H. Lambert, Chem. Sci.
2015, 6, 1537-1547.
[1]
a) H. Hattori, Appl. Catal., A 2001, 222, 247-259; b) Y. Ono, J. Catal.
2003, 216, 406-415; c) A. Ting, J. M. Goss, N. T. McDougal, S. E.
Schaus, in Asymmetric Organocatalysis (Ed.: B. List), Springer Berlin
Heidelberg, Berlin, Heidelberg, 2009, pp. 201-232; d) S. E. Denmark, G.
L. Beutner, Angew. Chem. Int. Ed. 2008, 47, 1560-1638, Angew. Chem.
2008, 120, 1584-1663.
[16] a) T. Tsubogo, S. Saito, K. Seki, Y. Yamashita, S. Kobayashi, J. Am.
Chem. Soc. 2008, 130, 13321-13332; b) M. Hut'ka, T. Tsubogo, S.
Kobayashi, Adv. Synth. Catal. 2013, 355, 1561-1569.
[17] J.-M. Clacens, D. Genuit, B. Veldurthy, G. Bergeret, L. Delmotte, A.
Garcia-Ruiz, F. Figueras, Appl. Catal., B 2004, 53, 95-100.
[18] S. Kobayashi, Chem. Asian J.2016, 11, 425-436.
[2]
[3]
[4]
H. Hattori, Appl. Catal., A 2015, 504, 103-109.
[19] a) T. Tsubogo, H. Oyamada, S. Kobayashi, Nature 2015, 520, 329-332;
b) S. Kobayashi, M. Okumura, Y. Akatsuka, H. Miyamura, M. Ueno, H.
Oyamada, ChemCatChem 2015, 7, 4025-4029; c) H. Ishitani, Y. Saito,
T. Tsubogo, S. Kobayashi, Org. Lett. 2016, 18, 1346-1349.
H. Pines, W. Haag, J. Org. Chem. 1958, 23, 328-329.
J.-M. Clacens, D. Genuit, L. Delmotte, A. Garcia-Ruiz, G. Bergeret, R.
Montiel, J. Lopez, F. Figueras, J. Catal. 2004, 221, 483-490.
J. Ni, D. Rooney, F. C. Meunier, Appl. Catal., B 2010, 97, 269-275.
[5]
This article is protected by copyright. All rights reserved.

10.1002/anie.201701789
Angewandte Chemie International Edition
COMMUNICATION
Layout 1:
COMMUNICATION
Made our base solid: A novel
methodology to synthesize glutamic
acid derivatives via highly
Parijat Borah, Yasuhiro Yamashita, Shū
Kobayashi *
Page No. – Page No.
stereoselective 1,4-addition of glycine
derivatives to α,β-unsaturated esters
using CsF·Al2O3 as a reusable solid
base catalyst was developed for both
batch and continuous-flow systems,
and Cs3AlF6 was identified as the
active basic site for the addition
reaction.
Catalytic Stereoselective 1,4-Addition
Reactions Using CsF on Alumina as
Solid Base: A Heterogeneous
Platform for Continuous-Flow
Synthesis of Glutamic Acid
Derivatives
This article is protected by copyright. All rights reserved.