Asymmetric aldol reactions between acetone and benzaldehydes catalyzed by chiral Zn2+ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane: Fine-tuning of the amino-acid side chains and a revised reaction mechanism

Article abstract of DOI:10.1002/asia.201300308

We previously reported that chiral Zn²⁺ complexes that were designed to mimic the actions of class-I and class-II aldolases catalyzed the enantioselective aldol reactions of acetone and its analogues thereof with benzaldehyde derivatives. Herein, we report the synthesis of new chiral Zn ²⁺ complexes that contain Zn²⁺-tetraazacyclododecane (Zn²⁺-[12]aneN₄) moieties and amino acids that contain aliphatic, aromatic, anionic, cationic, and dipeptide side chains. The chemical and optical yields of the aldol reaction were improved (up to 96 % ee) by using ZnL complexes of L-decanylglycyl-pendant [12]aneN₄ (L-ZnL ⁷), L-naphthylalanyl-pendant [12]aneN₄ (L-ZnL ¹⁰), L-biphenylalanyl-pendant [12]aneN₄ (L-ZnL ¹¹), and L-phenylethylglycyl-pendant [12]aneN₄ ligands (L-ZnL¹²). UV/Vis and circular dichroism (CD) titrations of acetylacetone (acac) with ZnL complexes confirmed that a ZnL-(acac)^- complex was exclusively formed and not the enaminone of ZnL and acac, as we had previously proposed. Moreover, the results of stopped-flow experiments indicated that the complexation of (acac)^- with ZnL was complete within milliseconds, whereas the formation of an enaminone required several hours. X-ray crystal-structure analysis of L-ZnL¹⁰ and the ZnL complex of L-diphenylalanyl-pendant [12]aneN₄ (L-ZnL¹³) shows that the NH₂ groups of the amino-acid side chains of these ligands are coordinated to the Zn²⁺ center as the fourth coordination site, in addition to three nitrogen atoms of the [12]aneN₄ rings. The reaction mechanism of these aldol reactions is discussed and some corrections are made to our previous mechanistic hypothesis. Homeward Zn-bound: New chiral Zn ²⁺ complexes of amino acids that contained adequate hydrophobic and bulky side chains were synthesized as catalysts for enantioselective aldol reactions between acetone and various benzaldehydes. Copyright

Full text of DOI:10.1002/asia.201300308

FULL PAPER
FULL PAPER
Asymmetric Synthesis
Susumu Itoh, Takuya Tokunaga,
Shotaro Sonoike, Masanori Kitamura,
Akihito Yamano,
Shin Aoki*
&&&& — &&&&
Asymmetric Aldol Reactions between
Acetone and Benzaldehydes Catalyzed
by Chiral Zn2+ Complexes of Amino-
acyl 1,4,7,10-Tetraazacyclododecane:
Fine-Tuning of the Amino-Acid Side
Chains and a Revised Reaction Mech-
anism
Homeward Zn-bound: New chiral
Zn2+ complexes of amino acids that
contained adequate hydrophobic and
bulky side chains were synthesized as
catalysts for enantioselective aldol
reactions between acetone and various
benzaldehydes.
1
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These are not the final page numbers! ÞÞ

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Shin Aoki et al.
DOI: 10.1002/asia.201300308
Asymmetric Aldol Reactions between Acetone and Benzaldehydes
Catalyzed by Chiral Zn2+ Complexes of Aminoacyl 1,4,7,10-
Tetraazacyclododecane: Fine-Tuning of the Amino-Acid Side Chains and a
Revised Reaction Mechanism
Susumu Itoh,[a] Takuya Tokunaga,[b] Shotaro Sonoike,[b] Masanori Kitamura,[b, c]
Akihito Yamano,[d] and Shin Aoki*[b, c]
Abstract: We previously reported that
chiral Zn2+ complexes that were de-
signed to mimic the actions of class-I
and class-II aldolases catalyzed the
enantioselective aldol reactions of ace-
tone and its analogues thereof with
benzaldehyde derivatives. Herein, we
report the synthesis of new chiral Zn2+
thylalanyl-pendant
[12]aneN4
(l-
that the complexation of (acac)À with
ZnL was complete within milliseconds,
whereas the formation of an enami-
none required several hours. X-ray
crystal-structure analysis of l-ZnL10
and the ZnL complex of l-diphenyla-
lanyl-pendant [12]aneN4 (l-ZnL13)
shows that the NH2 groups of the
amino-acid side chains of these ligands
are coordinated to the Zn2+ center as
the fourth coordination site, in addition
to three nitrogen atoms of the
[12]aneN4 rings. The reaction mecha-
nism of these aldol reactions is dis-
cussed and some corrections are made
to our previous mechanistic hypothesis.
ZnL10),
l-biphenylalanyl-pendant
[12]aneN4 (l-ZnL11), and l-phenyle-
thylglycyl-pendant [12]aneN4 ligands
(l-ZnL12). UV/Vis and circular dichro-
ism (CD) titrations of acetylacetone
(acac) with ZnL complexes confirmed
À
À
that a ZnL
G
complexes that contain Zn2+ tetraaza-
sively formed and not the enaminone
of ZnL and acac, as we had previously
proposed. Moreover, the results of
stopped-flow experiments indicated
À
cyclododecane (Zn2+ [12]aneN4) moi-
À
eties and amino acids that contain ali-
phatic, aromatic, anionic, cationic, and
dipeptide side chains. The chemical
and optical yields of the aldol reaction
were improved (up to 96% ee) by
using ZnL complexes of l-decanylglyc-
yl-pendant [12]aneN4 (l-ZnL7), l-naph-
Keywords: aldol reaction · asym-
metric catalysis · enzyme models ·
macrocyclic ligands · zinc
Introduction
lent studies of direct aldol reactions that use artificial orga-
nocatalysts and metallocatalysts have been reported.[2] Since
the direct aldol reaction by using l-proline (as an organoca-
talyst) was first reported by List, Barbas, and co-workers,[3]
numerous additional examples of organocatalysts for aldol
reactions have been reported.[4]
À
The aldol reaction is one of the most-important C C bond-
forming reactions and a wide variety of efficient asymmetric
catalysts have been developed for it.[1] To date, many excel-
In natural metabolic pathways in living systems, aldol re-
actions are catalyzed by aldolase enzymes in a stereospecific
and reversible manner.[5] For example, fructose 1,6-bis(phos-
phate) aldolase (FBP-aldolase, EC 4.1.2.13) catalyzes the
cleavage of d-fructose 1,6-bis(phosphate) (FBP) to give di-
hydroxyacetone phosphate (DHAP) and d-glyceraldehyde
3-phosphate (G3P) and the reverse formation of FBP from
DHAP and G3P. Natural aldolases are categorized as either
class-I or class-II, based on their reaction mechanisms. In
class-I aldolases, an enamine intermediate is formed be-
tween a lysine residue on the enzyme and the carbonyl
group of the substrate. In class-II aldolases, a zinc(II)-ion
cofactor acts as a Lewis acid, with enolates generated at the
active site. The use of aldolases in organic and bio-organic
synthesis have been found to be an effective method for
producing aldol products with high stereoselectivities in
aqueous solution.[6] In addition, catalytic antibodies that
were generated by immunizing mice with a 1,3-diketone
[a] S. Itoh
Production Technology Laboratories
Kaken Pharmaceutical Co. Ltd.
301 Gensuke, Fujieda, Shizuoka 426-8646 (Japan)
[b] T. Tokunaga, S. Sonoike, Dr. M. Kitamura, Prof. S. Aoki
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510 (Japan)
Fax : (+81)4-7121-3670
E-mail: shinaoki@rs.noda.tus.ac.jp
[c] Dr. M. Kitamura, Prof. S. Aoki
Center for Technologies against Cancer
Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510 (Japan)
[d] Dr. A. Yamano
X-ray Research Laboratory, Rigaku Corporation
3-9-12, Matsubara-cho
Akishima-shi, Tokyo 196-8666 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300308.
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Shin Aoki et al.
Scheme 1. Asymmetric aldol reactions of acetone catalyzed by chiral ZnL complexes and the one-pot chemoenzymatic synthesis of 1,3-diols 9a–9c with
À
an oxidoreductase by using a cofactor (NADH)-regenerating system. A previously proposed mechanism that proceeded through ZnL enolate complex 6
is also presented.
hapten have been developed to catalyze aldol reactions
through an enamine mechanism, analogous to class-I aldo-
lases.[7]
The majority of these above-described organocatalysts
function as mimics of class-I aldolases. On the other hand,
only several mimics of class-II aldolases have been report-
ed.[8] For example, Mlynarski et al. reported the preparation
of ZnL complexes of amino acids as chiral catalysts that
were inspired by class-II and class-I aldolases.[9] These cata-
lysts showed high reactivities and enantioselectivities for
a broad range of substrates in aqueous systems.
We previously reported chiral catalysts that were dually
functionalized with chiral amino acids and achiral Zn2+ com-
plexes of 1,4,7,10-tetraazacyclododecane ([12]aneN4 or
cyclen), such as l-prolyl-pendant cyclen 1 (l-ZnL1) and l-
Abstract in Japanese:
valyl-pendant cyclen
2
(l-ZnL2), in aqueous solution
(Scheme 1).[10] A mechanistic study suggested that the car-
bonyl group of acetone was activated by Lewis acidic Zn2+
ions and that its a proton atom was deprotonated by the
amine group of ZnL in a cooperative manner, as shown for
À
compound 5 to generate ZnL enolate complex 6. These re-
sults were applied to the one-pot synthesis of optically
active 1,3-diols (9a–9c) through a combination of enantiose-
lective aldol reactions catalyzed by l- and d-phenylalanyl-
pendant cyclens 3 and 4 (l-ZnL3 and d-ZnL3), thus afford-
ing 1,2-adducts 8a–8c with their successive reduction by the
recombinant oxidoreductase system Chiralscreeen OH.[11]
The aim of this study was to fine-tune the side chain of
chiral ZnL complexes to improve the aldol reactions be-
tween acetone and various benzaldehyde derivatives. We
synthesized various ZnL complexes that contained aliphatic,
aromatic, anionic, cationic, and dipeptide side chains (10–25,
l-ZnL4–ZnL19). The proposed reaction mechanism for this
aldol reaction is based on data that were obtained from UV/
Vis titrations, stopped-flow experiments, and CD titrations
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Shin Aoki et al.
of ZnL complexes with acetylacetone (acac). Based on the
Enantioselective Aldol Reactions in Aqueous Media
X-ray crystal structures of complexes 16 (l-ZnL10) and 19
(l-ZnL13), the mechanism for these aldol reactions is dis-
cussed with some revisions to our previous hypothesis.
Catalyzed by Chiral ZnL Complexes
The aldol reaction between acetone and 2-chlorobenzalde-
hyde was performed in acetone/H2O (4:1 or 9:1) in the pres-
ence of 50 mm ZnL complexes, a concentration at which the
ZnL complexes were considered to be formed quantitative-
ly, based on our previous results.[10,11] The results are sum-
marized in Table 1, with our previous results by using ZnL
complexes 1–3 (l-ZnL1–l-ZnL3).[10,11]
As shown in Table 1, entry 4, catalyst 10 (l-ZnL4), which
contained alanine as the amino-acid unit, afforded com-
pound (R)-8a in high optical yield. Catalysts 11 (l-ZnL5), 12
(l-ZnL6), and 13 (l-ZnL7), which contained aliphatic side
chains, exhibited higher catalytic activities than catalysts 1–3
(l-ZnL1–l-ZnL3; Table 1, entries 5–7). Catalysts 14 (l-ZnL8)
and 15 (l-ZnL9), which contained 4-trifluoromethylphenyla-
lanine and 3,4-dimethoxyphenylalanine amino acids, respec-
tively, afforded lower optical yields than catalyst 3 (l-ZnL3),
which contained a phenylalanine group (Table 1, entries 8
and 9). Catalysts 16 (l-ZnL10), 17 (l-ZnL11), and 18 (l-
ZnL12), which contained aromatic side chains, also afforded
higher catalytic activities than catalysts 1–3 (l-ZnL1–l-ZnL3;
Table 1, entries 10–12). On the other hand, catalyst 19 (l-
ZnL9), which contained a bulky diphenylmethyl group, gave
compound (R)-8a in moderate yield and 88% ee (Table 1,
entry 13). These results suggest that ZnL complexes that
contain sufficiently bulky side chains, such as decyl, naph-
thyl, biphenyl, and phenylethyl groups, can be expected to
have efficient catalytic activity. As shown in Table 1, en-
tries 14 and 15, catalyst 20 (l-ZnL14), which contains an
anionic propanoate side chain (from Glu), and catalyst 21
(l-ZnL15), which contains a cationic guanidium group (from
Arg), afforded compound (R)-8a in 78% ee and 92% ee, re-
spectively, thus indicating negligible electrostatic effects on
the enantioselectivity of the products. It was possible to im-
prove the ee values by increasing the amount of acetone and
performing the reaction at lower temperatures (Table 1, en-
tries 16–18 versus entries 5, 7, and 12, respectively).
Next, we synthesized catalysts 22–25 (ZnL16–ZnL19),
which contained dipeptide side chains, based on the assump-
tion that the presence of more hydrophobic and hydrogen-
bonding functionalities around the Zn2+ site would improve
their catalytic activity. However, these ZnL complexes re-
sulted in low chemical and optical yields (Table 1, en-
tries 19–22), thus suggesting that one amino-acid side chain
is suitable for aldol reactions catalyzed by the ZnL series.
Organic reactions in buffer systems should enable a one-
pot reaction to be achieved by using a combination of en-
zymes that work best in aqueous solutions at optimum pH
values.[14] Herein, we tested a number of buffer systems and
the results are listed in Table 2. Complex 1 (l-ZnL1) gave
compound (R)-8a in low chemical and optical yields in ace-
tone/HEPES buffer (pH 7.0) and acetone/Tris buffer
(pH 8.0), as described in our previous paper (Table 2, en-
tries 1 and 2).[10] In contrast, complexes 3 (l-ZnL3) and 13
(l-ZnL7) afforded high enantioselectivities, such as 90% ee
Results and Discussion
Synthesis of Chiral Ligands
The ligands for ZnL complexes 10–25 (l-ZnL4–ZnL19) were
synthesized from 3Boc-cyclen (Boc=tert-butoxycarbonyl)[12]
with N-Boc-protected amino-acid derivatives, as described
in our previous paper.[10,11] The ZnL complexes were pre-
pared in situ immediately before use by reacting the acid-
free ligand with Zn2+ ions. For details, see the Supporting
Information.
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Table 1. Asymmetric aldol reactions between acetone and 2-chlorobenzaldehyde (7a) catalyzed by complexes
1–3 (L-ZnL1–L-ZnL3) and 10–25 (L-ZnL4–ZnL19).
in
acetone/HEPES
buffer
(pH 7.4) and 94% ee in ace-
tone/HEPES buffer (pH 7.4)
systems (Table 2, entries 3 and
5), which were almost the same
as were obtained in non-buffer
systems (Table 1, entries 3 and
7).
Entry
Catalyst [mM][a]
mol%
Solvent
Conditions
Yield [%][b]
CTN[c]
ee [%][d]
1[e]
2[e]
3[f]
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1 (l-ZnL1) (50)
2 (l-ZnL2) (50)
3 (l-ZnL3) (50)
10 (l-ZnL4) (50)
11 (l-ZnL5) (50)
12 (l-ZnL6) (50)
13 (l-ZnL7) (50)
14 (l-ZnL8) (50)
15 (l-ZnL9) (50)
16 (l-ZnL10) (50)
17 (l-ZnL11) (50)
18 (l-ZnL12) (50)
19 (l-ZnL13) (50)
20 (l-ZnL14) (50)
21 (l-ZnL15) (50)
11 (l-ZnL5) (50)
13 (l-ZnL7) (50)
18 (l-ZnL12) (50)
22 (ZnL16) (50)
23 (ZnL17) (50)
24 (ZnL18) (50)
25 (ZnL19) (50)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (9:1)
acetone/H2O (9:1)
acetone/H2O (9:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
24 h, 378C
24 h, 378C
24 h, 258C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 308C
24 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
73
87
85
30
89
84
91
67
86
93
92
95
54
44
79
90
85
96
24
19
25
25
15
17
17
6
80 (R)
80 (R)
91 (R)
91 (R)
94 (R)
86 (R)
94 (R)
87 (R)
78 (R)
93 (R)
92 (R)
94 (R)
88 (R)
78 (R)
92 (R)
96 (R)
95 (R)
96 (R)
9 (R)
The use of
a
two-phase
system for these reactions was
also examined. The aldol reac-
tions proceeded very sluggishly
in the presence of catalysts 3
(l-ZnL3), 11 (l-ZnL5), and 19
(l-ZnL13) in a mixture of tolu-
18
17
18
13
17
19
18
19
11
9
16
18
17
19
5
ene/acetone/H2O
(4:5:1;
Table 3, entries 1–3). In con-
trast, catalyst 13 (l-ZnL7) gave
compound (R)-8a in 41% yield
and 91% ee in toluene/H2O
and 63% yield and 92% ee in
toluene/HEPES buffer (pH 7.4;
Table 3, entries 4 and 5), thus
implying that these hydropho-
bic ZnL complexes are effective
catalysts for aldol reactions in
liquid/liquid two-phase systems.
For comparison, catalyst 22
(ZnL16), which contained two
decyl groups, gave compound
(R)-8a in low chemical and op-
tical yields under the same con-
ditions.
4
5
5
33 (S)
9 (R)
6 (S)
[a] Numbers in parentheses correspond to the concentrations of the catalysts in the solvent; the ZnL com-
plexes are formed in situ. [b] Yield of isolated product. [c] CTN=catalytic turnover number (yield/equiv of
catalyst). [d] Determined by HPLC analysis on a chiral column (Ref. [13]). [e] Taken from Ref. [10]. [f] Taken
from Ref. [11].
Table 2. Asymmetric aldol reactions between acetone and 2-chlorobenzaldehyde (7a) catalyzed by complexes
1 (l-ZnL1), 3 (l-ZnL3), and 13 (l-ZnL7) in buffer systems.
Entry Catalyst [mm][a] mol%
Solvent
acetone/HEPES buffer[f] (1:4) 20 h, 258C
acetone/Tris buffer[g] (1:1)
3 h, 378C
acetone/HEPES buffer[h] (4:1) 24 h, 258C
Conditions Yield [%][b] CTN[c] ee [%][d]
Table 4 summarizes the aldol
reactions between acetone and
various other benzaldehydes, as
catalyzed by complexes 13 (l-
ZnL7) and 18 (l-ZnL12) in
a single-phase solution of ace-
tone/H2O. When 4-chloroben-
zaldehyde was used, compound
(R)-8b was obtained in good
yield and in 93% and 92% ee,
respectively (Table 4, entries 4
and 8) and, when 2-, 3-, and 4-
nitrobenzaldehydes were used
as acceptors, high chemical and
optical yields were similarly ob-
served (Table 4, entries 5–7 and
9–11).
1[e]
2[e]
3
4
5
1 (l-ZnL1) (10) 10
1 (l-ZnL1) (10) 10
17
15
91
2
2
18
4
39 (R)
20 (R)
90 (R)
8 (R)
3 (l-ZnL3) (50)
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
5
5
5
5
acetone/HEPES buffer[i] (1:5) 24 h, 258C 20[j]
acetone/HEPES buffer[h] (4:1) 24 h, 258C
acetone/HEPES buffer[i] (4:1) 24 h, 258C
93
67
19
13
94 (R)
91 (R)
6
[a] Numbers in parentheses correspond to the concentrations of the catalysts in the solvent; the ZnL com-
plexes are formed in situ. [b] Yield of isolated product. [c] CTN=catalytic turnover number (yield/equiv of
catalyst). [d] Determined by HPLC analysis on
[f] 100 mm, pH 7.0. [g] 20 mm, pH 8.0. [h] 10 mm, pH 7.4. [i] 100 mm, pH 7.4. [j] Yield of the crude product.
a chiral column (Ref. [13]). [e] Taken from Ref. [10].
Table 3. Asymmetric aldol reaction between acetone and 2-chlorobenzaldehyde in a two-phase system.
Entry Catalyst [mm][a]
mol%
Solvent
Conditions Yield
[%][b]
CTN[c] ee
[%][d]
1
2
3
4
5
3 (l-ZnL3) (50)
11 (l-ZnL5) (50)
19 (l-ZnL13) (50)
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
5
5
5
5
5
toluene/acetone/H2O (4:5:1)
toluene/acetone/H2O (4:5:1)
toluene/acetone/H2O (4:5:1)
toluene/acetone/H2O (4:5:1)
24 h, 308C
72 h, 258C 10
48 h, 308C
3
1
2
1
8
13
85 (R)
92 (R)
68 (R)
91 (R)
92 (R)
1
72 h, 258C 41
toluene/acetone/HEPES buffer[e] 72 h, 258C 63
(10:8:1)
toluene/acetone/H2O (4:5:1)
6
22 (ZnL16) (50)
5
24 h, 258C 15
3
5 (R)
[a] Numbers in parentheses correspond to the concentrations of the catalysts in the solvent; the ZnL com-
plexes are formed in situ. [b] Yield of isolated product. [c] CTN=catalytic turnover number (yield/equiv of
catalyst). [d] Determined by HPLC analysis on a chiral column (Ref. [13]). [e] 10 mm, pH 7.6.
5
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Shin Aoki et al.
Table 4. Asymmetric aldol reactions between acetone and various aldehydes catalyzed by
complexes 13 (l-ZnL7) and 18 (l-ZnL12) in acetone/H2O (4:1 in entries 1–3 and 9:1 in en-
tries 4–11).
UV/Vis titrations of acac (0.2 mm) with ZnL
complexes 10 (l-ZnL4, 0–50 equiv), 18 (l-ZnL12,
0–50 equiv), and 19 (l-ZnL13, 0–50 equiv) were
carried out in DMSO/H2O (1:2) and the results
are summarized in Table 5. An absorption at 287–
294 nm was observed upon the addition of com-
plexes 10 (l-ZnL4), 18 (l-ZnL12), and 19 (l-
13
À
À
ZnL ), which corresponded to the ZnL ACHTUNGTRENNUNG(acac)
complexes. The Kapp values of complexes 10 (l-
ZnL4) and 18 (l-ZnL12), as calculated by using the
software program BIND WORKS, were 135 and
131mÀ1, respectively, which were almost same as
that of complex 2 (l-ZnL2, 139mÀ1). On the other
hand, the Kapp for complex 19 (l-ZnL13) with acac
(26mÀ1) was smaller than that of complex 2 (l-
ZnL2), possibly owing to the steric bulkiness of its
amino-acid part.
Entry Catalyst [mm][a]
mol%
X
Product Conditions Yield CTN[c] ee
[%][b] [%][d]
1[e,f]
2[e,f]
3[e,g]
4[e]
1 (l-ZnL1) (50)
2 (l-ZnL2) (50)
5
5
4-NO2
4-NO2
4-NO2
4-Cl
4-NO2
3-NO2
2-NO2
4-Cl
8c
8c
8c
8b
8c
8d
8e
8b
8c
8d
8e
20 h, 378C
20 h, 378C
24 h, 308C quant. 10
78 16
86 17
63 (R)
86 (R)
90 (R)
94 (R)
96 (R)
95 (R)
90 (R)
95 (R)
95 (R)
95 (R)
92 (R)
3 (l-ZnL3) (50) 10
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
13 (l-ZnL7) (50)
18 (l-ZnL12) (50)
18 (l-ZnL12) (50)
18 (l-ZnL12) (50)
18 (l-ZnL12) (50)
5
5
5
5
5
5
5
5
72 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
72 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
74 15
92 18
92 18
96 19
83 17
92 18
97 19
89 18
5[e]
6[e]
7[e]
8[e]
9[e]
4-NO2
3-NO2
2-NO2
10[e]
11[e]
CD Titrations of Acetylacetone (acac) with
Complexes 2 (l-ZnL2), 13 (l-ZnL7), and 18 (l-
ZnL12)
[a] Numbers in parentheses correspond to the concentrations of the catalysts in the solvent;
the ZnL complexes are formed in situ. [b] Yield of isolated product. [c] CTN=catalytic turn-
over number (yield/equiv of catalyst). [d] Determined by HPLC analysis on a chiral column
(Ref. [13]). [e] Acetone/H2O=4:1 (entries 1–3), 9:1 (entries 4–11). [f] Taken from Ref. [10].
[g] Taken from Ref. [11].
Next, we performed individual CD titrations of
acac (0.2 and 0.1 mm) with l-proline (0–500 equiv)
and complex 2 (l-ZnL2, 0–50 equiv). Figure 1
shows the changes in the CD and absorption spec-
tra for acac with increasing concentrations of l-
UV Titrations of Acetylacetone with ZnL Complexes 10 (l-
proline and catalyst 2 (l-ZnL2) in DMSO/H2O (1:2) at
258C. Upon the addition of l-proline (0–500 equiv), a nega-
tive Cotton effect was observed at 318 nm (Figure 1a, top),
in good agreement with the UV absorption maximum (Fig-
ure 1a, bottom), which could be assigned to optically active
enaminone 26 (Scheme 2). In contrast, a negligible Cotton
effect at 294 and 318 nm was observed with increasing con-
centrations of catalyst 2 (l-ZnL2, 0–50 equiv; Figure 1b,
ZnL4), 18 (l-ZnL12), and 19 (l-ZnL13) in a Mechanistic
Study
In our previous paper, UV titrations of acetylacetone (acac)
with l-proline and ZnL complexes 1 (l-ZnL1) and 2 (l-
ZnL2) were conducted to characterize the major intermedi-
ates in these aldol reactions.[10] In the UV/Vis titrations of
acac with l-proline (as an organocatalyst), the absorption
maximum was shifted from 276 to 316 nm, thus suggesting
the formation of enaminone 26
À
bottom). These data suggest that the CD spectra of ZnL
(Scheme 2). On the other hand,
the UV/Vis absorption maxi-
mum was shifted from 276 to
294 nm, thus strongly suggesting
À
À
the formation of ZnL
N
complex 27, with the negligible
formation of enaminone 28.
The formation constants of
À
À
ZnL
(acac) complex 27 were
larger than the formation con-
stants of enaminone 26, thus
implying that complex 27 is
much more thermodynamically
favorable than enaminone 28.
Moreover, the catalytic activi-
ties of complexes 1 (l-ZnL1)
and 2 (l-ZnL2) for aldol reac-
tions and the Kapp of acac with
ZnL had a parallel relationship.
Scheme 2. Equilibria of acac with l-proline or Zn2+ complex.
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Shin Aoki et al.
1
2
4
Table 5. Formation constants (Kapp) for the Zn2+ enolates of complexes 1 (l-ZnL ), 2 (l-ZnL ), 10 (l-ZnL ),
À
18 (l-ZnL12), and 19 (l-ZnL13) with (acac)À in DMSO/H2O (1:2) at 258C.
Stopped-Flow Experiments to
À
Determine the Rates of ZnL
1 (l-ZnL1)
2 (l-ZnL2)
10 (l-ZnL4)
18 (l-ZnL12)
19 (l-ZnL13)
AHCTUNGTRENNUNG
(acac)À Complexation
lmax [nm]
Kapp [mÀ1
294
292
292
294
287
(Zn2+ enolate)
(Zn2+ enolate)
(Zn2+ enolate)
(Zn2+ enolate)
(Zn2+ enolate)
À
À
À
À
À
It was previously reported that
the formation of the enaminone
26 between acac and l-proline
reached equilibrium within 4 h
in DMSO, whereas the reaction
between acac and a ZnL com-
plex was complete within a few
seconds.[10] Herein, stopped-
flow experiments were per-
formed to more-precisely deter-
mine the rates of formation of
]
212[a]
139[a]
135
131
26
[a] Taken from Ref. [10].
À
À
ZnL
(acac) complex 27. The
increase in the UV/Vis absorp-
tion of acac (0.2 mm) with com-
plex
294 nm was monitored and
a rate constant of 6.18
2
(l-ZnL2, 3 mm) at
(Æ0.03)ꢁ
10À2 secÀ1 was calculated from
the resulting curve by fitting to
a single exponential equation
(see the Supporting Informa-
tion, Figure S1). Similar studies
of the complexation between
acac and complexes 13 (l-
ZnL7) and 18 (l-ZnL12) afford-
ed rate constants of 9.03-
A
U
10À2 secÀ1, respectively, which
were almost the same as that of
complex 2 (l-ZnL2). These for-
mation rates of complex 27 are
about 1.4ꢁ105 higher than that
for enaminone 26.
X-ray Crystal Structure of
Complex 16 (l-ZnL10)
We successfully crystallized
complexes 16 (l-ZnL10) and 19
(l-ZnL13) as their NO3 salts
from acid-free ligands l-L10 and
l-L13, respectively, with Zn-
AHCUTNGTER(GNUNN NO3)2·6H2O in Et2O/EtOH/
Figure 1. CD and absorption spectra of a) acac (0.2 mm) upon the addition of l-proline (0–500 equiv) and
b) acac (0.1 mm) upon the addition of complex 2 (l-ZnL2, 0–50 equiv) in DMSO/H2O (1:2) at 258C.
H2O. The ORTEP of complex
16 (l-ZnL10) is shown in
Figure 2 and that of complex 19
(acac)À complex 27 is very small and/or that the formation
(l-ZnL13) is shown in the Supporting Information, Figure S2.
In our previous hypothesis, the NH2 group of the amino-
acid moiety coordinated weakly (or not at all) to the Zn2+
center and acted as a base to deprotonate acetone at the
a position (Scheme 1). In contrast, we found that the Zn2+
center was not only coordinated by three nitrogen atoms
(N5, N8, and N11) of the cyclen ligand and a NO3 anion,
À
of ZnL enaminone complex 28 is negligible (Scheme 2). In
the cases with complexes 13 (l-ZnL7) and 18 (l-ZnL12), neg-
ligible amounts of the corresponding enaminone were also
formed.
7
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Shin Aoki et al.
in the ZnL complexes are necessary for producing products
with high reactivities and enantioselectivities. 2) Complex 13
(l-ZnL7), which contained a decyl side chain, catalyzed the
aldol reaction of acetone with 2-chlorobenzaldehyde in
a single-phase system that contained HEPES buffer and in
a two-phase system that contained toluene and water, thus
suggesting that hydrophobic ZnL complexes may function
as catalysts in single- and two-phase systems, even in the
presence of buffer solvents. 3) The UV titrations suggest
À
À
that the formation of ZnL
N
ferred to the formation of an enaminone intermediate, as
previously predicted. The complexation of ZnL with acac is
hampered by steric hindrance of the side chain. 4) A nega-
tive Cotton effect at 318 nm was observed in the CD titra-
tions of acac with l-proline, possibly owing to the formation
of an optically active enaminone (complex 26, Scheme 2). In
À
À
contrast, Cotton effects of ZnL
G
À
À
294 nm and ZnL
(acac) enaminone 28 at 318 nm were neg-
ligibly observed in the case of complexes 2 (l-ZnL2), 13 (l-
ZnL7), and 18 (l-ZnL12). 5) Stopped-flow experiments sug-
gested that the complexation of ZnL
(acac) was complete
in the order of milliseconds. 6) The X-ray crystal structures
of complexes 16 (l-ZnL10) and 19 (l-ZnL13) revealed that
the NH2 groups in the side chain of these ZnL complexes
coordinated to the Zn2+ atoms. As a result, the Zn2+ ions
were five (or six)-coordinated by three nitrogen atoms of
the cyclen ligand, by one nitrogen atom of the amino-acid
moiety, and by an external water molecule or NO3 anion.
Based on these results, we considered several reaction
mechanisms for the ZnL-catalyzed aldol reactions between
acetone and benzaldehydes, as shown in Scheme 3. Our pre-
vious hypothesis involved path A, in which the amine group
of the side chain in the ZnL complexes deprotonated the
a proton of acetone, which was activated by coordination to
the Lewis acidic Zn2+ center, as shown in structure 5, to gen-
Figure 2. a) ORTEP of complex 16 (l-ZnL10
are set at 50% probability. b) Coordination-bond lengths in complex 16
(l-ZnL10(NO3)2). A Zn2+ ion is 6-coordinated by these nitrogen atoms of
a cyclen ring, one nitrogen atom of the side chain, and two oxygen atoms
of the NO3 anion. All of the hydrogen atoms and one NO3 anion are
omitted for clarity. Crystal data and data-collection parameters are given
in the Supporting Information.
ACHTUGNTRENUN(GN NO3)2); thermal ellipsoids
ACHTUNGTRENNUNG
but also by the nitrogen atom (N14) of the b-naphthylalanyl
À
À
moiety, as shown in Figure 2. The approximate Zn N bond
erate the ZnL enolate complex (6, Scheme 1). However,
À
À
lengths are 2.12 ꢂ for Zn N(5), 2.14 ꢂ for Zn N(8), 2.15 ꢂ
given the data reported herein, this pathway appears to be
less plausible, because the basicity of the amino side chain
should be lowered by its coordination to the Zn2+ center, as
observed in the X-ray crystal structure.
À
À
for Zn N(11), and 2.09 ꢂ for Zn N(14), thus implying that
À
these Zn N coordinate-bond lengths are almost identical. In
this structure, the NO3 anion coordinates to the Zn2+ atom
À
À
and the bond lengths for the two Zn O (NO3 ) coordinate
Herein, two other possibilities were considered, namely
paths B and C. It has been reported that Zn2+-bound HOÀ
and alkoxide species can act as bases and nucleophiles.[16–18]
For instance, the Zn2+-bound HOÀ group in the class-II al-
À
À
bonds are about 2.24 ꢂ (Zn O(30)) and about 2.51 ꢂ (Zn
O(32)). It is very likely that this Zn2+-bound NO3 anion is
replaced by a H2O molecule in aqueous solution, based on
our previous findings.[12,15] The Zn2+ center in complex 19
(l-ZnL13) was also coordinated by the nitrogen atom of the
diphenylalanyl moiety and by one water molecule (see the
Supporting Information, Figure S2).
ACTHNUTRGNEUNG
dolase model complex 35b (ZnL20(OHÀ)) is considered to
deprotonate the a proton to the carbonyl group of the phe-
nacyl side chain to give Zn2+ enolate 35c (Zn
(H-1L20)) in
À
aqueous solution (Scheme 4).[16a] Accordingly, we hypothe-
size that, in path B, that the OHÀ moiety of complex 29b de-
protonates the a proton of acetone with the aid of the Lewis
Revision of the Reaction Mechanism
acidic Zn2+ center in complex 31 and generates ZnL
À
Based on the information that was obtained in our previous
papers and herein, we observed several key points in the
enantioselective aldol reactions with chiral ZnL complexes,
which are summarized as follows: 1) Reactivity and enantio-
selectivity are improved by fine-tuning the ZnL complexes.
Appropriate hydrophobicity and bulkiness of the side chains
(enolate)À complex 32.
ACHTUNGTRENNUNG
Path C (Scheme 3) shows another possibility, in which the
Zn2+-bound OHÀ group deprotonates the NH2 group to give
rise to NHÀ species 30, which deprotonates acetone, thus re-
À
À
N
sulting in the formation of ZnL
However, this pathway is unlikely because the pKa value of
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Shin Aoki et al.
tion of DHAP was mediated by
Glu (Glu169 in FBP aldolase
from Mycobacterium tuberculo-
sis (MtFBA)) and/or the neigh-
boring
water
molecules
(Scheme 5).[20]
Because there are no carbox-
ylate groups in our artificial
ZnL complexes, it is not easy to
speculate on the catalytic role
of the carboxylate groups in
class-II aldolases, such as
MtFBA. However, our catalytic
systems may add another possi-
bility for consideration, that is,
that Zn2+-bound HOÀ ligands
acts as a base to deprotonate
the donor substrates in aldol re-
actions.
Conclusions
Herein, we designed and syn-
thesized several new chiral ZnL
complexes
that
contained
amino acids with aliphatic, aro-
matic, anionic, cationic, and di-
peptide side chains. The chemi-
cal and optical yields of aldol
reactions between acetone and
Scheme 3. Proposed mechanism for the aldol reactions of acetone catalyzed by chiral ZnL complexes.
various
benzaldehydes
im-
the amine group would be over 30, which is much higher
than those of Zn2+-bound H2O and alcohol moieties in typi-
[12,15,18]
cal Zn2+ cyclen complexes (pKa ꢀ7–9).
À
A consideration of these points allows us to conclude that
path B is the most plausible among the three possibilities, al-
though we do not completely rule out the path A scenario.
À
À
A
Then, ZnL
(enolate) complex 32 reacts with an acceptor
aldehyde through six-membered transition state 33 to afford
compound 34, from which the aldol product is released and
ZnL 29 is regenerated.
Scheme 4. Formation of Zn2+ enolate in class-II aldolase model 35.
À
The active site and the reaction mechanism of class-II al-
dolases have been extensively
studied.[19] In terms of the de-
protonation step for the forma-
tion of a Zn2+ enolate inter-
À
mediate of DHAP, it has been
suggested that the carboxylate
group of Glu or Asp in the
active site acts as a base, based
on X-ray crystal structures of
FBP-aldolases that are bound
to DHAP, DHAP-G3P, and
FBP. In those papers, it was
proposed that the deprotona- Scheme 5. Proposed mechanism of deprotonation of DHAP in MtFBA.
9
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Shin Aoki et al.
4-(4-Chlorophenyl)-4-hydroxy-2-butanone (8b)[11,13]
proved when ZnL complexes 13 (l-ZnL7) and 16–18 (l-
ZnL10–l-ZnL12) were used, which contained adequate hy-
drophobic and bulky side chains (up to 96% chemical and
optical yields). Hydrophobic ZnL complex 13 (l-ZnL7),
which contained a decyl side chain, catalyzed the aldol reac-
tion in single-phase solvent systems that contained HEPES
buffer and in a two-phase system that contained toluene and
water. UV/Vis and CD titrations of acetylacetone (acac)
with various ZnL complexes suggest the exclusive formation
1H NMR (500 MHz, CDCl3/TMS): d=2.18 (s, 3H), 2.78–2.87 (m, 2H),
3.36 (br, 1H), 5.13 (m, 1H), 7.28–7.33 ppm (m, 4H; ArH); HPLC
(Daicel Chiralpak AD-H column, 0.46fꢁ25 cm, hexanes/2-propanol=
95:5, flow rate: 0.5 mLminÀ1, l=254 nm, 258C): tR (R)=26.3 min, tR
(S)=28.2 min.
4-(4-Nitrophenyl)-4-hydroxy-2-butanone (8c)[10,13]
1H NMR (500 MHz, CDCl3/TMS): d=2.23 (s, 3H), 2.81–2.91 (m, 2H),
3.57 (d, J=3.5 Hz, 1H), 5.27 (m, 1H), 7.54 (d, J=8.5 Hz, 2H; ArH),
8.22 ppm (d, J=8.5 Hz, 2H; ArH); HPLC (Daicel Chiralcel OB-H
À
À
of a ZnL
G
column,
0.46fꢁ25 cm,
hexanes/2-propanol=90:10,
flow
rate:
formation of an enaminone, as we had previously proposed.
0.8 mLminÀ1, l=254 nm, 258C): tR (R)=35.7 min, tR (S)=43.0 min.
4-(3-Nitrophenyl)-4-hydroxy-2-butanone (8d)[13]
À
Stopped-flow data suggest that the complexation of ZnL
A
(acac)À complexes reaches completion within milliseconds,
1H NMR (500 MHz, CDCl3/TMS): d=2.24 (s, 3H), 2.84–2.94 (m, 2H),
3.59 (d, J=3.5 Hz, 1H), 5.27 (m, 1H), 7.54 (t, J=8.0 Hz, 1H; ArH), 7.72
(d, J=8.0 Hz, 1H; ArH), 8.14 (m, 1H; ArH), 8.25 ppm (s, 1H; ArH);
HPLC (Daicel Chiralpak AD-H column, 0.46fꢁ25 cm, hexanes/2-propa-
nol=95:5, flow rate: 1.0 mLminÀ1, l=254 nm, 258C): tR (R)=24.3 min,
tR (S)=26.8 min.
whereas the formation of an enaminone requires several
hours. X-ray crystal structures of complexes 16 (l-ZnL10)
and 19 (l-ZnL13) revealed that the NH2 groups in the side
chain of these ZnL complexes were coordinated to the Zn2+
centers. These data indicate that the Zn2+-bound OHÀ
groups in the ZnL complexes (ZnL
deprotonate the a proton of acetone to generate a ZnL
(enolate)À complex (32) in these aldol reactions, as dis-
(OHÀ)) act as a base to
ACHTUNGTRENNUNG
4-(2-Nitrophenyl)-4-hydroxy-2-butanone (8e)[13]
À
1H NMR (500 MHz, CDCl3/TMS): d=2.24 (s, 3H), 2.70–3.17 (m, 2H),
3.72 (d, J=3.0 Hz, 1H), 5.68 (m, 1H), 7.45 (t, J=7.5 Hz, 1H; ArH), 7.68
(t, J=7.5 Hz, 1H; ArH), 7.90 (d, J=8.0 Hz, 1H; ArH), 7.97 ppm (d, J=
8.0 Hz, 1H; ArH); HPLC (Daicel Chiralpak OB-H column, 0.46fꢁ
25 cm, hexanes/2-propanol=95:5, flow rate: 1.0 mLminÀ1, l=254 nm,
258C): tR (S)=24.2 min, tR (R)=26.2 min.
ACHTUNGTRENNUNG
cussed in Scheme 3, path B, rather than our previous hy-
pothesis (path A), in which the amine group in the side
chain was hypothesized to act as the base. Aldol reactions
of other substrates, such as mono- and dihydroxyacetone,
with benzaldehydes and non-activated aldehydes are now
underway.[21]
These results should afford useful information concerning
the reaction mechanism of the aldol reaction catalyzed by
artificial Zn2+ catalysts and should extend our knowledge of
the mechanism of action of class-II aldolases.
UV Titrations
UV spectra were recorded on a JASCO UV/Vis spectrophotometer V-
550 at 25
G
at a given wavelength) were analyzed for apparent complexation con-
stants, Kapp, by using the BIND WORKS software program (Calorimetry
Sciences Corp).
CD Titrations
CD and absorption spectra were recorded on a Chiralscan CD spectropo-
larimeter (Applied Photophysics Ltd.). All of the solutions of acac with
various concentrations of l-proline and the ZnL complexes were pre-
pared before the measurements.
Experimental Section
General Procedure for the Catalytic Aldol Reactions between Acetone and
Various Benzaldehydes (Table 1–Table 4)
Stopped-Flow Experiments
The chiral ligands (l-L1–l-L13 and L16–L19, 0.025 mmol) were extracted
from their 0.2m NaOH aqueous solutions (1 mL) with CHCl3. TFA salts
of ligands l-L14 and l-L15 were deprotonated by column chromatography
on NH-silica gel (MeOH) to afford ligands l-L14 and l-L15. After drying
the combined organic layer over anhydrous Na2SO4, the solution was fil-
tered and concentrated under reduced pressure. The remaining residue
Stopped-flow spectrophotometry experiments were performed in DMSO/
H2O at 258C on an SX18MV stopped-flow reaction analyzer (Applied
Photophysics Ltd.).
Crystallographic Study of Complex 16 (l-ZnL10
ACTHNUGTRNEUGN(NO3)2)
was added to a solution of ZnACTHNUTRGNE(NUG NO3)2·6H2O (0.0375 mmol) in a solvent
All measurements were performed on a Rigaku Saturn 724+ diffractom-
eter by using multilayer mirror monochromated MoKa radiation at 93 K.
The structure was solved by using direct methods and expanded by using
Fourier techniques. All of the calculations were performed by using the
CrystalStructure crystallographic software package except for refine-
ments, which were performed by using SHELXL-97.
(0.1 or 0.05 mL) and acetone (0.4 or 0.45 mL) and the mixture was stirred
for 10 min. The aldehyde substrate (0.5 mmol) was added and the result-
ing reaction mixture was stirred for 24–96 h at 25 or 308C. The reaction
mixture was diluted with water (2 mL) and extracted with EtOAc (3ꢁ
5 mL). The combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel (hexanes/EtOAc)
to provide the pure aldol product. The optical purities of the aldol prod-
ucts were determined by HPLC on a chiral HPLC column, as described
below.[13]
Crystallographic data: C21H31N8O7Zn; Mr =572.91; colorless prisms; crys-
tal size 0.16ꢁ0.11ꢁ0.05 mm3; monoclinic; space group P2
CHTUNGTRENNUNG
1A
17.756(2),
b=10.8511(12),
c=27.114(3) ꢂ;
b=95.087(3)8;
5203.5(10) ꢂ3; Z=8; 1calcd =1.462 gcmÀ3; 84807 reflections measured;
19150 unique reflections (Rint =0.0000); 2qmax =51.0; R1=0.0994 and
wR2=0.3230; GOF=1.247.
4-(2-Chlorophenyl)-4-hydroxy-2-butanone (8a)[10,13]
CCDC 916249 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1H NMR (500 MHz, CDCl3/TMS): d=2.23 (s, 3H), 2.65–3.02 (m, 2H),
5.51 (m, 1H), 7.18–7.34 (m, 3H; ArH), 7.61–7.63 ppm (m, 1H; ArH);
HPLC (Daicel Chiralpak AD-H column, 0.46fꢁ25 cm, hexanes/EtOH=
95:5, flow rate: 1 mLminÀ1, l=254 nm, 258C): tR (S)=13.5 min, tR (R)=
14.8 min.
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Shin Aoki et al.
Crystallographic Study of Complex 19 (l-ZnL13·
(NO3) ·
E
Chem. Biol. Drug Des. 2010, 76, 181–186; s) S. Kobayashi, M.
Kokubo, K. Kawasumi, T. Nagano, Chem. Asian J. 2010, 5, 490–492;
t) A. Karmakar, T. Maji, S. Wittmann, O. Reiser, Chem. Eur. J.
2011, 17, 11024–11029; u) L. Lin, K. Yamamoto, S. Matsunaga, M.
Kanai, Angew. Chem. Int. Ed. 2012, 51, 10275–10279.
All measurements were performed on a Rigaku Saturn 724+ diffractom-
eter by using multilayer mirror monochromated MoKa radiation at 93 K.
The structure was solved by using direct methods and expanded by using
Fourier techniques. All of the calculations were performed by using the
CrystalStructure crystallographic software package except for refine-
ments, which were performed by using SHELXL-97.
[3] a) B. List, R. A. Lerner, C. F. Barbas III., J. Am. Chem. Soc. 2000,
122, 2395–2396; b) W. Notz, B. List, J. Am. Chem. Soc. 2000, 122,
7386–7387; c) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III., J.
Am. Chem. Soc. 2001, 123, 5260–5267; d) B. List, Acc. Chem. Res.
2004, 37, 548–557; e) W. Notz, F. Tanaka, C. F. Barbas III., Acc.
Chem. Res. 2004, 37, 580–591.
Crystallographic data: C23H37N7O9Zn; Mr =620.97; colorless blocks; crys-
tal size 0.18ꢁ0.16ꢁ0.10 mm3; orthorhombic; space group P212121; a=
8.9542(10), b=13.8731(16), c=22.133(3) ꢂ; V=2749.4(6) ꢂ3; Z=4;
1calcd =1.500 gcmÀ3; 34016 reflections measured; 6262 unique reflections
(Rint =0.0394); 2qmax =55.0; R1=0.0310 (wR2=0.1235); GOF=1.255.
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CCDC 916248 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank Prof. Reiko Kuroda (Research Institute for Science and Tech-
nology, Tokyo University of Science) for her helpful discussions. This
work was supported by Grants-in-Aid from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT) of Japan (19659026,
22390005, 22659005, and 24659058) and by the High-Tech Research
Center Project for Private Universities (matching the fund subsidy from
MEXT). M.K. is thankful for a Grant-in-Aid from MEXT of Japan
(20750081) and a Sasakawa Scientific Research Grant from the Japan
Science Society (Tokyo).
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Received: March 8, 2013
Revised: April 29, 2013
Published online: && &&, 0000
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