Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol and mannich-type reactions

Article abstract of DOI:10.1002/tcr.201100020

Catalytic asymmetric synthesis of unnatural amino acids with vicinal tetrasubstituted chiral carbon stereocenters is described. In the first part, direct catalytic asymmetric aldol reaction of simple non-activated ketone electrophiles with α-substituted α-isothiocyanato ester donors was realized. A Mg/Schiff base catalyst promoted the aldol reaction, and α-amino-β-hydroxy esters were obtained in up to 98% ee and 98:2 d.r. In the second part, the Mg/Schiff base catalyst and a Sr/Schiff base catalyst were utilized for stereodivergent direct asymmetric Mannich-type reaction of ketimines. The Mg/Schiff base catalyst gave syn-α,β-diamino esters, while the Sr/Schiff base catalyst produced anti-α,β-diamino esters in good to high enantioselectivity, up to 97% ee.

Full text of DOI:10.1002/tcr.201100020

Construction of Contiguous
Tetrasubstituted Chiral Carbon
Stereocenters via Direct Catalytic
Asymmetric Aldol and
T H E
C H E M I C A L
R E C O R D
Mannich-Type Reactions
SHIGEKI MATSUNAGA* AND TATSUHIKO YOSHINO
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
Received: July 30, 2011
ABSTRACT: Catalytic asymmetric synthesis of unnatural amino acids with vicinal tetrasubsti-
tuted chiral carbon stereocenters is described. In the first part, direct catalytic asymmetric aldol
reaction of simple non-activated ketone electrophiles with a-substituted a-isothiocyanato ester
donors was realized. A Mg/Schiff base catalyst promoted the aldol reaction, and a-amino-b-
hydroxy esters were obtained in up to 98% ee and 98:2 d.r. In the second part, the Mg/Schiff base
catalyst and a Sr/Schiff base catalyst were utilized for stereodivergent direct asymmetric Mannich-
type reaction of ketimines. The Mg/Schiff base catalyst gave syn-a,b-diamino esters, while the
Sr/Schiff base catalyst produced anti-a,b-diamino esters in good to high enantioselectivity, up to
97% ee. DOI 10.1002/tcr.201100020
Keywords: amino acids, aldol reaction, asymmetric synthesis, bifunctional catalysts, Mannich
reaction
Introduction
Catalytic asymmetric aldol reaction and Mannich-type reaction
are powerful methods for synthesizing chiral b-hydroxy carbo-
nyl compounds and b-amino carbonyl compounds.[1,2] Among
them, the “direct” variants provide atom-economical processes
over conventional Mukaiyama-type reactions, because the reac-
tion proceeds under simple proton transfer conditions via cata-
lytic in situ enolate formation.[3] Tremendous progress has been
achieved in the direct aldol and Mannich-type reactions in the
past decade, and many chiral metal catalysts and organocatalysts
have been developed for reactions of aldehyde and aldimine
electrophiles.[4,5] The authors, in collaboration with Prof. M.
Shibasaki, have also reported various bifunctional acid/base
asymmetric metal catalysts for those reactions.[6] Representative
catalysts developed in our group are shown in Figure 1, namely,
a trinulcear Zn/linked-BINOL catalyst,[7] linked-BINOL-
catalysts using either In(O-iPr)3, Y{N(SiMe3)2}3, or La(O-
iPr)3,[8] a heterobimetallic La/Li/Pybox catalyst,[9] a Ba(O-iPr)2/
BINOL catalyst,[10] dinuclear Ni2-Schiff base catalysts,[11] and
others. In these bifunctional metal catalyst systems, metal ary-
loxide moieties function as a Brønsted base to deprotonate the
a-proton to generate metal enolate species in situ. Lewis acidic
metal center also played key roles for activating electrophiles and
controlling their orientation, leading to high enantio- and
diastereoselectivity.
Despite intensive investigations on direct aldol and
Mannich-type reactions in the past decade, the use of ketone
and/or ketimine electrophiles in the direct reactions for con-
structing tetrasubstituted carbon stereocenters is still limited to
either activated ketones, such as a-keto esters, a-keto phospho-
nates, isatins, and their aza-analogues, or intramolecular direct
260 www.tcr.wiley-vch.de
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim

C o n t i g u o u s Te t r a s u b s t i t u t e d C h i r a l C a r b o n S t e r e o c e n t e r s
aldol reactions with limited examples.[4,5] Intermolecular direct
achieved using either preformed silyl enolates[15] or in situ
generated enolates with stoichiometric amounts of reducing
reagents, i.e. reductive aldol reactions,[16] a direct catalytic
asymmetric intermolecular aldol reaction of simple non-
activated ketone electrophiles under proton transfer conditions
has not been achieved. The direct intermolecular aldol reaction
of non-activated ketone electrophiles is difficult due to the
small equilibrium constants for ketone electrophiles in com-
parison with those of aldehyde electrophiles (Scheme 1a vs.
Scheme 1b). For example, the equilibrium constant for the
aldol reaction of benzaldehyde as an electrophile and acetone as
a donor is 11.7 M-1, while that of acetophenone as an electro-
phile and acetone as a donor is 1.89 ¥ 10-3 M-1.[17] Therefore,
rapid retroaldol reaction of tertiary aldols was observed under
basic conditions even at -78 °C.[18] To overcome the inherent
instability of the tertiary aldols from ketone electrophiles under
basic conditions and to obtain products under kinetic control,
we hypothesized that irreversibly trapping the unstable tertiary
aldols in situ is important to produce more stable adducts.
On the basis of pioneering works by Ito and co-workers on
direct catalytic asymmetric aldol reaction of aldehydes with
aldol reaction of simple non-activated ketones and Mannich-
type reaction of ketimines derived from simple ketones are still
formidable tasks.[12] Thus, the development of new catalysts
for realizing direct aldol reaction of ketone electrophiles and
Mannich-type reaction of ketimine electrophiles is highly desir-
able. Moreover, catalytic asymmetric construction of vicinal
tetrasubstituted chiral carbon stereocenters in carbon-carbon
bond-forming reactions is rare,[13] possibly owing to severe steric
hindrance. In this account, we describe our efforts to address
these issues. Group 2 metal/Schiff base 1 complexes (Figure 2)
promoted a direct aldol reaction of simple ketone electrophiles
and a Mannich-type reaction of ketimines with a-substituted
a-isothiocyanate esters 2, leading to unnatural amino acids
with vicinal tetrasubstituted carbon stereocenters.[14]
Intermolecular Direct Catalytic Asymmetric Aldol
Reaction of Ketone Electrophiles
Although catalytic asymmetric intermolecular aldol reactions
with simple non-activated ketone electrophiles have been
᭤
Shigeki Matsunaga is an associate professor at the University of Tokyo. He was born in 1975
(Kyoto) and received his Ph.D. from The University of Tokyo under the direction of Prof.
Masakatsu Shibasaki. He started his academic career in 2001 as an assistant professor in Prof.
Shibasaki’s group at The University of Tokyo. He was promoted to lecturer in 2008, and to his
current position in 2011. He is the recipient of the Chemical Society of Japan Award for Young
Chemists (2006), Mitsui Chemicals Catalysis Science Award of Encouragement (2009), Banyu
Chemist Award (2009), Inoue Research Science Award (2010), Lectureship Award MBLA
2010, and others. His research interests are in the development of new catalytic reactions using
cooperative functions of multimetallic complexes, mechanistic studies, and the synthesis of
biologically active compounds.
᭿
᭤
Tatsuhiko Yoshino was born in Gunma, Japan in 1986. He recieved B.S. degree from The
University of Tokyo in 2009 under the guidance of Professor Masakatsu Shibasaki. He is
currently studying for Ph.D. under the direction of Professor Motomu Kanai in the Graduate
School of Pharmaceutical Sciences at the same university. His current research interests are
focused on development of novel catalytic atom-economical reactions for organic synthesis.
᭿
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim
www.tcr.wiley-vch.de 261

T H E C H E M I C A L R E C O R D
O
OH
thf
OH HO
OH HO
O
O
O
O
O
O
Zn
Zn
thf
Zn
thf
O
O
HO
+ In(O-iPr)3, La(O-iPr)3, Y[N(SiMe3)2]3
metal/linked-BINOL catalysts
trinuclear Zn/linked-BINOL catalyst
O
O
N
O
N
O
N
OH
Ni
Ni
+ Ba(O-iPr)2
N
N
La
(OAr)3
+
OH
O
O
LiOAr
homodinuclear
Ni2-Schiff base complex
heterobimetallic
La/Li pybox catalyst
Ba/BINOL catalyst
Fig. 1. Representative acid/base bifunctional metal catalysts developed in our group for direct aldol reactions of
aldehydes and Mannich-type reactions of aldimines.
a) aldehyde electrophiles
OH
X
O
O
H
R1
O
X
OMe
OMe
+
OMe
R1
Y
H
Y
favorable
N
N
O
b) ketone electrophiles
S C N
OH
O
R2
R1
O
Y
OH HO
Y
OMe
O
X
+
R
OMe
R2
R1
X
Y
X
X
unfavorable
S
Y
2a: R = Me
2b: R = Et
1a: X = OMe, Y = H
1b: X = tBu, Y = H
1c: X = H, Y = H
c) in situ trapping of tertiary aldol
S
•
O
O
O
R2
R1
R2
R1
O
1d: X = OMe, Y = OMe
SCN
+
NH
N
OMe
R2
R1
R3
R3
OMe
R3
Fig. 2. Structures of Schiff bases 1a-1d and a-substituted a-isothiocyanato
esters 2.
O
OMe
O
Scheme 1. In situ trapping strategy to obtain aldol-type adducts from ketone
electrophiles.
a-isocyano esters[19] and closely related recent works by Willis,
Seidel, and Feng using a-isothiocyanato imides and aldehyde
electrophiles,[20,21] we selected a-isocyano esters and a-
isothiocyanato esters as donors. For the challenging construc-
tion of vicinal tetrasubstituted carbon stereocenters, a-methyl
substituted donors were used in the initial screening. As
shown in Scheme 1c, we anticipated that thermodynamically
unfavorable tertiary aldol adduct can be rapidly trapped in
intramolecular fashion to afford protected unnatural a-
amino-b-hydroxy acids.
ketone electrophiles. As a part of our ongoing project on bifunc-
tional Schiff base catalysis,[22–25] we screened various metal/
Schiff base complexes. Bimetallic Schiff base catalysts,[23,24]
which often showed superior stereoselectivity and reactivity to
monometallic Schiff base catalysts, did not afford satisfactory
results for the present aldol reaction. Instead, a 1:1 mixture of
Bu2Mg and Schiff base 1a (Figure 2) derived from vanillin and
binaphthyldiamine gave promising reactivity, enantioselectiv-
ity, and diastereoselectivity (Table 1, entry 1, >95% yield, 93:7
d.r., and 95% ee). In contrast, Schiff base 1b bearing tert-butyl
substituents, which is often used as a most effective ligand in
Although a-isocyano esters did not afford promising
results in terms of both yield and stereoselectivity, a-methyl
a-isothiocyanato ester 2a showed good reactivity towards
262 www.tcr.wiley-vch.de
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim

C o n t i g u o u s Te t r a s u b s t i t u t e d C h i r a l C a r b o n S t e r e o c e n t e r s
Table 1. Optimization studies of direct aldol reaction of
acetophenone and a-isothiocyanato ester.
metal/salen chiral catalysts, resulted in poor reactivity and selec-
tivity (entry 2). Schiff base 1c without a substituent showed
good reactivity, but resulted in poor stereoselectivity (entry 3,
10% ee). Thus, the methoxy groups in Schiff base 1a are
essential for the present reaction. The 1H NMR spectrum of the
Bu2Mg/Schiff base 1a was quite complicated, which is possibly
due to the oligomeric structure of the catalyst. ESI-MS analysis
also supported the oligomeric nature of the Mg catalyst. The
chelating ortho-methoxy group would play a key role to
enhance the oligomeric Mg/Schiff base = n:n complex forma-
tion rather than a standard 1:1 complex. Other metal sources,
such as Et2Zn, Ba(O-iPr)2, and La(O-iPr)3 which we previously
utilized in direct aldol and Mannich-type reactions,[7–10] also
resulted in poor stereoselectivity or reactivity (entries 4–6).
Among the solvents screened, the best diastereoselectivity and
enantioselectivity were observed in toluene, giving product 4aa
in 97% yield, 97:3 d.r., and 97% ee (entry 7).
S
metal source/
O
(R)-ligand 1 = 1:1
O
O
SCN
Me
Ph
(10 mol %)
+
Me
NH
OMe
Ph
solvent (1.0 M)
MS 5Å, RT
Me
2a
Me
OMe
3a
O
4aa
(2.0 equiv)
metal
source
time
%
entry
ligand solvent [h] yield[a] d.r.[a] % ee
1
2
3
4
5
6
7
Bu2Mg
Bu2Mg
Bu2Mg
Et2Zn
Ba(OiPr)2
La(OiPr)3
Bu2Mg
1a
1b
1c
1a
1a
1a
1a
THF
THF
THF
THF
THF
THF
43 >95
43 13
93:7
95
0
52:48
43 >95
68:32 10[c]
43
0
—
—
43 >95
38:62 21[c]
43 90
75:25 14[c]
toluene 36 97[b]
97:3
97
The substrate scope of the reaction is summarized in
Table 2. The Bu2Mg/Schiff base 1a complex promoted the
addition of a-isothiocyanato ester 2a to aryl and heteroaryl
methyl ketones (entries 1–10). The reaction proceeded even
with 2.5 mol % catalyst loading, while maintaining high yield,
d.r., and enantioselectivity (entry 2). A longer reaction time
[a]Determined by 1H NMR analysis of the crude mixture. [b]Isolated yield after
purification by column chromatography. [c]ent-4aa was obtained as the major
product.
Table 2. Bu2Mg/Schiff base-catalyzed direct asymmetric aldol reaction of ketone eletrophiles with a-substituted a-isothiocyanato esters 2.
S
O
Bu2Mg/(R)-Schiff base 1
O
O
R'
=1:1 (x mol %)
SCN
NH
+
OMe
R
toluene (1.0 M)
MS 5Å, RT
R
R'
R''
CO2Me
R''
2a: R'' = Me
2b: R'' = Et
3
(2.0 equiv)
4
ketone:3
ligand 1
time
entry
R
R′
2
[x mol %]
[h]
4
% yield[a]
d.r.[b]
% ee
1
2[c]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3a
3b
3h
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
1a (10)
1a (2.5)
1a (10)
1a (10)
1a (10)
1a (10)
1a (10)
1a (10)
1a (10)
1a (10)
1a (20)
1d (20)
1d (20)
1d (20)
1a (10)
1a (10)
1a (10)
36
69
36
48
48
48
48
48
48
48
48
48
48
48
48
48
48
4aa
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4ab
4bb
4hb
97
95
89
99
92
91
68
87
93
71
75
81
79
96
94
76
84
97:3
96:4
97:3
96:4
95:5
95:5
85:15
86:14
98:2
91:9
—
74:26
81:19
78:22
91:9
95:5
96:4
97
97
98
98
95
95
89
97
98
95
94
97
93
96
82
95
95
4-Cl-C6H4
3-Cl-C6H4
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
2-furyl
3-thienyl
4-pyridyl
–(CH2)4–
PhCH2CH2
cyclopropyl
Ph
4-Cl-C6H4
3-thienyl
[a]Isolated yield based on the amount of 2 used. [b]Determined by 1H NMR analysis of the crude mixture. [c]Reaction was performed in toluene (2.0 M).
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim
www.tcr.wiley-vch.de 263

T H E C H E M I C A L R E C O R D
Table 3. Optimization studies of stereodivergent direct
Mannich-type reaction of ketimine and a-isothiocyanato ester.
O
Me
Ph
N
O
S
O
Me
CO2Me
metal source/(R)-1
= 1:1 (10 mol %)
2a (2 equiv)
O
OH
S
S
5aa
PPh2
Me
Ph
O
Ph2P
Me
Ph2P
Ar
a
b
N
Me
Ph
NH2·HCl
Me
N
N
+
NH
NH
NH
+
Ar
Me
OH
solvent, MS 5Å, RT
Me
CO2Me
CO2Me
7aa
82% in 2 steps
Me
Ph
Ar
Me
HN CHO
CO2Me
CO2Me
8a
Me
Me
Me
4aa
Ar = 4-Br-C6H4
6aa CO2Me
syn-9aa
anti-9aa
metal
source
time
%
d.r.[a]
% ee
Scheme 2. Transformation of aldol adduct into a-amino-b-hydroxy ester.
Reagents and conditions: a) Raney Ni, H2 (1 atm) MeOH, 50 °C, 14 h; then
silica gel column; b) conc. HCl, MeOH, 55 °C, 3 h, 82% yield (from 4aa).
entry
(R)-1 solvent [h] yield[a] [synlanti] [syn]
1
2
3
Bu2Mg
Bu2Mg
Bu2Mg
Bu2Mg
Ca(OiPr)2 1d
Sa(OiPr)2 1d
Ba(OiPr)2 1d
1a
1d
1d
1d
THF
THF
47
28
>95
>95
>95
87[c]
trace
86[c]
trace
68:32
71:29
86:14
91:9
ND
44
67
80
84
ND
92[d]
ND
CHCl3 20
CHCl3 48
CHCl3 48
CHCl3 48
CHCl3 48
(69 h), however, was required owing to the modest catalyst
turnover frequency even under highly concentrated conditions.
Various acetophenone derivatives with either an electron-
donating or electron-withdrawing substituent at the para or
meta position of the aromatic ring gave products in good yield,
d.r., and high enantioselectivity (entries 3–6, 95–98% ee).
Compound 3f with a 4-MeO substituent, however, resulted in
a somewhat lower stereoselectivity and yield (entry 7, 89% ee).
Heteroaryl ketones 3g-3i were also applicable, giving products
in 95–98% ee (entries 8–10). Ketones 3j-3m showed lower
reactivity than aryl methyl ketones, and 20 mol % of catalyst
was required to obtain the products in good yield (entries
11–14). Cyclic ketone 3j gave 4ja in 75% yield and 94% ee
(entry 11). For alkyl methyl ketone 3k, the Bu2Mg/1a complex
resulted in poor yield (<30%). Modification of the Schiff base
ligand was effective to improve yield, and a Bu2Mg/1d complex
gave 4ka in 81% yield and 97% ee (entry 12). Because ligand 1d
with additional MeO substituents showed better reactivity for
ketone 3k than 1a, we believe that the nucleophilicity of a
Mg-enolate generated from the Bu2Mg/1 catalysts is important
to efficiently promote the present reaction. The Bu2Mg/1d
complex was also applicable to ketone 3l and alkenyl ketone 3m,
giving products in 93–96% ee (entries 13–14). The reaction
with a-ethyl isothiocyanato ester 2b proceeded smoothly to
afford products in good yield and diastereoselectivity (76–94%,
92:8–96:4 d.r.), but the enantioselectivity somewhat decreased
to 82–95% ee (entries 15–17). Synthetic utility of the products
was demonstrated via transformation of 4aa into a-amino-b-
hydroxy ester (Scheme 2). Treatment of 4aa with Raney Ni in
MeOH gave the desulfurated adducts 5aa and 6aa, which were
readily hydrolyzed under acidic conditions to give a-amino-b-
hydroxy ester•HCl salt 7aa in 82% yield (two steps).
4[b]
5
6
7
6:94
ND
[a]Determined by 1H NMR analysis of the crude mixture. [b]Reaction was run
at -10 °C. [c]Isolated yield after column chromatography. [d]Enantiomeric
excess of anti-9aa.
a-amino equivalent unit provide straightforward access to chiral
a,b-diamino acids.[27] For the synthesis of a,b-diamino acids
bearing an a-tetrasubstituted carbon center, several groups
including ours have reported Mannich-type reactions of
aldimines with a,a-disubstituted donors, such as an alanine
methyl ester Schiff base,[28] a-substituted nitroacetates,[11a,29]
and a-substituted oxazolones.[30] In contrast, there is no report
of the catalytic asymmetric Mannich-type reaction for b-
tetrasubstituted a,b-diamino acid synthesis, which require the
reaction with much less reactive ketimines. On the basis of
successful results in direct aldol reaction of ketone electrophiles
described in the previous section, we decided to expand the
utility of the Mg/Schiff base 1a catalyst for the Mannich-type
reaction of ketimines.
Among ketimines screened, diphenylphosphinoyl (Dpp)
ketimines gave promising results in terms of reactivity and
selectivity. Optimization studies are summarized in Table 3. A
1:1 ratio of Bu2Mg/Schiff base 1a (10 mol %) promoted the
addition of a-methyl a-isothiocyanato ester 2a to ketimines 8a
to give 9aa in >95% yield in THF at room temperature (entry
1). Diastereoselectivity and enantioselectivity were, however,
moderate (syn/anti = 68:32, 44% ee). Schiff base 1d with addi-
tional methoxy substituents improved the enantioselectivity to
67% ee (entry 2). Among the solvents screened, CHCl3 gave
the best selectivity, and 9aa was obtained in 86:14 (syn/anti)
diastereoselectivity and 80% ee at room temperature (entry 3).
The best syn selectivity and enantioselectivity were obtained
at -10 °C (entry 4, 91:9 and 84% ee). In entries 5–7, other
Group 2 metals were screened. Although Ca(O-iPr)2 and
Ba(O-iPr)2 gave poor results, Sr(O-iPr)2 gave 9aa in 86%
Direct Catalytic Asymmetric Mannich-Type Reaction
of Ketimines
Chiral a,b-diamino acids are important structural motifs found
in many biologically active compounds.[26] Direct catalytic
asymmetric Mannich-type reactions with donors bearing an
264 www.tcr.wiley-vch.de
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim

C o n t i g u o u s Te t r a s u b s t i t u t e d C h i r a l C a r b o n S t e r e o c e n t e r s
Table 4. Mg/Schiff base-catalyzed syn-selective direct Mannich-type
reaction of ketimines.
O
S
Ph2P
Me
O
N
HN
O
Bu2Mg/(R)-1d
O
Me
Ar
S
S
a
PPh2
NH
= 1:1 (10 mol %)
Ph2P
Me
R
Ph2P
R
N
N
N
2a (2 equiv)
N
Ar
CO2Me
CO2Me
NH
NH
+
Me
anti-9da
Ar = 4-Me-C6H4
R
Me
Me
solvent, MS 5Å
temp
Me
CO2Me
10da, 85%
CO2Me
8
Me
Me
syn-9
(major)
anti-9
(minor)
b
S
Ph
temp time
[°C] [h]
%
d.r.[b] % ee
entry R:ketimine
8
9
yield[a] [synlanti] [syn]
HN
HN
N
Me
Me
Ar
c
NH
1[c]
2[c]
3[c]
4[d]
5[d]
6[d]
4-Br-C6H4 8a -10 48 9aa
4-Cl-C6H4 8b -10 48 9ba 90 92:8
4-F-C6H4 8c 44 9ca 96 93:7
4-Me-C6H4 8d -25 48 9da 94 92:8
87 91:9
84
85
84
79
82
81
Ar
CO2Me
CO2Me
Me
Me
11da, 96%
12da, 71%
0
Scheme 3. Transformation of Mannich-adduct into imidazolines. Reagents
and reaction conditions: a) Raney Ni, MeOH, H2 (1 atm), 60 °C, 22 h, 85%
yield; b) Cp2Zr(H)Cl, toluene, RT, 4 h, 96% yield; c) PhB(OH)2, CuTC (3
equiv), Pd(PPh3)4 (10 mol %), DMF, microwave, 130 °C, 1 h, 71% yield.
3-Me-C6H4 8e -25 48 9ea
99 90:10
96 92:8
8f
-5 17 9fa
O
O
7[c]
8[d]
9[c]
2-naphthyl 8g
0
48 9ga
99 93:7
95
81
80
3-thienyl
2-furyl
8h -25 48 9ha 80 93:7
8i -5 48 9ia 70 93:7
4-dimethylamino group had adverse effects on the reactivity,
while high anti selectivity and enantioselectivity were
maintained (entry 8, syn/anti = 4:96, 97% ee). Heteroaryl
ketimines were also applicable as shown in entries 10–12. The
products were obtained in 84–92% ee, but slightly lower anti
selectivity was observed in comparison with aryl ketimines.
Unfortunately, neither Mg nor Sr Schiff base 1d catalyst was
suitable for other types of ketimines, such as aryl ethyl
ketimines and aliphatic ketimines, owing to the poor reactivity
of these ketimines. The a-ethyl-a-isothiocyanato ester 2b
also showed much lower reactivity and stereoselectivity than
a-methyl-a-isothiocyanato ester 2a (Table 5, entry 5 vs. entry
13). This is possibly due to the severe steric hindrance in the
construction of vicinal tetrasubstituted carbon centers from
diphenylphosphinoyl ketimines. Further studies are required to
overcome the steric hindrance and broaden the substrate scope
of ketimines and a-isothiocyanato esters.
To show the synthetic utility of the protected a,b-diamino
esters 9, transformations that utilize the unique cyclic thiourea
unit in 9 were demonstrated (Scheme 3). Treatment of anti-
9da with Raney Ni in MeOH gave the desulfurated adduct
10da in 85% yield. Because the 2-aryl-substituted imidazolines
are useful in the field of medicinal chemistry for the design of
Nutlin analogues as potent antitumor agents,[31] direct desulfu-
rative cross-coupling reaction of cyclic urea to 2-aryl-
imidazoline was also investigated.[32] After removal of the
diphenylphosphinoyl group in 9da with Cp2Zr(H)Cl (96%
yield), a Pd-catalyzed cross-coupling reaction of 11da with
PhB(OH)2 proceeded in the presence of excess Cu(thiophen-
2-carboxylate) (CuTC) in DMF under microwave irradiation
(130 °C, 1 h) to give 2-phenyl-imidazoline 12da with vicinal
tetrasubstituted carbon stereocenters in 71% yield.
[a]Isolated yield of 9 after purification by column chromatography. [b]Deter-
mined by 1H NMR analysis of the crude mixture. [c]Reaction was run in
CHCl3 (0.2 M). [d]Reaction was run in THF (0.2 M).
isolated yield (entry 6). In addition, the use of Sr(O-iPr)2/
Schiff base 1d = 1:1 mixture led to an unexpected reversal
of the diastereoselectivity, and the anti adduct was obtained
in high diastereoselectivity (6:94 = syn/anti) and enantioselec-
tivity (92% ee, anti-9aa) at room temperature.
The substrate scope of the Mg and Sr-catalyzed reaction is
summarized in Tables 4 and 5. The reaction temperature and
solvent were optimized for each ketimine, and the best results
are listed. Various aryl and heteroaryl ketimines were applicable
with the Mg/Schiff base 1d, and products were obtained in
good to high yield. Although enantioselectivity was more or
less 80% ee (79–85% ee), except for ketimine 8g (9ga, 95% ee,
entry 7), high syn selectivity (90:10–93:7) was achieved in all
cases in Table 4. The results of the Sr/Schiff base-catalyzed
anti-selective reaction are shown in Table 5. Absolute and rela-
tive configurations of the products in Table 4 and Table 5 were
unequivocally determined by X-ray crystallographic analysis,
and the enantiofacial selectivity of the reaction of ketimines
catalyzed by the Sr/Schiff base 1d was opposite to that of the
reaction catalyzed by the Mg/Schiff base 1d. Aryl ketimines
gave Mannich adducts with high anti selectivity and enanti-
oselectivity at either room temperature or -5 °C (entries 1–9).
Good yields were obtained even with ketimines bearing an
electron-donating group at the para position, such as
4-Me-C6H4 imine 8d (entry 5) and 4-MeO-C6H4 imine 8k
(entry 7). On the other hand, a strongly electron-donating
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim
www.tcr.wiley-vch.de 265

T H E C H E M I C A L R E C O R D
Table 5. Sr/Schiff base-catalyzed anti-selective direct Mannich-type reaction of ketimines.
O
Sr(O-iPr)2/(R)-1d
= 1:1 (10 mol %)
2a or 2b (2 equiv)
O
O
S
PPh2
S
Ph2P
R
Ph2P
Me
R
N
N
N
NH
NH
+
R
Me
solvent, MS 5Å,
temp
Me
CO2Me
CO2Me
8
R'
syn-9
(minor)
R'
anti-9
(major)
R' = Me from 2a, Et from 2b
temp
[°C]
time
[h]
%
d.r.[b]
[synlanti]
% ee
[anti]
entry
R:ketimine
8
2
9
yield[a]
1[c]
2[c]
3[c]
4[c]
5[d]
6[d]
7[d]
8[d]
9[d]
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-CF3-C6H4
4-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
4-Me2N-C6H4
O
8a
8b
8c
8j
8d
8e
8k
8l
2a
2a
2a
2a
2a
2a
2a
2a
2a
25
25
25
25
25
25
25
25
-5
48
48
48
48
20
24
24
69
47
9aa
9ba
9ca
9ja
9da
9ea
9ka
9la
86
82
71
85
97
99
91
45
76
6:94
10:90
6:94
11:89
6:94
8:92
4:96
4:96
6:94
92
87
90
92
95
93
97
97
95
8f
9fa
O
2a
2a
2a
2a
2b
10[d]
11[d]
12[d]
13[d]
2-thienyl
3-thienyl
2-furyl
8m
8h
8i
0
-5
-10
25
48
48
48
24
9ma
9ha
9ia
70
74
84
33
13:87
12:88
17:83
15:85
90
92
84
57
4-Me-C6H4
8d
9db
[a]Isolated yield of 9 after purification by column chromatography. [b]Determined by 1H NMR analysis of the crude mixture. [c]Reaction was run in CHCl3 (0.2 M).
[d]Reaction was run in CHCl3/THF = 2:1 (0.17 M).
In Tables 4 and 5, interesting reversal of diastereoselec-
tivity was observed just by changing the Group 2 metal
source from Bu2Mg to Sr(O-iPr)2. Because both the
Mg/Schiff base 1d and Sr/Schiff base 1d have complicated
1
oligomeric structures, H NMR analysis was not useful to
gain information on structural differences. Instead, circular
dichroism (CD) spectra provided an insight into the differ-
ences in aggregation form between the two catalysts.[33] As
shown in Figure 3, the CD spectra of Schiff base 1d alone
was clearly different from those of the Mg/Schiff base 1d and
Sr/Schiff base 1d, suggesting that a chiroptically different
aggregate was formed in each metal/Schiff base 1d = 1:1 solu-
tion. Moreover, clear differences between the Mg/Schiff base
1d and Sr/Schiff base 1d in the 210–250 nm region were
observed, which can be assigned to the difference in the dihe-
dral angle of the binaphthyl unit in the Mg/Schiff base 1d
and Sr/Schiff base 1d.[34] Because the dihedral angle of the
binaphthyl unit often plays a key role in the stereodiscrimi-
nating step of asymmetric reactions, we believe that the dif-
ference in the dihedral angles caused the observed reversal of
diastereoselectivity.
Figure 3. CD spectra of a) Schiff base 1d (black line), b) the Bu2Mg/1d = 1:1
(blue line), and c) the Sr(O-iPr)2/1d = 1:1 (red line).
266 www.tcr.wiley-vch.de
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim

C o n t i g u o u s Te t r a s u b s t i t u t e d C h i r a l C a r b o n S t e r e o c e n t e r s
37, 29; (c) B. Weiner, W. Szymanski, D. B. Janssen,
Conclusion
A. J. Minnaard, B. L. Feringa, Chem. Soc. Rev. 2010, 39, 1656.
[6] Accounts: (a) S. Matsunaga, M. Shibasaki, Bull. Chem. Soc.
Jpn. 2008, 81, 60; (b) M. Shibasaki, S. Matsunaga,
N. Kumagai, Synlett 2008, 1583; (c) M. Shibasaki, M. Kanai,
S. Matsunaga, N. Kumagai, Acc. Chem. Res. 2009, 42, 1117;
(d) M. Shibasaki, S. Matsunaga, J. Synth. Org. Chem. Jpn.
2010, 68, 1142.
[7] (a) N. Kumagai, S. Matsunaga, T. Kinoshita, S. Harada,
S. Okada, S. Sakamoto, K. Yamaguchi, M. Shibasaki, J. Am.
Chem. Soc. 2003, 125, 2169; (b) S. Matsunaga, N. Kumagai,
S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 4712;
(c) S. Matsunaga, T. Yoshida, H. Morimoto, N. Kumagai,
M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 8777; (d)
T. Yoshida, H. Morimoto, N. Kumagai, S. Matsunaga,
M. Shibasaki, Angew. Chem. Int. Ed. 2005, 44, 3470.
[8] (a) S. Harada, S. Handa, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed. 2005, 44, 4365; (b) M. Sugita, A. Yamaguchi,
N. Yamagiwa, S. Handa, S. Matsunaga, M. Shibasaki, Org.
Lett. 2005, 7, 5339; (c) T. Yukawa, B. Seelig, H. Morimoto,
S. Matsunaga, A. Berkessel, M. Shibasaki, J. Am. Chem. Soc.
2010, 132, 11988.
We have succeeded for the first time in the direct catalytic
asymmetric intermolecular aldol reaction of simple non-
activated ketone electrophiles and Mannich-type reaction
of ketimines derived from non-activated ketones using
a-substituted a-isothiocyanato esters as donors. Oligomeric
Group 2 metal/Schiff base complexes promoted the reaction
under proton transfer conditions, giving products in high dias-
tereoselectivity and enantioselectivity. The methods provided
access to unnatural a-amino acids bearing vicinal tetrasubsti-
tuted carbon stereocenters, which are not accessible via well-
established catalytic asymmetric hydrogenation processes. At
the moment, the substrate scope of the reactions is still limited,
especially in the case of direct Mannich-type reactions. Further
studies to expand the scope by modification of the Group 2
metal/Schiff base catalysts as well as trials to utilize the unique
unnatural a-amino acids with vicinal tetrasubstituted carbon
stereocenters for designing new biologically active compounds,
such as anti-tumor agents, and biological tools are intensively
ongoing in our group.
[9] (a) H. Morimoto, G. Lu, N. Aoyama, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2007, 129, 9588; (b) G. Lu,
H. Morimoto, S. Matsunaga, M. Shibasaki, Angew. Chem. Int.
Ed. 2008, 47, 6847; (c) H. Morimoto, T. Yoshino, T. Yukawa,
G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem. Int. Ed.
2008, 47, 9125.
Acknowledgements
We thank Prof. M. Shibasaki at the Institute of Microbial
Chemistry, Tokyo, for his generous support and fruitful dis-
cussions throughout the project. We also thank all co-authors,
especially Dr. H. Morimoto and Dr. G. Lu, for their outstand-
ing contributions. This work was supported by Grant-in-Aid
for Young Scientists (A) (23689002), Scientific Research on
Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” (23105509) from JSPS and MEXT,
the Inoue Science Foundation, Noguchi Foundation, and
Uehara Memorial Foundation. T.Y. thanks JSPS for fellowship.
[10] A. Yamaguchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc.
2009, 131, 10842.
[11] (a) Z. Chen, H. Morimoto, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2008, 130, 2170; (b) Z. Chen, K. Yakura,
S. Matsunaga, M. Shibasaki, Org. Lett. 2008, 10, 3239; (c)
Y. Xu, G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem. Int.
Ed. 2009, 48, 3353; (d) N. E. Shepherd, H. Tanabe, Y. Xu,
S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2010, 132,
3666.
[12] After our first report in Ref. [14], a related work on direct aldol
reaction to simple ketones was reported using 3-isothiocyanato
oxindoles as donors, see: (a) W.-B. Chen, Z.-J. Wu, J. Hu,
L.-F. Cun, X.-M. Zhang, W.-C. Yuan, Org. Lett. 2011, 13,
2472; for related work on direct catalytic asymmetric
a-addition of allyl cyanides to ketimines, see: (b) R. Yazaki,
T. Nitabaru, N. Kumagai, M, Shibasaki, J. Am. Chem. Soc.
2008, 130, 14477.
REFERENCES
[1] Reviews on asymmetric aldol reactions: (a) Modern Aldol Reac-
tions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; (b)
L. M. Geary, P. G. Hultin, Tetrahedron: Asymmetry 2009, 20,
131.
[2] Review on catalytic asymmetric Mannich(-type) reactions:
G. K. Friestad, A. K. Mathies, Tetrahedron, 2007, 63, 2541.
[3] Recent review on direct C-C bond-forming reactions under
proton transfer conditions, N. Kumagai, M. Shibasaki, Angew.
Chem. Int. Ed. 2011, 50, 4760.
[4] Review on direct catalytic asymmetric aldol reaction:
B. M. Trost, C. S. Brindle, Chem. Soc. Rev. 2010, 39, 1600.
[5] Reviews on direct catalytic asymmetric Mannich(-type) reac-
tion: (a) A. Ting, S. E. Schaus, Eur. J. Org. Chem. 2007,
5797; (b) J. M. M. Verkade, L. J. C. van Hemert,
P. J. L. M. Quaedflieg, F. P. J. T. Rutjes, Chem. Soc. Rev. 2008,
[13] Review: E. A. Peterson, L. E. Overman, Proc. Nat. Acad. Sci.,
USA 2004, 101, 11943.
[14] (a) T. Yoshino, H. Morimoto, G. Lu, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 17082; (b) G. Lu,
T. Yoshino, H. Morimoto, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed. 2011, 50, 4382
[15] Catalytic asymmetric intermolecular aldol reaction to simple
ketone electrophiles using silyl enolates: (a) S. E. Denmark,
Y. Fan J. Am. Chem. Soc. 2002, 124, 4233; (b) K. Oisaki,
Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2003, 125,
5644; (c) S. E. Denmark, Y. Fan, M. D. Eastgate, J. Org. Chem.
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim
www.tcr.wiley-vch.de 267

T H E C H E M I C A L R E C O R D
2005, 70, 5235; (d) K. Oisaki, D. Zhao, M. Kanai,
Biomol. Chem. 2005, 3, 2126; (c) W. Li, S. S. Thakur,
S.-W. Chen, C.-K. Shin, R. B. Kawthekar, G.-J. Kim, Tetra-
hedron Lett. 2006, 47, 3453; (d) C. Mazet, E. N. Jacobsen,
Angew. Chem. Int. Ed. 2008, 47, 1762; (e) J. Park, K. Lang,
K. A. Abboud, S. Hong, J. Am. Chem. Soc. 2008, 130, 16484;
(f) W. Hirahata, R. M. Thomas, E. B. Lobkovsky,
G. W. Coates, J. Am. Chem. Soc. 2008, 130, 17658; (g) J. Sun,
F. Yuan, M. Yang, Y. Pan, C. Zhu, Tetrahedron Lett. 2009, 50,
548; (h) B. Wu, J. C. Gallucci, J. R. Parquette,
T. V. RajanBabu, Angew. Chem. Int. Ed. 2009, 48, 1126; for
other examples, see a review in Ref. [22].
M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7164.
[16] Catalytic asymmetric reductive aldol reaction to simple
ketones: (a) J. Deschamp, O. Chuzel, J. Hannedouche,
O. Riant, Angew. Chem. Int. Ed. 2006, 45, 1292; (b) D. Zhao,
K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006,
128, 14440; intramolecular variant, see: (c) H. W. Lam,
P. M. Joensuu, Org. Lett. 2005, 7, 4225.
[17] J. P. Guthrie, J. Am. Chem. Soc. 1991, 113, 7249.
[18] M. Hatano, E. Takagi, K. Ishihara, Org. Lett. 2007, 9, 4527.
[19] Reviews: (a) M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857;
(b) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru,
V. G. Nenajdenko, Chem. Rev. 2010, 110, 5235.
[26] Review: A. Viso, R. Fernández de la Pradilla, A. García,
A. Flores, Chem. Rev. 2005, 105, 3167.
[20] a-Isothiocyanato imides for direct aldol reaction of aldehydes:
(a) M. C. Willis, G. A. Cutting, V. J.-D. Piccio, M. J. Durbin,
M. P. John, Angew. Chem. Int. Ed. 2005, 44, 1543; (b) L. Li,
E. Klauber, G. D. Seidel, J. Am. Chem. Soc. 2008, 130, 12248;
(c) X. Chen, Y. Zhu, Z. Qiao, M. Xie, L. Lin, X. Liu, X. Feng,
Chem. Eur. J. 2010, 16, 10124.
[21] a-Isothiocyanato imides for direct Mannich-type reaction of
aldimines: (a) G. A. Cutting, N. E. Stainforth, M. P. John,
G. Kociok-Köhn, M. C. Willis, J. Am. Chem. Soc. 2007, 129,
10632; (b) L. Li, M. Ganesh, D. Seidel, J. Am. Chem. Soc.
2009, 131, 11648; (c) Z. Shi, P. Yu, P. J. Chua, G. Zhong, Adv.
Synth. Catal. 2009, 351, 2797; (d) X. Chen, S. Dong, Z. Qiao,
Y. Zhu, M. Xie, L. Lin, X. Liu, X. Feng, Chem. Eur. J. 2011,
17, 2583.
[27] Review: R. Gómez Arrayás, J. C. Carretero, Chem. Soc. Rev.
2009, 38, 1940.
[28] J. Hernández-Toribio, R. Gómez Arrayás, J. C. Carretero, J.
Am. Chem. Soc. 2008, 130, 16150.
[29] (a) A. Singh, J. N. Johnston, J. Am. Chem. Soc. 2008, 130,
5866; (b) D. Uraguchi, K. Koshimoto, T. Ooi, J. Am. Chem.
Soc. 2008, 130, 10878; (c) B. Han, Q.-P. Liu, R. Li, X. Tian,
X.-F. Xiong, J.-G. Deng, Y.-C. Chen, Chem. Eur. J. 2008, 14,
8094; (d) A. Puglisi, L. Raimondi, M. Benaglia,
M. Bonsignore, S. Rossi, Tetrahedron Lett. 2009, 50, 4340; (e)
D. Uraguchi, K. Koshimoto, C. Sanada, T. Ooi, Tetrahedron:
Asymmetry 2010, 21, 1189.
[30] (a) D. Uraguchi, Y. Ueki, T. Ooi, J. Am. Chem. Soc. 2008, 130,
14088; (b) X. Liu, L. Deng, X. Jiang, W. Yan, C. Liu, R. Wang,
Org. Lett. 2010, 12, 876.
[22] For a review on bimetallic Schiff base catalysts: R. M. Haak,
S. J. Wezenberg, A. W. Kleij, Chem. Commun. 2010, 46,
2713.
[31] Review: (a) L. Römer, C. Klein, A. Dehner, H. Kessler,
J. Buchner, Angew. Chem. Int. Ed. 2006, 45, 6440; see also, (b)
L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski,
Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs, C. Klein,
N. Fotouhi, E. A. Liu Science, 2004, 303, 844; (c) C. Tovar,
J. Rosinski, Z. Filipovic, B. Higgins, K. Kolinsky, H. Hilton,
X. Zhao, B. T. Vu, W. Qing, K. Packman, O. Myklebost,
D. C. Heimbrook, L. T. Vassilev, Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 1888.
[32] (a) R. S. Bon, N. E. Sprenkels, M. M. Koningstein,
R. F. Schmitz, F. J. J. de Kanter, A. Dömling, M. B. Groen,
R. V. A. Orru, Org. Biomol. Chem. 2008, 6, 130; (b)
C. L. Kusturin, L. S. Liebeskind, W. L. Neumann, Org. Lett.
2002, 4, 983; (c) A. Lengar, C. O. Kappe, Org. Lett. 2004, 6,
771.
[33] Because Schiff base 1d without metal source was relatively
unstable in CHCl3 and gradually decomposed, THF (without
stabilizer) was used for the CD analysis in Figure 3. THF was
also used as solvent for the asymmetric Mannich-type reaction,
and showed similar diastereoselectivity tendency.
[34] For detailed conformational studies of binaphthyl compounds
and assessment of the dihedral angle in solution phase using
CD analysis, see: (a) C. Rosini, S. Superchi, H. W. I. Peerlings,
E. W. Meijer, Eur. J. Org. Chem. 2000, 61; (b) L. Di Bari,
G. Pescitelli, P. Salvadori, J. Am. Chem. Soc. 1999, 121, 7998;
(c) S. F. Mason, R. H. Seal, D. R. Roberts, Tetrahedron 1974,
30, 1671.
[23] For heterobimetallic Schiff base catalysts containing rare earth
metals, see: (a) S. Handa, V. Gnanadesikan, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2007, 129, 4900; (b)
S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga,
M. Shibasaki, Angew. Chem. Int. Ed. 2008, 47, 3230; (c)
H. Mihara, Y. Xu, N. E. Shepherd, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 8384; (d)
S. Handa, V. Gnanadesikan, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2010, 132, 4925; (e) M. Furutachi, S. Mouri,
S. Matsunaga, M. Shibasaki, Chem. Asian J. 2010, 5, 2351; (f)
Y. Xu, L. Lin, M. Kanai, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2011, 133, 5791.
[24] For homobimetallic Schiff base catalysts, see: (a) Z. Chen,
M. Furutachi, Y. Kato, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed. 2009, 48, 2218; (b) Y. Kato, M. Furutachi,
Z. Chen, H. Mitsunuma, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2009, 131, 9168; (c) S. Mouri, Z. Chen,
H. Mitsunuma, M. Furutachi, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2010, 132, 1255; (d) Y. Xu, S. Matsunaga,
M. Shibasaki, Org. Lett. 2010, 12, 3246; (e) H. Mitsunuma,
S. Matsunaga, Chem. Commun. 2011, 47, 469.
[25] For selected examples of related bifunctional bimetallic Schiff
base complexes in asymmetric catalysis, see: (a) V. Annamalai,
E. F. DiMauro, P. J. Carroll, M. C. Kozlowski, J. Org. Chem.
2003, 68, 1973; (b) J. Gao, F. R. Woolley, R. A. Zingaro, Org.
268 www.tcr.wiley-vch.de
The Chemical Record, Vol. 11, 260–268 (2011) © 2011 The Chemical Society of Japan and Wiley-VCH, Weinheim