Mechanistic consideration of asymmetric CN and CC bond formations with bifunctional chiral ir and ru catalysts

Article abstract of DOI:10.1246/bcsj.20110307

The mechanism of two enantioselective reactions, direct amination of α-cyanoacetates 3 with azodicarboxylates 4 and CC bond formation reaction of α-cyanoacetates with acetylenic esters 6, catalyzed by chiral bifunctional Ir and Ru complexes, Cp*Ir[(S,S)-N

Full text of DOI:10.1246/bcsj.20110307

316
Bull. Chem. Soc. Jpn. Vol. 85, No. 3, 316-334 (2012)
© 2012 The Chemical Society of Japan
Selected Papers
Mechanistic Consideration of Asymmetric C-N and C-C Bond
Formations with Bifunctional Chiral Ir and Ru Catalysts
Yasuharu Hasegawa, Ilya D. Gridnev, and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552
Received October 14, 2011; E-mail: tikariya@apc.titech.ac.jp
The mechanism of two enantioselective reactions, direct amination of ¡-cyanoacetates 3 with azodicarboxylates 4
and C-C bond formation reaction of ¡-cyanoacetates with acetylenic esters 6, catalyzed by chiral bifunctional Ir and
Ru complexes, Cp*Ir[(S,S)-N-sulfonated dpen] 1 and Ru[(S,S)-N-sulfonated dpen](©6-arene) 2 (DPEN: 1,2-diphenyl-
ethylenediamine) was studied by NMR spectroscopic analysis combined with DFT analysis. Notably, these two reactions
using the same chiral amide catalysts 1, 2 and pronucleophile, ¡-cyanoacetates 3 gave quantitatively the conjugate
adducts bearing quaternary chiral carbon centers in excellent enantiomeric excess albeit with the opposite absolute
configuration depending on the acceptor molecules 4 and 6. NMR investigation of the reactions between Ir complexes
1a-1c with ¡-cyanoacetates 3 showed that a stereoselective deprotonation reaction takes place to give an equilibrium
mixture of N-bound amine complexes 8 and 9, the former with intramolecular hydrogen bonding and the latter without it,
respectively. Computational study revealed the full details of the mechanism of the asymmetric C-N and C-C bond
forming reactions catalyzed by the chiral Ir catalyst 1b. In the C-N bond forming reaction, the dimethyl azodicarboxylate
4a undergoes productive bifunctional activation by a non-hydrogen-bonded N-bound complex 9b(re) resulting in the
formation of the R-product through the energetically favorable transition state. On the other hand, the linear geometry of
the acetylenic ester molecule 6 allows its bifunctional activation with both types of the N-bound complexes: 8b and 9b
with and without the intramolecular hydrogen bond respectively. The hydrogen-bond stabilized transition state for the
C-C bond formation leading to the S-enantiomer is significantly lower in energy than the corresponding non-hydrogen-
bonded transition state leading to the R-enantiomer. Thus, chiral induction of these two reactions is determined by the
structures of the acceptor molecules.
The understanding of mechanisms of chiral molecular
nary carbon centers are one of the most important and
challenging objectives in organic synthetic chemistry as well
as theoretical chemistry.
catalysis is an area of intensive research in synthetic organic
chemistry. Although a significant number of enantioselective
catalytic reactions have been discovered in the past three
decades, only a few of them can approach the selectivity and
effectiveness of naturally occurring enzymatic transformations.1
In order to explore powerful asymmetric catalysis with chiral
transition-metal-based molecular catalysts, a rational design of
the catalyst molecules and a deep understanding of the intricate
mechanisms of the chiral induction are highly desired.
A significant extension and improvement of the practical
repertoire for asymmetric hydrogenation1,2 and oxidation3 of
olefins has been realized on the basis of intensive mechanistic
considerations as well as a wide range of molecular catalyst
screening. On the other hand, asymmetric C-C bond formation,
particularly, the enantioselective construction of quaternary
carbon with chiral molecular catalysts attracts much attention
because this reaction plays a key role in the preparation of
complex natural products and pharmaceuticals.4 However, it is
still a challenge in synthetic organic chemistry since asym-
metric reductive transformations are not applicable in that case.
Hence, powerful catalytic processes to generate chiral quater-
Several catalytic methods to generate quaternary stereo-
centers have been reported.5 They include, for example,
asymmetric ¡-alkylation and ¡-arylation of carbonyl com-
pounds catalyzed by chiral palladium,6 nickel,7 copper,8 or
indium9 complexes. Unfortunately, the scope of these reactions
remains rather limited. Enantioselective Diels-Alder reactions
have also been successfully applied to the creation of chiral
quaternary carbon centers. Chiral copper,10 chromium,11 co-
balt,11d,11e,12 ruthenium13 complexes or Corey’s chiral Lewis
acid catalysts14 are effective for these reactions to provide
the corresponding chiral adducts with excellent enantiomeric
excess. Furthermore, asymmetric conjugate addition of
pronucleophiles to ¡,¢-unsaturated carbonyl compounds
presents one of the most powerful and atom economical
synthetic approaches to access enantiomerically enriched qua-
ternary carbon skeletons. However, chiral metal-based catalysts
for the enantioselective conjugate addition remain relatively
rare, notably being limited to multifunctional chiral catalysts15
such as multi-metal centered catalysts16 and metal-enolates.17
Published on the web February 23, 2012; doi:10.1246/bcsj.20110307

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
317
Ts
Rn
chiral Ir cat 1:
C6H5
N
Ru
N
R
S
N
O
O
Ir
C6H5
H
1a: R = CH3 (Ms)
C6H5
C6H5
H
H
1b: R = 4-CH3-C6H4 (Ts)
1c: R = (1R)-camphor (Cs)
1d: R = (CH3)5C6 (PMs)
Ar
Ar
amine hydrido
complex
N
H
O
O
H
chiral Ru cat 2:
H
R
O
S
N
O
OH
OH
Ts
Rn
C6H5
C6H5
2a: R = CH3 (Ms)
C6H5
C6H5
N
2b: R = 4-CH3-C6H4 (Ts)
2c: R = (1R)-camphor (Cs)
2d: R = (CH3)5C6 (PMs)
Ru
Ru
N
H
N
H
amido complex
Scheme 1. Representative bifunctional catalysts and mechanism of asymmetric transfer hydrogenation with chiral catalyst.
The modern view of the most effective chiral molecular
catalysts has drifted from the initial ideas of structural
robustness and monofunctionality,1f and it is now widely
recognized that chiral bifunctional catalysts with acid-base
synergy are especially effective in creating chiral 3D pockets
suitable for arranging highly enantioselective transforma-
tions.2i,2q,18,19 In addition, it has been recently recognized that
metal and cooperating ligands can activate reacting substrates
in a bifunctional mode and facilitate the enantioselective bond
forming steps.20 Ultimately such catalysts with a variable
structure would be able to perform multiple enantioselective
transformations in response to an external signal.21,22
Recently, we have shown that chiral bifunctional Ir and Ru
catalysts, Cp*Ir[(S,S)-N-sulfonated dpen] 1 and Ru[(S,S)-N-
sulfonated dpen](©6-arene) 2 (DPEN: 1,2-diphenylethylene-
diamine) that were initially developed for asymmetric trans-
fer hydrogenation of ketones and imines with 2-propanol as
shown in Scheme 1,23 are applicable to other stereoselective
transformations24 triggered by the proton transfer from a
pronucleophile to the 16e amido Ir or Ru complex, thus effec-
tuating the catalytic C-C20d,25,26 or C-N20d,27 bond formation
on the resulting catalyst intermediate, chiral amine complex.
The objectives of this work are mechanistic consideration
of two new catalytic reactions promoted by chiral bifunc-
tional amido complexes 1 and 2: asymmetric C-N and C-C
bond formation in the reactions of ¡-cyanoacetates 3 as the
pronucleophile with dialkyl azodicarboxylates 427-29 or acety-
lenic esters 626,30,31 as the acceptor molecule, respectively.
Noticeably, both reactions gave the corresponding chiral
adducts 5 and 7 with excellent ees’, but with the opposite
configuration of the quaternary carbon atom centers. It means
that different forms of the catalyst or the catalyst-donor
complex become active in the reaction with different acceptor
molecules, in which the structures and properties of the
substrates determine the stereochemistry of the bond formation
steps. Some examples of such substrate-controlled inversion
in terms of enantioselectivity are known,32 however, they
remain relatively rare. Detailed mechanistic studies of such
asymmetric catalytic reactions can reveal the structural features
responsible for the switch of the reaction pathways, and hence
of the sense of enantioselection.1f,2p,33
In this paper we report the optimization of reaction
conditions for these two reactions, catalyst tuning, and struc-
tural modification of the substrates, as well as an experimental
mechanistic study combined with a computational investigation
of the catalytic cycle and the origin of the enantioselectivity
in these two reactions, leading to the chiral adducts with the
opposite configuration.
Results and Discussion
Enantioselective C-N Bond Formation in the Conjugate
Addition of ¡-Substituted ¡-Cyanoacetates to Azodicar-
boxylic Diesters. We have recently reported that a chiral
amido Ir complex, Cp*Ir[(S,S)-Msdpen] 1a (MsDPEN: (S,S)-
N-(methylsulfonyl)-1,2-diphenylethylenediamine)
catalyzed
asymmetric direct amination of tert-butyl ¡-phenyl-¡-cyano-
acetate (3a) using dimethyl azodicarboxylate (4a) (a substrate/
catalyst ratio, S/C = 100, 3a:4a = 1:1) in a 0.5 M toluene
solution at 0 °C for 2 h to produce the corresponding hydrazine
adduct 5a in 99% yield and with 85% ee as shown in Scheme 2
and Table 1 (Run 1).27 Since the noncatalyzed reaction of
3a and 4a gave quantitatively the racemic product, 5a (Run 2),
the reaction conditions were modified to minimize the non-
catalyzed reaction. In fact, a slow addition of azodicarboxylate,
4a, to a toluene solution of 3a containing the Ir catalyst 1a
with a syringe pump for 20 min at 0 °C followed by stirring of
the reaction mixture for 2 h afforded 5a in 95% ee. Decreasing
the reaction temperature to ¹40 °C resulted in an additional
increase in the ee value of 5a to 97% (Runs 4 and 5).
The stereochemical outcome of the reaction with the chiral
Ir catalyst was delicately influenced by the structure of the
Ir complexes. The CsDPEN (Cs: (R)-camphorsulfonyl) com-
plex 1c gave the best selectivity; the ee value of the product
reached 98% ee in this case (Run 7). In toluene, THF, or
C2H5(CH3)2COH, high ee values were observed (Runs 4, 8,
and 9), while acetone and CH2Cl2 gave unsatisfactory results
(Runs 10 and 11). Acetonitrile gave a racemic adduct probably
because of its strong binding to the center metal. An increase in

318
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
CO2R2
HN
CO2R2
CN
R1
chiral cat 1, 2
N
N
+
N
R1
R2O2C
solvent, 2 h
C6H5
R2O2C
C6H5
CN
5
3
4
S/C = 100
1:1
99% yield (R)
up to 99% ee
3a: R1 = CO2C(CH3)3
3b: R1 = CON(CH3)2
4a: R2 = CH3
4b: R2 = CH(CH3)2
Scheme 2. Enantioselective C-N bond formation catalyzed by chiral Ir and Ru catalysts.
Table 1. Representative Results of the Conjugate Addition of ¡-Substituted ¡-Cyanoacetates to Azodicarboxylic Diestersa)
Run
Catalyst
Donor
Acceptor
Solvent
Temp/°C
Yield/%b)
% eec)
1d)
2
3
4
5
6
7
8
1a
®
1a
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
2a
1a
1b
1c
1a
1a
2a
2b
2c
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4a
4a
4a
4a
4a
4a
4a
4a
4a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
C2H5(CH3)2COH
acetone
CH2Cl2
CH3CN
toluene
toluene
toluene
toluene
toluene
0
0
30
0
¹40
0
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
98
99
99
99
99
99
99
85
®
90
95
97
89
98
83
83
73
67
10
66
66
98
98
99
89
83
96
93
96
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C2H5(CH3)2COH
CH2Cl2
toluene
toluene
toluene
a) Unless otherwise noted, the reaction was carried out by a slow addition of 4 to a toluene solution of 3 containing the
amido catalyst 1, 2 with a syringe pump for 20 min followed by stirring for 2 h in 5 mL solvent. The molar ratio of
cat:acceptor:donor is 1:100:100. b) Isolated yield after flash chromatography on silica gel. c) Determined by HPLC
analysis using CHIRALPAK AD (4.6 mm © 250 mm). d) 4a was added right after 3a and stirred for 2 h.
the steric bulkiness in the ester group of the acceptors 4 caused
a decrease in the ee value of the products, the ee value
decreasing from 95% ee for the methyl ester 4a to 66% ee for
the isopropyl ester 4b (Run 13). Since the yields are quanti-
tative and the optical purity of the products is high, the reaction
is applicable to a 1-g-scale preparation of chiral hydrazine
adducts; the reaction of 3a (1.1 g) and 4a gave quantitatively
1.8 g of the corresponding chiral adduct with 95% ee.
Notably, the use of the less acidic ¡-cyanoacetamide 3b
(pKa µ 17) instead of ¡-cyanoacetate 3a (pKa µ 13) caused a
significant increase in the enantioselectivity, probably because
the background reaction was slower in that case. As shown in
Table 1, the reaction of 3b and dimethyl azodicarboxylate 4a
(S/C = 100, 3b:4a = 1:1) in a 0.5 M toluene solution contain-
ing Ir catalyst 1a at 0 °C for 2 h produced the corresponding
hydrazine adduct in quantitative yield and 98% ee (Run 15).
The ee value of the product reached 99% ee with the CsDPEN-
Ir complex 1c (Run 17). The solvent effect on the outcome of
the reaction using 3b had a similar trend as observed in the
reaction with 3a (Runs 18 and 19). Chiral Ru catalysts 2 that
exhibited inferior performance in the reaction of 3a and 4a
(Run 14) were also effective in the reaction of 3b and 4a. In
fact, the corresponding product with 96% ee was obtained with
the MsDPEN-Ru complex 2a. The Ts- and Cs-DPEN catalysts,
2b and 2c also gave satisfactory results (Runs 20-22).
The absolute configuration of the chiral adducts 5 obtained
from the reaction of 3 with 4 was determined to be R by X-ray
crystallographic analysis as well as by the comparison of
optical rotation of 5 to the reported data (see Supporting
Information).27,28f
Enantioselective C-C Bond Formation from the Con-
jugate Addition of ¡-Substituted ¡-Cyanoacetates to Acety-
lenic Esters.
The use of a different acceptor, acetylenic
ester compounds 6 for the conjugate addition reaction of
¡-cyanoacetates 3 mediated by bifunctional Ir or Ru catalysts
1 or 2 (3:6:cat = 100:100:1) at 0 °C produces chiral adducts

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
319
CH3O2C
R3
H
CO2CH3
CN
chiral cat 1, 2
CO2C(CH3)3
Ar
+
Ar
CO2C(CH3)3
solvent, 24 h, 0 °C
R3
CN
3
1:1
7
6
S/C = 100
up to 95%ee (S)
up to >25 Z/E
6a: R3 = CO2CH3
6b: R3 = H
3a: Ar = C6H5
3c: Ar = 4-CH3O-C6H4
3d: Ar = 4-Cl-C6H4
3e: Ar = 4-Br-C6H4
Scheme 3. Enantioselective C-C bond formation catalyzed by chiral Ir and Ru catalysts.
Table 2. Representative Results of the Conjugate Addition of ¡-Substituted ¡-Cyanoacetates to Acetylenic Esters
Run
Cat
Donor
Acceptor
Solvent
Yield/%
Z/E
% ee (Z/E)
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2b
2b
1a
1b
1c
2b
2b
2b
2b
2b
3a
3a
3a
3a
3a
3a
3a
3a
3c
3d
3e
3a
3a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
toluene
toluene
toluene
CH2Cl2
C2H5(CH3)2COH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
97
97
98
98
99
96
96
95
98
99
99
99
99
20/1
20/1
23/1
2/1
86/22
91/52
83/25
82/81
72/72
84/10
90/23
81/10
89/n.d.
92/27
95/5
2/1
20/1
20/1
23/1
20/1
17/1
20/1
1/22
1/2
n.d./79
0/0
CH3CN
a) Unless otherwise noted, the reactions were carried out by a slow addition of 6 to a solution of 3 containing the
chiral amido catalyst 1, 2 with a syringe pump for 20 min followed by stirring for 24 h in 5 mL solvent. The molar
ratio of cat:donor:acceptor is 1:100:100. b) Isolated yield after flash chromatography on silica gel. c) Determined by
HPLC analysis using CHIRALPAK AD-H (4.6 mm © 250 mm).
7 in almost quantitative yields with good to excellent ees’ and
excellent Z/E selectivities (Scheme 3).26 Table 2 lists some
of the representative results. Chiral Ir and Ru catalysts work
equally well in this conjugate addition.
reactions for 6a and 6b, the proton and nucleophile added over
the acetylenic triple bond in a syn fashion.
The S configuration of the asymmetric carbon atom and the
Z-structure of the reaction product were confirmed by a single-
crystal X-ray crystallographic analysis.26
The stereochemical outcome of the reaction was signifi-
cantly influenced by the structure of the catalyst as well as by
the reaction conditions. The best results in terms of enantio-
selectivity and the Z/E selectivity were obtained with the
sterically congested TsDPEN catalysts 1b and 2b; Cp* ligand
for the Ir and hexamethylbenzene for the Ru complexes. Other
Ru complexes having mesitylene and p-cymene as the arene
ligand gave unsatisfactory results.26 Nonpolar solvents like
toluene or dichloromethane provided high enantioselectivities,
while the use of polar solvents led to a dramatic decrease of the
ee values and the Z/E selectivities. The ¡-aryl-¡-cyanoacetates
with substituted aromatic ring 3c-3e reacted with 6a in the
presence of the chiral Ru catalyst 2b at 0 °C to give after 24 h
the corresponding chiral adducts 7 with 89-95% ee in excellent
yields. Thus, the present reaction provides sufficiently high ee
with much higher Z/E ratios than the reported organocatalyst-
promoted reaction.30a On the other hand, the reaction of
¡-cyanoacetate 3a and acetylenic monoester 6b catalyzed by
the chiral Ru catalyst 2b gave the corresponding adduct 7e with
an excellent E selectivity albeit a modest ee value. In both
General Mechanistic Considerations.
Recently, we
have studied the mechanism of enantioselection in the asym-
metric Michael addition reaction of malonic ester and ¢-keto
esters catalyzed by the chiral amido Ru catalysts, Ru[(R,R)-
Tsdpen](arene).25 On the basis of the detailed computational
study using the real catalysts, we concluded that the exper-
imentally detectable C- and O-bound enolates are not the
productive intermediates in these reactions as shown in
Scheme 4.25e Although several transition states for the C-C
bond formation starting from the O-bound enolates have been
found, these transformations are characterized by very high
activation energies (25-30 kcal mol¹1), and hence they do not
represent viable reaction pathways. On the other hand, the
reaction pathways implying the formation of chelating ion
pairs followed by the coordination of the Michael acceptor at
the Ru atom have realistically low activation barriers and
clearly explain the sense and order of enantioselection.
However, in the reactions shown in the Schemes 2 and 3, the
nature of the donor substrate, ¡-cyanoacetates 3, is significantly

320
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Ms
Ms
N
Ms
Rn
Rn
Rn
C6H5
N
C6H5
C6H5
C6H5
C6H5
N
Ru
O
Ru
+
Ru
CH2(CO2CH3)2
CO2CH3
H
N
N
N
C6H5
C
C
O
OCH3
H
H
H
H
H
H
2
OCH3
CH3O2C
O
Ms
N
C6H5
Ru
H
Ms
N
C6H5
Rn
H
+
H
C6H5
N
Ru
N
H
H
O
CH3O
H
O
O
H
Rn
H
O
CH3O
O
OCH3
O
O
O
H
OCH3
CH3O
+ 2
OCH3
H
Scheme 4. Mechanism of enantioselective Michael addition catalyzed by chiral Ru complexes.
Ms
C6H5
N
CN
+
Ir
C6H5
CO2C(CH3)3
N
H
C6H5
1:1.5
3a
(S,S)-1a
Ms
N
Ms
C6H5
C6H5
C6H5
C6H5
N
N
+
Ir
+
Ir
N
N
slow
N
fast
C
C
O
H
H
H
–
H
C6H5
–
O
OC(CH3)3
9a
C6H5
8a
OC(CH3)3
Scheme 5. Deprotonation of ¡-cyanoacetate 3a with amido complex 1a, leading to an equilibrium mixture of amine complexes
8a and 9a.
different from that of malonic ester. Since the cyano group of 3
is highly nucleophilic and sterically compact, its N-coordina-
tion to the metal center should be facile, and thus the donor
activation mechanism in these reactions is also expected to
be different.
cyanoacetate as the donor substrate, we used them for the
mechanistic studies. First we studied the NMR spectra of
the stoichiometric reaction of ¡-cyanoacetate 3a and the amido
Ir complex 1a (3a:1a = 1.5:1) in CD2Cl2. At ambient temper-
1
ature, the signals in the H and 13C NMR spectra broadened;
On the basis of the accumulated knowledge, we investigated
details of the mechanism of the deprotonation of ¡-cyano-
acetates 3 with the bifunctional amido catalysts 1 and 2 to form
the cyanoacetato amine complexes 8-11 and carried out a
computational study of these C-N and C-C bond forming
reactions. These studies revealed the details of the catalytic
cycle and the origin of enantioselectivity in both reactions, as
well as the Z-stereoselectivity in the case of acetylenic diesters.
The presence of an NH moiety in the cooperating ligands is
crucially important for their catalytic performance.
they became sharp at ¹50 °C exhibiting two sets of signals
1
in the H and 13C NMR spectra corresponding to two amine
complexes 8a and 9a in a 2:1 ratio. The assignment of the
signals in the 1H NMR and 13C NMR spectra was accomplished
by routine 2D correlation techniques (see Supporting Informa-
tion). Two amine protons in the 1H NMR spectrum of the minor
isomer 9a resonate at ¤ 3.72 (triplet, trans- to the NH2CHC6H5
proton) and 4.78 (doublet, cis- to the NH2CHC6H5 proton). In
the 1H NMR spectrum of the major isomer 8a, the corre-
sponding doublet resonates in a higher field than that of 9a (¤
4.30), whereas the triplet is strongly downfield shifted (¤ 6.16,
not concentration dependent) indicating the presence of an
intramolecular hydrogen bond in 8a that is absent in 9a as
shown in Scheme 5. From 13C DEPT and HMBC spectra taken
Experimental Studies of the Reactions between Amido
Complexes 1, 2 and ¡-Cyanoacetate 3a. Since the chiral
amido Ir catalysts 1 worked equally well for both enantio-
selective conjugated C-N and C-C bond formation using ¡-

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
321
1
Figure 1. Section plot of the H-1H NOESY spectrum (400 MHz, 223 K, CD2Cl2, ¸m 0.5 s, ¤) of the equilibrium mixture obtained
after the addition of 1.5 equivalents of ¡-cyanoacetate 3a to a solution of amido complex 1a in CD2Cl2.
at ¹50 °C, we have located the positions of non-protonated
carbon atoms of 8a and 9a in the 13C NMR spectrum. The
deprotonated anionic carbons resonate at ¤ 58.4 and 56.2
for 8a and 9a respectively, whereas the nitrile carbon atom is
notably downfield shifted compared to the free substrate 3a
(See Figure S5). These data indicate an N-binding of the
substrate in 8a and 9a. This conclusion was additionally
supported by a decreased frequency of the CN band in the IR
spectrum of the mixture of two amine complexes 8a and 9a
may be attributed to the diastereomer with alternative config-
uration of the Ir atom. These signals do not exhibit exchange
cross-peaks with the signals of 1a, 3a, 8a, and 9a, hence these
species are not involved in the fast catalytic reaction.
Similar observations were made when the NMR spectra of
the mixtures of other Ir and Ru catalysts with ¡-cyanoacetate
3a were studied. In all cases, the formation of the interconvert-
ing mixtures of the corresponding N-bound complexes with
and without intramolecular hydrogen bond was confirmed by
the NMR data. Unfortunately, accurate measurements of the
activation barriers of interconversion between the two species
were only possible in the case of 1a due to the overlap of the
signals in all the other cases. Nevertheless, since the line-shape
changes within a certain temperature range were qualitatively
very similar, one can conclude that these activation barriers
are around 7-8 kcal mol¹1. In the same fashion, averaged
signals of the N-bound complexes observed at ambient tem-
perature were in exchange with the signals of free amido
catalyst 1a and ¡-cyanoacetate 3a. Hence, the activation
barriers of the deprotonation stage are uniformly higher
than those for the interconversion of the N-bound complexes.
The configuration of the metal atom was confirmed to be S in
each case by observation of NOE between the NH2CHC6H5
proton and the methyl groups of the C5(CH3)5 or C6(CH3)6
moiety.
Single crystals for the X-ray study were obtained from the
reaction mixture of ethyl-4-chlorophenylcyanoacetate and Ir
complex 1c that yielded compound 9c (Figure 3, see Support-
ing Information). In the solid state, the deprotonated substrate
is N-bound, but the intramolecular H-bond is absent, presum-
ably due to the more effective intermolecular hydrogen bond
between the carbonyl group in the Cs group and one of the
NH2 protons. The Ir metal center has S configuration; the same
diastereomer of 9c was observed in solution.
¹1
¹1
(¯CN = 2174 cm against ¯CN = 2263 cm in 3a).34
There are two dynamic processes observed for the system in
different temperature intervals. The line shape changes in the
1H NMR and 13C NMR spectra within the temperature interval
from ¹60 to 30 °C confirm the interconversion between 8a and
¹1
9a. The kinetics of this exchange (EA = 7.7 kcal mol for the
¹1
rearrangement of 8a to 9a, and 7.3 kcal mol for the reverse
reaction) was measured from a series of phase-sensitive 2D
1H-1H NOESY spectra taken in the temperature interval from
¹60 to ¹35 °C (Figure 1).
The phase-sensitive 2D 1H-1H NOESY spectra taken at
ambient temperature (Figure 2, left) exhibited exchange cross-
peaks observed due to another dynamic process, the equi-
librium between the free substrate 3a and amido complex 1a on
one side and the mixture of two amine complexes 8a and 9a
(averaged spectrum of 8a and 9a) on the other side. Complexity
of the system did not allow accurate kinetic analysis of
this equilibrium. However, the quantification of the NOESY
spectra suggests that the activation barrier of this equilibrium
¹1
is about 10 kcal mol higher than that for the exchange of
8a and 9a.
Furthermore, the NOE cross-peak between the NH2CHC6H5
proton and the methyl groups of the Cp* unit unequivocally
defined the configuration of the Ir atom in 8a and 9a (Figure 2,
right). Minor signals observed in the aged samples (Figure 2)

322
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
1
Figure 2. Section plots of H-1H NOESY spectrum (400 MHz, 298 K, CD2Cl2, ¸m 1 s) of the equilibrium mixture obtained after
addition of 1.5 equivalents of ¡-cyanoacetate 3a to a solution of amido complex 1a in CD2Cl2; left: exchange cross-peaks between
1a and 8a (in rapid exchange with 9a) and between 8a (in rapid exchange with 9a) and 3a; right: NOE cross-peak between the
NH2CHC6H5 proton and C5(CH3)5 moiety of 8a (in rapid exchange with 9a) is of comparable intensity with the evident NOE cross-
peak between the mesyl group and NMsCHC6H5 proton (An intensive exchange cross-peak between the acidic CH proton of 3a and
traces of water can also be seen in the spectrum).
Cs
C6H5
N
+
Ir
N
C6H5
N
H
C
H
O
–
OC2H5
9c
Cl
Figure 3. Molecular structure of complex 9c.
Computational Study of the Deprotonation of ¡-Cyano-
acetate 3a with Chiral Amido Ir and Ru Complexes.
Experimental data unequivocally indicate that the deprotona-
tion step proceeds stereoselectively, yielding amine complexes
with S configuration of the metal center in the case of (S,S)-
diamine ligand (Scheme 5 and Figure 3). Stereoselectivity of
this step is essential for the overall enantioselective reaction;
hence we looked computationally for the origin of enantio-
selectivity on this stage of the catalytic cycle.
Dipole-dipole complexes 12 and 13 of proper geometry
for the deprotonation reaction as well as ion pairs 14 and 15
that are immediate products of the deprotonation were opti-
mized for reaction pathways starting from the amido Ir and
Ru complexes 1 and 2; the transition states connecting 12 and 14
or 13 and 15 were located, affording the activation energies
and thermodynamic data for the deprotonation step as listed
in Table 3.
By analyzing the structures of the participants of a repre-
sentative deprotonation reaction (Figure 4), one can see that a
molecule of ¡-cyanoacetate 3a must occupy a substantial area
above the chelate cycle in order to position its proton appro-
priately for the deprotonation. This kind of arrangement can be
achieved only from one side of the amido complex molecule,
viz. the one not hindered by the adjacent phenyl ring. Further-
more, the resulting ion pair 14 or 15 does not easily dissociate
to yield the cationic complex 16 or 17; the computed values for
¹1
the energy of dissociation are in the range of 27-65 kcal mol
(Table 3). The ion pair cannot directly provide an N-bound
complex without complete dissociation due to tremendous
spatial hindrance expected for such a process.

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
323
Table 3. Computational Data on the Dehydrogenation Step, Level of Theory B3LYP/SDD (Ru or Ir)/
6-31G*(C,H,S,N,O)/IFEPCM(toluene)
R
N
R
N
R
N
Ph
1
,
E1
EA
Ph
Ph
Ph
Ph
Ph
Ph
E2
OBut
+
+
M
X
M
X
C
M
X
C
N
N
H
Ph
N
Ph
N
O
H
OBut
OBut
H
H
H
H
C
N
N
16a,b; 17a,b
O
O
14a,b; 15a,b
12a,b; 13a,b
Ph = C6H5, But = C(CH3)3
E3(O)
E3(C)
R
R
N
Ph
Ph
Ph
X
N
X
Ph
E3(Nh)
E3(Nsi)
E3(Nre)
M
M
OBut
CN
Ph
O
N
N
Ph
NC
H
H
H
O
H
tBuO
R
R
N
R
N
18a,b; 19a,b
20a,b; 21a,b
Ph
Ph
Ph
Ph
Ph
N
X
X
N
X
+
M
+
+
M
M
N
N
N
N
N
H
Ph
O
C
O
Ph
C
C
H
H
Ph
H
H
H
Ph
OBut
OBut
O
OBut
8a,b; 10a,b
9a,b(si); 11a,b(si)
9a,b(re); 11a,b(re)
M = Ir, X = Cp*, R = Ms: 8a, 9a, 12a, 14a, 16a, 18a, 20a
M = Ir, X = Cp*, R = Ts: 8b, 9b, 12b, 14b, 16b, 18b, 20b
M = Ru, X = C6(CH3)6, R = Ms: 10a, 11a, 13a, 15a, 17a, 19a, 21a
M = Ru, X = C6(CH3)6, R = Ts: 10b, 11b, 13b, 15b, 17b, 19b, 21b
1 a)
¹1
Complex
EA
Im.freq./cm
¦E1 a)
¦E2 a) ¦E3(C)a) ¦E3(O)a) ¦E3(Nh)a) ¦E3(Nsi)a) ¦E3(Nre)a)
1a
1b
2a
2b
9.4
10.3
8.3
i1368.5
i1365.6
i1397.1
i1393.4
3.7
3.3
¹2.6
¹2.1
28.6
27.6
64.6
62.2
2.8
4.6
8.8
1.8
2.7
0.0
1.2
¹11.8
¹11.5
¹13.7
¹13.0
¹7.0
¹6.2
¹9.2
¹8.4
¹11.3
¹10.8
b)
®
®
b)
9.9
10.9
a) E: kcal mol¹1. b) No minimum could be found, all attempts of optimization produced the corresponding complex with
intramolecular hydrogen bond 10a or 10b.
Hence, we concluded that the deprotonation step takes place
stereospecifically producing ion pair 14 or 15. Then another
molecule of ¡-cyanoacetate (or its anion) must approach the ion
pair to yield the experimentally observed N-bound complexes 8
and 9 or 10 and 11 via SN2-like mechanism.20b,20d,24 The overall
process becomes exothermic due to the formation of the M-N
bond, whereas the formation of the corresponding C- or O-
bound complexes34h,34j is not observed due to their relative
thermodynamic instability as shown in Table 3. The reason of
the significant variation in the stabilities of differently bound
complexes is the straight shape of the nitrile group that can
easily achieve the appropriate position for the coordination with
the metal yielding again a straight M-N-C moiety. On the other
hand, the M-O-C moiety of the O-bound complexes is bent
dramatically increasing the spatial demand in the crowded area
around the metal atom. This is still more valid for the for-
mation of a C-bound complex, since a heavily substituted sp3-
carbon atom is not easy to accommodate nearby the metal atom.
The most stable conformer of the N-bound complexes 8 and
9 possesses an intramolecular hydrogen bond between the
oxygen atom of the ¡-cyanoacetate unit and the axial NH
proton. This hydrogen bond can be broken yielding either
9a(re) or 9a(si), depending on the direction of the intra-
molecular rotation. The experimentally measured rate of
interconversion between 8a and 9a (vide supra) is higher
than the rate of the equilibrium between amine and amido
complexes. Hence, any of the conformers shown in Figure 5
are kinetically available under the reaction conditions. Since
only the prochiral plane facing the NH2 group protons is
suitable for bifunctional activation, the absolute configuration
of the product corresponds to the structure of the productive
N-bound amine complex. Thus, 9a(re) is a precursor of R-
product, whereas 8a and 9a(si) can only produce S-enantiomer
if bifunctional activation takes place. This conclusion is the key
point for the analysis of the enantioselective C-N and C-C
bond forming reactions of 3a catalyzed by Ir and Ru complexes
1 and 2 (vide infra). The enantio-face selection of ¡-cyano-
acetate anion bound to metal atom might be determined by the
structure of the acceptor molecules.
The analogous N-bound TsDPEN-Ir complexes 8b, 9b(re),
and 9b(si) have similar relative stabilities to their MsDPEN
Ir complexes 8a, 9a(re), and 9a(si). On the other hand, Ru
complexes 11a(si) and 11b(si) are unstable and invariably
isomerize to the corresponding H-bound complexes 10a and

324
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Figure 4. Computational results for the deprotonation step between Ir complex 1a and ¡-cyanoacetate 3a. It is clearly seen that
approach of the ¡-cyanoacetate from another side of the complex is impossible due to the hindrance from the Ph group in the
¡ position to NH. But: C(CH3)3.
Figure 5. Optimized structures of the N-bound Ir complexes 8a, 9a(si), and 9a(re). The energies are given relative to 1a + 3a.
10b during the attempts of their structure optimization.
Nevertheless, the equilibrium between 10a and 11a(re) or
between 10b and 11b(re) provides the same opportunity to
use either of two prochiral planes of the coordinated ¡-cyano-
acetate for the following reaction with electrophile.
CO2CH3
CN
N
N
+
C6H5
CO2C(CH3)3
CH3O2C
3a
4a
1:1
Origin of Enantioselectivity in the Conjugate Addition
Reaction of ¡-Cyanoacetate to Azodicarboxylate. In order
to get insight into the mechanism of the enantioselective
C-N bond formation, we have analyzed computationally the
possible modes of productive association of the azodicarbox-
ylate 4a with 8b, 9b(si), and 9b(re) (Table 3). The reaction of
3a and 4a catalyzed by the Ir complex 1b has been chosen
for the computational study. Although the ee value of the chiral
adduct is not the best in this combination, 1b is equally
effective in either C-N or C-C bond formation.
Ts
C6H5
C6H5
N
Ir
N
H
CO2CH3
HN
(S,S)-1b
toluene, 0 °C, 2 h
ð1Þ
CO2C(CH3)3
C6H5
N
CH3O2C
CN
5a: 89% ee (R)

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
325
Ts
N
Ts
N
Ts
C6H5
C6H5
C6H5
C6H5
C6H5
N
Ir
Ir
Ir
N
N
N
N
N
O
C6H5
N
O
H
H
C
C
C
H
H
H
H
C6H5
C6H5
OR
O
C6H5
9b(si)
9b(re)
8b
OR
OR
Ts
Ts
Ts
C6H5
C6H5
C6H5
C6H5
N
C6H5
C6H5
N
N
Ir
Ir
Ir
N
N
N
N
N
N
CO2CH3
O
C
CO2CH3
C6H5
CO2CH3
C6H5
C
C
H
H
H
H
H
N
H
N
N
N
OR
O
N
N
O
O
OR
C6H5
CH3O2C
OR
CH3O2C
22b
23b(re)
23b(si)
OCH3
TS3b
TS4b(R)
TS4b(S)
Ts
N
Ts
N
C6H5
C6H5
C6H5
C6H5
Ir
Ir
N
N
N
N
CO2CH3
CO2CH3
O
C
H
C
N
H
C6H5
H
H
N
N
N
OR
C6H5
O
OR
CH3O2C
24b(R)
CH3O2C
24b(S)
TS5b(S)
TS5b(R)
Ts
N
C6H5
C6H5
Ts
R = C(CH3)3
C6H5
C6H5
Ir
N
Ir
N
CO2CH3
CO2CH3
HN
N
H
N
CO2CH3
CO2CH3
HN
C
N
N
C
N
H
RO2C
C6H5
C6H5
25b(R)
CO2R
25b(S)
Scheme 6. C-N bond formation reaction between 3a and 4a catalyzed by Ir complex 1b.
Scheme 6 shows the possible pathways for the C-N bond
forming process on the ¡-cyanoacetato amine complexes 8b
and 9b. To be activated in a bifunctional manner, electrophilic
reagent 4a must make a hydrogen bond with one of the amine
protons simultaneously while approaching its nitrogen atom
to the negatively charged carbon atom of the ¡-cyanoacetato
complex 8b or 9b. In the case of 8b, one of the amine protons
(axial NH) is involved in the intramolecular hydrogen bond
with the coordinated cyanoacetate moiety, hence only the
other amine proton (equatorial NH) can participate in the dual
activation of the electrophile 4b. If one of the amine protons
of 8b, not involved in the intramolecular hydrogen bond, forms
an intermolecular hydrogen bond with the nitrogen atom of
azodicarboxylate 4a, another nitrogen atom is automatically
brought apart from the reactive site due to the fixed geometry
of the double N=N bond. On the other hand, by making a
hydrogen bond with the available amine proton using the
oxygen atom of the azodicarboxylate 4a, one can build a
dipole-dipole complex 22b with one of the nitrogen atoms
lying in a close proximity to the reactive carbon atom
(Figure 6, left).
Since the pre-equilibrium between the N-bound complexes
8b, 9b(si), and 9b(re) is relatively fast, the intermediates, 9b(si)
and 9b(re) can provide numerous possibilities for the formation
of a hydrogen bond with azodicarboxylate molecule using their
amine protons. However, the requirement of the dual activation
for the further C-N bond formation reaction significantly
reduces the number of potentially interesting structures. Thus,
when either the nitrogen or the oxygen atom is coordinated
to the equatorial amine proton of 9b(si) or 9b(re), the bond-
forming nitrogen atom of the azodicarboxylate does not reach
reasonable proximity to another reaction center. On the other
hand, by involving the N=N bond into three-dimensional
spatial arrangement with bifunctional activation, one can build
productive dipole-dipole complexes 23b(si) (Figure 6, center)
and 23b(re) (Figure 6, right).

326
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Figure 6. Optimized structures of the productive dipole-dipole complexes 22b, 23b(si), and 23b(re). The energies are given relative
to 1b + 3a + 4a.
The computed profile of the potential energies for the C-N
bond formation reaction (Scheme 6) starting from 22b, 23b(si),
and 23b(re) is shown in Figure 7. The reaction proceeds in a
stepwise manner: first the C-N bond is formed to produce the
intermediate 24b(S) from 22b and 23b(si) and the intermediate
24b(R) from 23b(re), respectively. The subsequent proton
migration takes place with relatively low activation barriers
yielding weak associates 25b(R) and 25b(S) respectively,
which further dissociate yielding the reaction product 5a and
the amido Ir amido 1b to complete the catalytic cycle.
However, one can see from Figure 8 that unlike the transition
states, TS4b(R) and TS4b(S) that clearly demonstrate the dual
activation mechanism with very short Nacceptor£H distances, in
TS3b, the NH2 group does not participate in the bond forming
reaction because of relatively long Nacceptor£H and Oacceptor£H
distances. Thus, the reaction through TS4b(R) is still energeti-
cally favorable due to its more efficient dual activation.
Origin of Enantioselectivity in the Reaction of ¡-
Cyanoacetates with Acetylenic Diesters.
The conjugate
addition of 3a to the acetylenic diester 6a with the same
catalyst 1b proceeds in a highly stereoselective manner to
provide the corresponding S, Z-adduct 7a with high ee (eq 2).
The experimentally observed R-enantioselectivity (eq 1) is
explained by the fact that both transition states (TS3b and
TS4b(S)) for C-N bond formation leading to the formation of
S-enantiomer are less stable than the transition state TS4b(R)
mainly due to steric hindrance of the ester groups in these two
structures as shown in Figure 8. Both ester units in TS4b(R)
are positioned in less crowded areas whereas one of the ester
groups in TS4b(S) must be accommodated in a close pocket
made by the chelate cycle and the BOC group. In the structure
of TS3b this unfavorable steric interaction is eliminated by
shifting the molecule of the incoming azodicarboxylate 4a
from the crowded area at the expense of losing the hydrogen
bond between one of the nitrogen atoms and the axial NH
proton. The latter effect is partially compensated by a weak
hydrogen bond between the carboxymethyl group and the
equatorial NH-proton, and TS3b is notably more stable
than TS4b(S). The structurally similar transition state TS4b(S)
is too high in energy compared to TS4b(R) (energy difference:
5.2 kcal mol¹1) to compete effectively with the R-manifold.
The computational analysis for the enantioselective C-N
bond formation with bifunctional chiral catalyst clearly demon-
strates the effectiveness of the bifunctional effect: simultaneous
dual activation of two reactive centers in the reacting substrate
requires a very distinct shape of the chiral pocket that can be
efficiently constructed only for one of the chiral pathways. The
pathway operating through TS3b also competes with the main
reaction manifold (via TS4b(R)) more efficiently than the
structurally similar pathway occurring through TS4b(S).
CO2CH3
CN
CO2C(CH3)3
+
C6H5
CO2CH3
1:1
6a
3a
Ts
C6H5
C6H5
N
Ir
N
H
CH3O2C
CH3O2C
H
(S,S)-1b
toluene, 24 h, 0 °C
CO2C(CH3)3
C6H5
ð2Þ
CN
7a 90% ee (S)
20/1 Z/E
In a similar manner to the previous case, we have looked for
the productive dipole-dipole complexes formed from 6a with
8b and 9b(re) that would result in the formation of S- and R-
enantiomers of the reaction product, respectively (Scheme 7).
We did not analyze the pathway including the intermediate,
9b(si), since according to the results discussed in the previous
section, it is evidently disfavored and is not expected to con-
tribute significantly to the formation of the S-product. Figure 9
illustrates the potential energy profile of the C-C bond forma-
tion between 3a and 6a catalyzed by 1b.

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
327
Figure 7. Profile of the potential energies for the C-N bond formation reaction between 3a and 4a catalyzed by Ir complex 1b.
Figure 8. Optimized structures and relative energies of the transition states TS3b, TS4b(S), and TS4b(R).
A linearly shaped molecule of acetylenic diester can be
effectively activated on the N-bound Ir complex 8b by making
a hydrogen bond with the NH proton not involved in the
intramolecular hydrogen bond, leading to the intermediate
26b, as shown in Scheme 7. As a result of the ligand
cooperative effect, the bond forming carbon atoms are brought
closely together, and the second methoxycarbonyl group
finds a nonhindered position over the phenyl ring of the
¡-cyanoacetate unit of the dipole-dipole complex 26b as
depicted in Figure 10. A similar arrangement is also possible
in the interaction of complex 9b(re) with 6a. However, as
shown in Scheme 7, the methoxycarbonyl group that is not

328
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Ts
Ts
N
Ts
C6H5
C6H5
C6H5
C6H5
C6H5
N
N
Ir
Ir
Ir
N
N
N
N
N
O
C6H5
N
O
H
H
C
C
H
C
H
H
H
C6H5
C6H5
OR
O
C6H5
8b
9b(si)
9b(re)
OR
OR
CH3O2C
CO2CH3
CH3O2C
CO2CH3
Ts
N
Ts
N
Ts
C6H5
C6H5
C6H5
C6H5
C6H5
N
N
Ir
Ir
Ir
N
H
N
N
O
N
C6H5
N
H
C
H
C
C
OR
CO2CH3
C6H5
H
C6H5
H
H
C6H5
O
O
CO2CH3
OR
O
O
CO2CH3
O
CH3O
OR
CH3O
27b(si)
CH3O
26b
27b(re)
TS6b
TS7b(S)
TS7b(R)
Ts
N
Ts
C6H5
C6H5
C6H5
N
Ir
Ir
N
N
N
N
C6H5
C
CO2R
C
H
H
C6H5
H
R = C(CH3)3
H
O
R
O
S
C6H5
O
CO2CH3
CO2CH3
OR
28b(S)
OCH3
28b(R)
OCH3
Scheme 7. The formation of C-C bond in the reaction of 3a with 6a catalyzed by 1b.
involved in the formation of the hydrogen bond must reside
over a large BOC group. Although this steric repulsive
interaction might be reduced by the distortion of the geometry
of the hydrogen bond, such a motion causes serious destabi-
lization of the dipole-dipole complex 27b(re) compared to
the complex 26b.
Due to the same steric repulsive interaction of the BOC
group, the transition state TS6b is significantly stable than
TS7b(R) (Scheme 7 and Figure 10), leading to the energeti-
cally favorable intermediate 28b(S). This explains the stereo-
chemistry of the enantioselective C-C bond formation yielding
preferentially S-enantiomer in this reaction.
Origin of Z-Selectivity in the Reaction of ¡-Cyano-
acetates with Acetylenic Diesters. After the stage of the C-C
bond formation, the resulting intermediate 28b(S) has a bent
allenic structure as shown in Scheme 7. The high Z/E ratios
of the reaction product suggest that the proton transfer occurs
directly from nitrogen to carbon, since the protonation of the
oxygen atom would yield a hydroxyallene intermediate with
similar potential for transferring the proton in two alternative
positions (Scheme 8). However, before the proton transfer
could take place, the negatively charged allenic unit must
change its bending mode to 29b(S) yielding the intermediate
30b(S). Computations show that this transformation and the
following proton transfer are characterized by very low
activation barriers of 1.6 and 1.9 kcal mol¹1, respectively.
Hence, the high Z-selectivity of the major S-product is nicely
explained by the facile intramolecular proton transfer as shown
in Scheme 8.
On the other hand, although the rebending of the allenic
unit is even more facile in the case of the intermediate 28b(R),
the proton transfer from the resulting 29b(R) was computed
¹1
to have a much higher activation barrier of 10.5 kcal mol
(Figure 9). Taking account of the reversibility of the C-C bond
formation step, this could serve as an additional stereo-
discriminating factor favoring the formation of the S product.
However, most probably this effect is leveled by the inter-
molecular protonation.
The much higher barrier of the intramolecular proton transfer
in the case of 29b(R) compared to 29b(S) is explained by
the relative instability of the corresponding transitions state
TS9b(R) compared to TS9b(S) (Figure 11). The TS9b(S) is
very close in structure to the intermediate 29b(S), and the
methoxycarbonyl substituent comfortably residing over the
flat phenyl ring. In the transition state TS9b(R) the necessary
linear arrangement of the nitrogen, hydrogen, and carbon atoms
can be only achieved at the expense of rotating the whole
¹
CH3O2C-CR=C -CO2CH3 unit about 40 degrees around the
freshly formed C-C bond (Figure 11). Similarly to the C-C
bond formation step, the main stereoregulating interaction is

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
329
Figure 9. Profile of the potential energies for the C-C bond formation reaction between 3a and 6a catalyzed by Ir complex 1b.
the steric hindrance from the BOC group of the ¡-cyanoacetate.
Important dihedral angles (CH3O2C-CR=C -CO2CH3) are
shown in green, TS9b(S): 46.3°, TS9b(R): 95.1°.
strongly disfavored and does not provide a serious competition
to the major reaction manifold. Nevertheless, the perfect
enantioselectivity is difficult to achieve due to the competition
of background reaction and various possibilities of the mono-
functional activation of the electrophile. In order to improve
the ee value of the product, one should tune the catalytic
performance to increase the difference of the rates of catalytic
and noncatalytic reactions.
The sense of enantioselection in the C-C bond forming
reaction of 3 and acetylenic diester 6 is opposite to that in the
reaction of 3 to 4. A straight molecule of 6 cannot effec-
tively use the same activation pathway as the sharply bent
molecule of 4. If it tries to make a hydrogen bond with the
available NH proton of 9 or 11 with one of its carboxy-
methyl groups, keeping the C-C bond forming carbons in
reasonable proximity, another carboxymethyl group inevi-
tably encounters the bulky BOC substituent. The most effective
way to avoid this hindrance is to switch the prochiral planes
of the coordinated ¡-cyanoacetate via rearrangement to 8 or 10
that changes hindering group to the much less demanding
phenyl substituent, and the reaction provides the antipodal
enantiomer.
¹
Conclusion
The present mechanistic studies on two asymmetric con-
jugate addition of ¡-cyanoacetates 3 to electrophiles catalyzed
by the same bifunctional Ir and Ru catalysts 1 and 2 producing
the chiral adducts with the opposite sense of chirality revealed
important specific features of the conformationally flexible
catalyst-substrate complexes generated from the catalysts with
3. Depending on the structure of the acceptor molecule, either
one or the other conformation of the catalyst-donor complex
becomes more reactive that determines the sense of enantio-
selection of the corresponding C-N and C-C bond forming
reactions.
In the case of the C-N bond forming reaction, the
conformation of the intermediate 9 or 11 without intramolec-
ular hydrogen bond is capable of forming the uniquely shaped
transition state with the incoming azodicarboxylate 4 providing
the reaction pathway with the lowest energy. The similar
arrangement of the reactants leading to the other enantiomer is

330
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Figure 10. Optimized geometries and relative energies of the dipole-dipole complexes 26b, 27b(re) and of the transition states
TS6b(S), TS7b(R).
1
Hence, the stereochemical outcome of the catalytic reaction
significantly depends on the exact shape of the acceptor
molecule that is not involved in the formation of a catalyst-
donor complex. Computational analysis clearly shows that
the present substrate-controlled enantioselectivity is strongly
attributed to the metal-ligand cooperating bifunctional effect
based on the M-NH2 units. This effect is crucially important
for determining the sense of the chiral induction in the C-N
or C-C bond formation. In addition, the present mechanistic
considerations underline the importance of the structural
flexibility of the bifunctional molecular catalysis. Since our
catalytic systems studied here are structurally relatively simple,
the further diversified structural modification of the bifunc-
tional catalyst molecules could result in development of unique
molecular catalysts with the 3D asymmetry adjustable for
each particular reactions. Further studies along these lines are
underway in our laboratories.
probe. H NMR shifts are relative to the signal of the solvent:
CHCl3, ¤ 7.26; CDHCl2, 5.32; 13C{1H} NMR shifts are relative
to the signal of the solvent: CDCl3, ¤ 77.00; CD2Cl2, ¤ 53.5;
peak multiplicities are given as follows: s, singlet; d, doublet;
t, triplet; m, multiplet. The coupling constants are described
in hertz (Hz). Assignments of the signals in the spectra were
carried out with the use of routine 2D correlation techniques.
HPLC analyses were conducted on a JASCO PU-980 equipped
with a UV-970 detector. IR spectra were recorded on a JASCO
FT/IR-610 spectrometer. Mass spectra analyses were per-
formed on a Hitachi M-80B, Thermo Fisher Scientific Polaris
Q, and Waters LCT PremierTm XE.
The full details of catalytic reactions are described in the
Supporting Information.
Computational Details. All computations were carried out
using the hybrid Becke functional (B3)35 for electron exchange
and the correlation functional of Lee, Yang, and Parr (LYP),36
as implemented in the Gaussian 09 software package.37 For
ruthenium and iridium, the SDD basis set with the associated
effective core potential was employed.38 All other atoms were
modeled at the 6-31G(d) level of theory.39 Geometry optimi-
zations were performed with the account of the solvent effects
(IFEPCM, toluene) without applying any geometry constraints
(C1 symmetry).
Experimental
General.
All manipulation of oxygen- and moisture-
sensitive materials was carried out under an argon atmosphere
by use of standard Schlenk techniques. Solvents were pur-
chased and dried by refluxing over sodium benzophenone ketyl
(THF, toluene, and diethyl ether), P2O5 (CH2Cl2, hexane, and
CH3CN), CaSO4 (acetone) and distilled under argon.
1H, 13C{1H} spectra were recorded on a JEOL JNM-LA300
or JEOL ESX-400 instrument equipped with a field-gradient
Starting geometries for the transition state search were
located either by QST2 or QST3 procedures, or by the guess
based on the structure of the previously found TS. The transition

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
331
Ts
N
Ts
C6H5
C6H5
C6H5
N
Ir
Ir
N
N
N
N
C6H5
C
CO2R
C
H
H
C6H5
H
H
O
R
O
C6H5
S
O
CO2CH3
CO2CH3
OR
28b(R)
28b(S)
OCH3
OCH3
TS8b(S)
TS8b(R)
Ts
N
Ts
N
C6H5
C6H5
C6H5
C6H5
Ir
Ir
N
H
N
O
N
N
C6H5
CO2R
C6H5
C
C
H
H
H
CO2R
O
29b(R)
CO2CH3
CO2CH3
29b(S)
OCH3
OCH3
TS9b(S)
TS9b(R)
Ts
N
Ts
N
C6H5
C6H5
C6H5
C6H5
Ir
Ir
N
H
N
H
N
N
C6H5
CO2R
CO2R
C6H5
C
C
H
H
O
30b(S)
30b(R)
O
CO2CH3
CO2CH3
OCH3
OCH3
R = C(CH3)3
1b + 7aR-Z
1b + 7aS-Z
Scheme 8. Stereoselective intramolecular C-H bond formation.
Figure 11. Optimized geometries and relative energies of transition states TS9b(S) and TS9b(R).
states were subsequently fully optimized as saddle points of first
order, employing the Berny algorithm.40 Frequency calculations
were carried out to confirm the nature of the stationary points,
yielding zero imaginary frequencies for all the Ir and Ru com-
plexes and one imaginary frequency for all the transition states,
which represented the vector for the C-N or C-C bond forma-
tion, or for the proton transfer in all respective cases. Zero-point
energy corrections were carried out for all computed energies.
This work was supported by a Grant-in-Aid for Scien-
tific Research (Priority Areas No. 18065007 “Chemistry of
concerto Catalysis” and (S) No. 22225004) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan
and by Chemistry GCOE Program of the Tokyo Institute
of Technology. The computational results reported in this
paper were obtained on Tsubame-2 supercomputer of the Tokyo
Institute of Technology.

332
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
j) W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am.
Chem. Soc. 1990, 112, 2801. k) W. Zhang, E. N. Jacobsen, J. Org.
Chem. 1991, 56, 2296. l) E. N. Jacobsen, W. Zhang, A. R. Muci,
J. R. Ecker, L. Deng, J. Am. Chem. Soc. 1991, 113, 7063.
Supporting Information
Experimental details including C-N and C-C bond formation
reactions, NMR charts, X-ray data for the assignment of
absolute configuration, absolute energies, and Cartesian coor-
dinates of the computed structures. This material is available
free of charge via the Internet at http://www.csj.jp/journals/bcsj/.
4
a) Comprehensive Asymmetric Catalysis III, ed. by E. N.
Jacobsen, A. Pfaltz, H. Yamamoto, Springer, Berlin, 1999. b) M.
Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187.
5
For reviews, see: a) Quaternary Stereocenters: Challenges
and Solutions in Organic Synthesis, ed. by J. Christoffers, A. Baro,
Wiley-VCH, Weinheim, Germany, 2006. b) E. J. Corey, A.
Guzman-Perez, Angew. Chem., Int. Ed. 1998, 37, 388. c) J.
Christoffers, A. Mann, Angew. Chem., Int. Ed. 2001, 40, 4591. d) I.
Denissova, L. Barriault, Tetrahedron 2003, 59, 10105. e) C. J.
Douglas, L. E. Overman, Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363. f ) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347,
1473. g) J. Comelles, M. Moreno-Mañas, A. Vallribera, ARKIVOC
2005, Part ix, 207. h) B. M. Trost, C. Jiang, Synthesis 2006, 369.
i) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5, 873. j) I.
Marek, G. Sklute, Chem. Commun. 2007, 1683. k) P. G. Cozzi,
R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969.
l) A. Alexakis, M. Vuagnoux-d’Augustin, D. Martin, S. Kehrli, L.
Palais, H. Hénon, C. Hawner, Chimia 2008, 62, 461. m) M.
Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853. n) M. Bella, T.
Gasperi, Synthesis 2009, 1583. o) C. Hawner, A. Alexakis, Chem.
Commun. 2010, 46, 7295. p) J. P. Das, I. Marek, Chem. Commun.
2011, 47, 4593.
References
1
For reviews and book chapters, see: Reviews: a) R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley, New York,
1994. b) J. Seyden-Penne, Chiral Auxiliaries and Ligands in
Asymmetric Synthesis, Wiley, New York, 1995. c) J. P. Genet, in
Reductions in Organic Synthesis: Recent Advances and Practical
Applications in ACS Symposium Series, ed. by A. F. Abdel-Magid,
1996, Vol. 641, Chap. 2. doi:10.1021/bk-1996-0641.ch002. d) W.
S. Knowles, Angew. Chem., Int. Ed. 2002, 41, 1998. e) R. Noyori,
Angew. Chem., Int. Ed. 2002, 41, 2008. f ) I. D. Gridnev, T.
Imamoto, Acc. Chem. Res. 2004, 37, 633. g) Comprehensive
Asymmetric Catalysis II, ed. by E. N. Jacobsen, A. Pfaltz, H.
Yamamoto, Springer, Berlin, 1999.
2
For some of the representative examples, see: a) H. B.
Kagan, Bull. Soc. Chim. Fr. 1988, 846. b) V. P. Conticello, L.
Brard, M. A. Giardello, Y. Tsuji, M. Sabat, C. L. Stern, T. J. Marks,
J. Am. Chem. Soc. 1992, 114, 2761. c) A. Lightfoot, P. Schnider, A.
Pfaltz, Angew. Chem., Int. Ed. 1998, 37, 2897. d) M. V. Troutman,
D. H. Appella, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
4916. e) R. Noyori, T. Ohkuma, Angew. Chem., Int. Ed. 2001, 40,
40. f ) A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hörmann, S.
McIntyre, F. Menges, M. Schönleber, S. P. Smidt, B. Wüstenberg,
N. Zimmermann, Adv. Synth. Catal. 2003, 345, 33. g) M.
Kitamura, R. Noyori, in Ruthenium in Organic Synthesis, ed. by
S.-i. Murahashi, Wiley-VCH, Weinheim, 2004, p. 3. h) S. E.
Clapham, A. Hadzovic, R. H. Morris, Coord. Chem. Rev. 2004,
248, 2201. i) J. Blacker, J. Martin, in Asymmetric Catalysis on
Industrial Scale: Challenges, Approaches and Solutions, ed. by
H. U. Blaser, E. Schmidt, Wiley, New York, 2004, p. 201. j) S.
Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz,
Science 2006, 311, 642. k) A. J. Blacker, in Handbook of
Homogeneous Hydrogenation, ed. by J. G. de Vries, C. J. Elsevier,
Wiley-VCH Verlag GmbH & KgaA, Weinheim, 2007, p. 1215.
l) S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 2007, 40, 1402.
m) Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357. n) W. Zhang, Y.
Chi, X. Zhang, Acc. Chem. Res. 2007, 40, 1278. o) A. J. Minnaard,
B. L. Feringa, L. Lefort, J. G. de Vries, Acc. Chem. Res. 2007, 40,
1267. p) I. D. Gridnev, T. Imamoto, Chem. Commun. 2009, 7447.
q) J. S. M. Samec, J.-E. Bäckvall, P. G. Andersson, P. Brandt,
Chem. Soc. Rev. 2006, 35, 237.
6
a) T. Hayashi, K. Kanehira, T. Hagihara, M. Kumada,
J. Org. Chem. 1988, 53, 113. b) M. Sawamura, H. Nagata, H.
Sakamoto, Y. Ito, J. Am. Chem. Soc. 1992, 114, 2586. c) B. M.
Trost, R. Radinov, E. M. Grenzer, J. Am. Chem. Soc. 1997, 119,
7879. d) B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 1999,
121, 6759. e) B. M. Trost, J. Xu, M. Reichle, J. Am. Chem. Soc.
2007, 129, 282. f ) J. A. Keith, D. C. Behenna, J. T. Mohr, S. Ma,
S. C. Marinescu, J. Oxgaard, B. M. Stoltz, W. A. Goddard, III,
J. Am. Chem. Soc. 2007, 129, 11876. g) A. M. Taylor, R. A.
Altman, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 9900.
h) B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2010, 132,
15534.
7
a) D. J. Spielvogel, S. L. Buchwald, J. Am. Chem. Soc.
2002, 124, 3500. b) D. J. Spielvogel, W. M. Davis, S. L.
Buchwald, Organometallics 2002, 21, 3833. c) G. Chen, F. Y.
Kwong, H. O. Chan, W.-Y. Yu, A. S. C. Chan, Chem. Commun.
2006, 1413. d) X. Liao, Z. Weng, J. F. Hartwig, J. Am. Chem. Soc.
2008, 130, 195.
8
a) A. O. Larsen, W. Leu, C. N. Oberhuber, J. E. Campbell,
A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 11130. b) K. E.
Murphy, A. H. Hoveyda, Org. Lett. 2005, 7, 1255. c) K.-s. Lee,
M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc.
2006, 128, 7182. d) T. L. May, M. K. Brown, A. H. Hoveyda,
Angew. Chem., Int. Ed. 2008, 47, 7358. e) F. Gao, K. P. McGrath,
Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 14315. f ) F.
Gao, Y. Lee, K. Mandai, A. H. Hoveyda, Angew. Chem., Int. Ed.
2010, 49, 8370.
3
For reviews and the earliest examples, see: a) T. Katsuki, in
Comprehensive Asymmetric Catalysis II, ed. by E. N. Jacobsen,
A. Pfaltz, H. Yamamoto, Springer, Berlin, 1999, p. 621. b) E. N.
Jacobsen, M. H. Wu, in Comprehensive Asymmetric Catalysis II,
ed. by E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Springer, Berlin,
1999, p. 649. c) Catalytic Asymmetric Synthesis, ed. by I. Ojima,
Wiley-VHC, New York, 2000, p. 231. d) H. Adolfsson, in Modern
Oxidation Methods, ed. by J.-E. Bäckvall, Wiley-VCH, Weinheim,
2004, p. 21. e) C. Bonini, G. Righi, Tetrahedron 2002, 58, 4981.
f ) K. B. Sharpless, Angew. Chem., Int. Ed. 2002, 41, 2024. g) T.
Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974.
h) B. E. Rossiter, T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc.
1981, 103, 464. i) K. A. Jørgensen, Chem. Rev. 1989, 89, 431.
9
T. Fujimoto, K. Endo, H. Tsuji, M. Nakamura, E.
Nakamura, J. Am. Chem. Soc. 2008, 130, 4492.
10 a) D. A. Evans, J. A. Murry, P. von Matt, R. D. Norcross,
S. J. Miller, Angew. Chem., Int. Ed. Engl. 1995, 34, 798. b) M.
Johannsen, S. Yao, Chem. Commun. 1997, 2169. c) S. Yao, M.
Johannsen, H. Audrain, R. G. Hazell, K. A. Jørgensen, J. Am.
Chem. Soc. 1998, 120, 8599. d) V. K. Aggarwal, E. S. Anderson,
D. E. Jones, K. B. Obierey, R. Giles, Chem. Commun. 1998, 1985.
e) S. R. Chemler, U. Iserloh, S. J. Danishefsky, Org. Lett. 2001, 3,

Y. Hasegawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
333
2949. f ) A. K. Ghosh, M. Shirai, Tetrahedron Lett. 2001, 42, 6231.
g) J. Ishihara, M. Horie, Y. Shimada, S. Tojo, A. Murai, Synlett
2002, 403. h) I.-H. Chen, K. Oisaki, M. Kanai, M. Shibasaki, Org.
Lett. 2008, 10, 5151.
11 a) Y. Huang, T. Iwama, V. H. Rawal, J. Am. Chem. Soc.
2000, 122, 7843. b) Y. Huang, T. Iwama, V. H. Rawal, Org. Lett.
2002, 4, 1163. c) S. A. Kozmin, T. Iwama, Y. Huang, V. H. Rawal,
J. Am. Chem. Soc. 2002, 124, 4628. d) L.-F. You, R. P. Hsung,
A. A. Bedermann, A. V. Kurdyumov, Y. Tang, G. S. Buchanan,
K. P. Cole, Adv. Synth. Catal. 2008, 350, 2885. e) K. C. Nicolaou,
G. S. Tria, D. J. Edmonds, M. Kar, J. Am. Chem. Soc. 2009, 131,
15909.
Angew. Chem., Int. Ed. 2009, 48, 559. j) T. Zweifel, J.-V. Naubron,
T. Büttner, T. Ott, H. Grützmacher, Angew. Chem., Int. Ed. 2008,
47, 3245. k) R. J. Hamilton, S. H. Bergens, J. Am. Chem. Soc.
2008, 130, 11979. l) S. W. Kohl, L. Weiner, L. Schwartsburd, L.
Konstantinovski, L. J. W. Shimon, Y. Ben-David, M. Iron, D.
Milstein, Science 2009, 324, 74.
19 a) K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2007, 129, 7439. b) T. Mashiko, N. Kumagai,
M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 14990. c) J.
Hartwig, Organotransition Metal Chemistry, Univ. Science Books,
Sausalito, 2010, Chap. 14. d) Bifunctional Molecular Catalysis
in Topics in Organometallic Chemistry, ed. by T. Ikariya, M.
Shibasaki, Springer, New York, 2011, Vol. 37. doi:10.1007/978-3-
642-20731-0.
12 Y. Huang, T. Iwama, V. H. Rawal, J. Am. Chem. Soc. 2002,
124, 5950.
13 a) E. P. Kündig, C. M. Saudan, V. Alezra, F. Viton, G.
Bernardinelli, Angew. Chem., Int. Ed. 2001, 40, 4481. b) J.
Rickerby, M. Vallet, G. Bernardinelli, F. Viton, E. P. Kündig,
Chem.®Eur. J. 2007, 13, 3354.
20 For reviews, see: a) R. Noyori, S. Hashiguchi, Acc. Chem.
Res. 1997, 30, 97. b) T. Ikariya, K. Murata, R. Noyori, Org.
Biomol. Chem. 2006, 4, 393. c) T. Ikariya, A. J. Blacker, Acc.
Chem. Res. 2007, 40, 1300. d) T. Ikariya, I. D. Gridnev, Chem.
Rec. 2009, 9, 106. e) M. Shibasaki, M. Kanai, S. Matsunaga, N.
Kumagai, Acc. Chem. Res. 2009, 42, 1117. f ) T. Ikariya, I. D.
Gridnev, Top. Catal. 2010, 53, 894.
21 For the recent examples of a switch in the enantioselectivity
with the same chiral ligand, see: a) D.-M. Du, S.-F. Lu, T. Fang, J.
Xu, J. Org. Chem. 2005, 70, 3712. b) A. Frölander, C. Moberg,
Org. Lett. 2007, 9, 1371. c) N. Abermil, G. Masson, J. Zhu, Org.
Lett. 2009, 11, 4648. d) A. Nojiri, N. Kumagai, M. Shibasaki,
J. Am. Chem. Soc. 2009, 131, 3779. e) K. Y. Spangler, C. Wolf,
Org. Lett. 2009, 11, 4724. f ) H. Y. Kim, H.-J. Shih, W. E. Knabe,
K. Oh, Angew. Chem., Int. Ed. 2009, 48, 7420. g) H. Y. Kim, K.
Oh, Org. Lett. 2009, 11, 5682. h) Y. Liu, D. Shang, X. Zhou, Y.
Zhu, L. Lin, X. Liu, X. Feng, Org. Lett. 2010, 12, 180. i) N.
Shibata, M. Okamoto, Y. Yamamoto, S. Sakaguchi, J. Org. Chem.
2010, 75, 5707.
22 For the examples of a dynamic interconversion between
the possible catalyst intermediates, see: a) M. V. Peters, R. S. Stoll,
A. Kühn, S. Hecht, Angew. Chem., Int. Ed. 2008, 47, 5968. b) R. S.
Stoll, M. V. Peters, A. Kühn, S. Heiles, R. Goddard, M. Bühl,
C. M. Thiele, S. Hecht, J. Am. Chem. Soc. 2009, 131, 357.
23 a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R.
Noyori, J. Am. Chem. Soc. 1995, 117, 7562. b) J. Takehara, S.
Hashiguchi, A. Fujii, S.-i. Inoue, T. Ikariya, R. Noyori, Chem.
Commun. 1996, 233. c) J.-X. Gao, T. Ikariya, R. Noyori,
Organometallics 1996, 15, 1087. d) A. Fujii, S. Hashiguchi, N.
Uematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118,
2521. e) S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura, T.
Ikariya, R. Noyori, Angew. Chem., Int. Ed. Engl. 1997, 36, 288.
f ) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1997, 119, 8738. g) T. Ikariya, S. Hashiguchi, K.
Murata, R. Noyori, Org. Synth. 2005, 82, 10.
14 a) E. J. Corey, T. Shibata, T. W. Lee, J. Am. Chem. Soc.
2002, 124, 3808. b) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc.
2003, 125, 6388. c) K. T. Sprott, E. J. Corey, Org. Lett. 2003, 5,
2465. d) Q.-Y. Hu, G. Zhou, E. J. Corey, J. Am. Chem. Soc. 2004,
126, 13708. e) Q.-Y. Hu, P. D. Rege, E. J. Corey, J. Am. Chem.
Soc. 2004, 126, 5984. f ) K. Futatsugi, H. Yamamoto, Angew.
Chem., Int. Ed. 2005, 44, 1484. g) S. Hong, E. J. Corey, J. Am.
Chem. Soc. 2006, 128, 1346. h) S. A. Snyder, E. J. Corey, J. Am.
Chem. Soc. 2006, 128, 740. i) J. N. Payette, H. Yamamoto, J. Am.
Chem. Soc. 2007, 129, 9536. j) M. N. Paddon-Row, L. C. H.
Kwan, A. C. Willis, M. S. Sherburn, Angew. Chem., Int. Ed. 2008,
47, 7013. k) J. N. Payette, H. Yamamoto, Angew. Chem., Int. Ed.
2009, 48, 8060. l) E. J. Corey, Angew. Chem., Int. Ed. 2009, 48,
2100. m) K. Shibatomi, K. Futatsugi, F. Kobayashi, S. Iwasa, H.
Yamamoto, J. Am. Chem. Soc. 2010, 132, 5625. n) S. Mukherjee,
E. J. Corey, Org. Lett. 2010, 12, 632.
15 a) C. Ogawa, K. Kizu, H. Shimizu, M. Takeuchi, S.
Kobayashi, Chem.®Asian J. 2006, 1, 121. b) Y. Kawato, N.
Takahashi, N. Kumagai, M. Shibasaki, Org. Lett. 2010, 12, 1484.
c) F. Santoro, M. Althaus, C. Bonaccorsi, S. Gischig, A. Mezzetti,
Organometallics 2008, 27, 3866.
16 a) E. Emori, T. Arai, H. Sasai, M. Shibasaki, J. Am. Chem.
Soc. 1998, 120, 4043. b) S. Harada, N. Kumagai, T. Kinoshita, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2582.
17 a) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc.
2002, 124, 11240. b) Y. Hamashima, H. Takano, D. Hotta, M.
Sodeoka, Org. Lett. 2003, 5, 3225. c) Y. Hamashima, H. Somei, Y.
Shimura, T. Tamura, M. Sodeoka, Org. Lett. 2004, 6, 1861. d) Y.
Tsuchiya, Y. Hamashima, M. Sodeoka, Org. Lett. 2006, 8, 4851.
e) J. Christoffers, A. Baro, Angew. Chem., Int. Ed. 2003, 42, 1688.
f ) M. Sodeoka, Y. Hamashima, Chem. Commun. 2009, 5787.
18 a) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R.
Noyori, Angew. Chem., Int. Ed. Engl. 1997, 36, 285. b) C. P.
Casey, S. W. Singer, D. R. Powell, R. K. Hayashi, M. Lavana,
J. Am. Chem. Soc. 2001, 123, 1090. c) K. Abdur-Rashid, S. E.
Clapham, A. Hadzovic, J. N. Harvey, A. J. Lough, R. H. Morris,
J. Am. Chem. Soc. 2002, 124, 15104. d) C. P. Casey, J. B. Johnson,
J. Org. Chem. 2003, 68, 1998. e) C. A. Sandoval, T. Ohkuma, K.
Muñiz, R. Noyori, J. Am. Chem. Soc. 2003, 125, 13490. f ) J.
Zhang, M. Gandelman, L. J. W. Shimon, H. Rozenberg, D.
Milstein, Organometallics 2004, 23, 4026. g) J. Zhang, G. Leitus,
Y. Ben-David, D. Milstein, J. Am. Chem. Soc. 2005, 127, 10840.
h) F. Läng, F. Breher, D. Stein, H. Grützmacher, Organometallics
2005, 24, 2997. i) T. Zweifel, J.-V. Naubron, H. Grützmacher,
24 a) K. Murata, H. Konishi, M. Ito, T. Ikariya, Organo-
metallics 2002, 21, 253. b) T. Koike, T. Ikariya, Adv. Synth. Catal.
2004, 346, 37. c) T. Koike, T. Ikariya, Organometallics 2005, 24,
724.
25 a) M. Watanabe, K. Murata, T. Ikariya, J. Am. Chem. Soc.
2003, 125, 7508. b) H. Wang, M. Watanabe, T. Ikariya,
Tetrahedron Lett. 2005, 46, 963. c) M. Watanabe, A. Ikagawa,
H. Wang, K. Murata, T. Ikariya, J. Am. Chem. Soc. 2004, 126,
11148. d) T. Ikariya, H. Wang, M. Watanabe, K. Murata,
J. Organomet. Chem. 2004, 689, 1377. e) I. D. Gridnev, M.
Watanabe, H. Wang, T. Ikariya, J. Am. Chem. Soc. 2010, 132,
16637.
26 Y. Hasegawa, I. D. Gridnev, T. Ikariya, Angew. Chem., Int.

334
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Mechanisms of Asymmetric C-N and C-C Bond Formation
Ed. 2010, 49, 8157.
27 Y. Hasegawa, M. Watanabe, I. D. Gridnev, T. Ikariya,
J. Am. Chem. Soc. 2008, 130, 2158.
33 a) I. D. Gridnev, N. Higashi, T. Imamoto, J. Am. Chem. Soc.
2000, 122, 10486. b) I. D. Gridnev, M. Yasutake, N. Higashi, T.
Imamoto, J. Am. Chem. Soc. 2001, 123, 5268. c) S. Feldgus, C. R.
Landis, Organometallics 2001, 20, 2374. d) P. J. Donoghue, P.
Helquist, O. Wiest, J. Org. Chem. 2007, 72, 839. e) T. Imamoto, T.
Itoh, K. Yoshida, I. D. Gridnev, Chem.®Asian J. 2008, 3, 1636.
34 For N-bound cyanocarbanion complexes, see: a) S.-I.
Murahashi, T. Naota, H. Taki, M. Mizuho, H. Takaya, S.
Komiya, Y. Mizuho, N. Oyasato, M. Hiraoka, M. Hirano, A.
Fukuoka, J. Am. Chem. Soc. 1995, 117, 12436. b) M. Sawamura,
M. Sudoh, Y. Ito, J. Am. Chem. Soc. 1996, 118, 3309. c) R.
Kuwano, Chem. Commun. 1998, 71. d) M. Hirano, A. Takenaka,
Y. Mizuho, M. Hiraoka, S. Komiya, J. Chem. Soc., Dalton Trans.
1999, 3209. e) M. Hirano, S. Kiyota, M. Imoto, S. Komiya, Chem.
Commun. 2000, 1679. f ) S.-I. Murahashi, K. Take, T. Naota, H.
Takaya, Synlett 2000, 1016. g) M. Kujime, S. Hikichi, M. Akita,
Organometallics 2001, 20, 4049. h) T. Naota, A. Tannna, S.
Kamuro, S.-I. Murahashi, J. Am. Chem. Soc. 2002, 124, 6842.
i) D. A. Culkin, J. F. Hartwig, Organometallics 2004, 23, 3398.
j) T. Naota, A. Tannna, S. Kamuro, M. Hieda, K. Ogata, S.-I.
Murahashi, Chem.®Eur. J. 2008, 14, 2482. k) K. D. Wells, M. J.
Ferguson, R. McDonald, M. Cowie, Organometallics 2011, 30,
815.
28 For selected examples of asymmetric C-N bond formation
with azodicarboxylate catalyzed by organocatalysts see: a) G.
Guillena, D. J. Ramón, Tetrahedron: Asymmetry 2006, 17, 1465.
b) B. List, J. Am. Chem. Soc. 2002, 124, 5656. c) N.
Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig, K. A.
Jørgensen, J. Am. Chem. Soc. 2002, 124, 6254. d) S. Saaby,
M. Bella, K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 8120.
e) H. Iwamura, S. P. Mathew, D. G. Blackmond, J. Am. Chem. Soc.
2004, 126, 11770. f ) X. Liu, H. Li, L. Deng, Org. Lett. 2005, 7,
167. g) M. Terada, M. Nakano, H. Ube, J. Am. Chem. Soc. 2006,
128, 16044. h) X. Xu, T. Yabuta, P. Yuan, Y. Takemoto, Synlett
2006, 137. i) Y. Liu, R. Melgar-Fernández, E. Juaristi, J. Org.
Chem. 2007, 72, 1522. j) X.-L. Huang, X.-Y. Chen, S. Ye, J. Org.
Chem. 2009, 74, 7585. k) T. Bui, M. Borregan, C. F. Barbas, III,
J. Org. Chem. 2009, 74, 8935. l) M. Terada, D. Tsushima, M.
Nakano, Adv. Synth. Catal. 2009, 351, 2817.
29 a) D. A. Evans, S. G. Nelson, J. Am. Chem. Soc. 1997, 119,
6452. b) D. A. Evans, D. S. Johnson, Org. Lett. 1999, 1, 595. c) Y.
Yamashita, H. Ishitani, S. Kobayashi, Can. J. Chem. 2000, 78, 666.
d) K. Juhl, K. A. Jørgensen, J. Am. Chem. Soc. 2002, 124, 2420.
e) M. Marigo, K. Juhl, K. A. Jørgensen, Angew. Chem., Int. Ed.
2003, 42, 1367. f ) H. Vogt, S. Vanderheiden, S. Bräse, Chem.
Commun. 2003, 2448. g) J. Comelles, M. Moreno-Mañas, E.
Pérez, A. Roglans, R. M. Sebastián, A. Vallribera, J. Org. Chem.
2004, 69, 6834. h) R. Matsubara, S. Kobayashi, Angew. Chem., Int.
Ed. 2006, 45, 7993. i) J. Comelles, À. Pericas, M. Moreno-Mañas,
A. Vallribera, G. Drudis-Solé, A. Lledos, T. Parella, A. Roglans, S.
García-Granda, L. Roces-Fernández, J. Org. Chem. 2007, 72,
2077. j) T. Mashiko, K. Hara, D. Tanaka, Y. Fujiwara, N. Kumagai,
M. Shibasaki, J. Am. Chem. Soc. 2007, 129, 11342. k) J. M.
Berlin, G. C. Fu, Angew. Chem., Int. Ed. 2008, 47, 7048. l) T.
Mashiko, N. Kumagai, M. Shibasaki, Org. Lett. 2008, 10, 2725.
m) Z. Yang, Z. Wang, S. Bai, K. Shen, D. Chen, X. Liu, L. Lin, X.
Feng, Chem.®Eur. J. 2010, 16, 6632.
35 a) A. D. Becke, J. Chem. Phys. 1993, 98, 1372. b) A. D.
Becke, J. Chem. Phys. 1993, 98, 5648.
36 C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785.
37 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,
E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S.
Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,
J. Cioslowski, D. J. Fox, Gaussian 09 (Revision A.02), Gaussian,
Inc., Wallingford CT, 2009.
30 For addition to acetylenic ester, see: a) X. Wang, M.
Kitamura, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 1038. b) T.
Misaki, K. Kawano, T. Sugimura, J. Am. Chem. Soc. 2011, 133,
5695.
31 For addition to acetylenic ketone, see: a) M. Bella, K. A.
Jørgensen, J. Am. Chem. Soc. 2004, 126, 5672. b) Q. Lan, X.
Wang, S. Shirakawa, K. Maruoka, Org. Process Res. Dev. 2010,
14, 684. c) Z. Chen, M. Furutachi, Y. Kato, S. Matsunaga, M.
Shibasaki, Angew. Chem., Int. Ed. 2009, 48, 2218.
32 a) M. J. Burk, Y. M. Wang, J. R. Lee, J. Am. Chem. Soc.
1996, 118, 5142. b) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park,
S. Thayumanavan, Acc. Chem. Res. 1996, 29, 552. c) J. A.
Wilkinson, S. B. Rossington, J. Leonard, N. Hussein, Tetrahedron
Lett. 2004, 45, 1191. d) O. Kitagawa, S. Matsuo, K. Yotsumoto, T.
Taguchi, J. Org. Chem. 2006, 71, 2524.
38 D. Andrae, U. Häußermann, M. Dolg, H. Stoll, H. Preuß,
Theor. Chim. Acta 1990, 77, 123.
39 a) R. Ditchfield, W. J. Hehre, J. A. Pople, J. Chem. Phys.
1971, 54, 724. b) W. J. Hehre, R. Ditchfield, J. A. Pople, J. Chem.
Phys. 1972, 56, 2257. c) P. C. Hariharan, J. A. Pople, Theor. Chim.
Acta 1973, 28, 213. d) P. C. Hariharan, J. A. Pople, Mol. Phys.
1974, 27, 209. e) M. S. Gordon, Chem. Phys. Lett. 1980, 76, 163.
40 C. Y. Peng, B. Schlegel, Isr. J. Chem. 1994, 34, 449.