Catalytic asymmetric nitro-Mannich reactions with a Yb/K heterobimetallic catalyst

Article abstract of DOI:10.3390/molecules15031280

A catalytic asymmetric nitro-Mannich (aza-Henry) reaction with rare earth metal/alkali metal heterobimetallic catalysts is described. A Yb/K heterobimetallic catalyst assembled by an amide-based ligand promoted the asymmetric nitro-Mannich reaction to afford enantioenriched anti-β- nitroamines in up to 86% ee. Facile reduction of the nitro functionality allowed for efficient access to optically active 1,2-diamines.

Full text of DOI:10.3390/molecules15031280

Molecules 2010, 15, 1280-1290; doi:10.3390/molecules15031280
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Catalytic Asymmetric Nitro-Mannich Reactions with a Yb/K
Heterobimetallic Catalyst
Tatsuya Nitabaru, Naoya Kumagai * and Masakatsu Shibasaki *
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan; E-Mail: ff097020@mail.ecc.u-tokyo.ac.jp (T.N.)
* Authors to whom correspondence should be addressed; E-Mails: nkumagai@mol.f.u-tokyo.ac.jp
(N.K.); mshibasa@mol.f.u-tokyo.ac.jp (M.S.).
Received: 1 February 2010; in revised form: 10 February 2010 / Accepted: 2 March 2010 /
Published: 4 March 2010
Abstract: A catalytic asymmetric nitro-Mannich (aza-Henry) reaction with rare earth
metal/alkali metal heterobimetallic catalysts is described. A Yb/K heterobimetallic catalyst
assembled by an amide-based ligand promoted the asymmetric nitro-Mannich reaction to
afford enantioenriched anti-β-nitroamines in up to 86% ee. Facile reduction of the nitro
functionality allowed for efficient access to optically active 1,2-diamines.
Keywords: nitro-Mannich; ytterbium; heterobimetallic; asymmetric catalysis; amide-
based ligand
1. Introduction
The catalytic asymmetric nitro-Mannich (aza-Henry) reaction is a useful carbon-carbon bond-
forming reaction that assembles imines 1 and nitroalkanes 2 under proton-transfer conditions,
affording enantiomerically enriched β-nitroamines 3 [1,2]. Facile reduction of the nitro functionality of
the nitro-Mannich product to amines allowed for efficient access to synthetically versatile optically
active 1,2-diamines (Scheme 1) [3–5]. Due to its synthetic utility, increasing efforts have been directed
toward developing an efficient catalytic asymmetric nitro-Mannich reaction. Since our report on the
catalytic asymmetric nitro-Mannich reaction with a binaphthol-based heterobimetallic catalyst [6],
various metal-based catalysts [7–13] and organocatalysts [14–25] have been uncovered for diastereo-
and enantioselective nitro-Mannich reactions. We previously developed a highly anti- and

Molecules 2010, 15
1281
enantioselective nitroaldol reaction with a rare earth metal/alkali metal heterobimetallic catalytic
system assembled by an amide-based chiral ligand [26,27]. In this catalyst design, bifunctional
catalysis [28–32] exerted by an Nd/Na bimetallic catalyst, where the Nd cation acts as a Lewis acid
and the Na–aryloxide acts as Brønsted base, is key to achieving high catalytic activity and
stereoselectivity. In our continuing program to expand the utility of the heterobimetallic bifunctional
catalyst organized by the amide-based ligand [33–37], we planned to develop a diastereo- and
enantioselective nitro-Mannich reaction based on rare earth metal/alkali metal heterobimetallic catalysis.
Scheme 1. Catalytic asymmetric nitro-Mannich reaction for the synthesis of 1,2-diamines.
R2
R2
R2
R2
R2
H
catalytic asymmetric
nitro-Mannich reaction
NH
NH
NH
NH
R3
NO2
N
reduction
R3
R3
R3
R3
+
+
+
R1
R1
R1
R1
R1
NO2
anti-3
β-nitroamines
NO2
syn-3
NH2
anti
NH2
syn
1
2
1,2-diamines
2. Results and Discussion
2.1. Identification of a Suitable Heterobimetallic Catalyst for Asymmetric Nitro-Mannich Reaction
Initial trials were performed to identify the best combination of rare earth metals and alkali metals
with an amide-based ligand 4a, which is the best ligand for a catalytic asymmetric nitroaldol reaction
of aldehydes and nitroalkanes [27]. In the model reaction of Boc-imine 1a [38] derived from
benzaldehyde and nitroethane (2a), various heterobimetallic catalysts were prepared from rare earth
metal alkoxides [RE(OiPr)3] and alkali metal sources and evaluated based on the chemical yield and
stereoselectivity of the desired product 3aa (Table 1). The Nd/Na/4a heterogeneous heterobimetallic
catalyst, which was isolated as an insoluble material in THF, afforded high stereoselectivity in
anti-selective asymmetric nitroaldol reactions (Scheme 2), but gave poor results in the asymmetric
nitro-Mannich reaction, affording anti-3aa preferentially in 87% yield with anti/syn = 3.7/1 and 0% ee
(anti) (entry 1). Assuming that aldehyde and imine 1a have different coordination modes, it is
reasonable that the Nd/Na/4a catalytic system failed to exhibit highly stereoselectivity. The use of
other alkali metals led to a substantial loss in catalytic activity (entries 2,3), therefore we searched for
other rare earth metals. The heterobimetallic catalytic system comprising various rare earth metals and
Na exhibited generally high catalytic activity to afford 3aa in high yield with moderate anti-selectivity
by using 3 mol % of catalyst loading, whereas the dominant anti-diastereomer was nearly racemic
(entries 4–8). Thus, we turned our attention to the use of other alkali metals. Despite the low catalytic
activity of RE/Li/4a catalysts, RE/K/4a catalysts promoted the desired reaction (Table 2). Although
the low catalytic activity was observed for catalysts prepared from KHMDS compared with their
NaHMDS counterparts, promising anti-selectivity and enantioselectivity were obtained, particularly
when using Er or Yb as rare earth metals (entries 6,7). The low catalytic activity was compensated for
by using 10 mol % of catalyst. Decreasing the catalyst loading to 5 mol % resulted in a marginal loss
of enantioselectivity (entry 8).

Molecules 2010, 15
Scheme 2. Catalytic asymmetric nitroaldol reaction promoted by Nd/Na/4a heterobimetallic catalyst.
1282
Nd/Na/4a Heterobimetallic Catalyst
OH
R2
NO2
O
O
F
OH
1–6 mol %
R2
H
+
R1
N
HO
R1
H
–40 to –30 °C, yield 75–95%
anti/syn = 3.4/1 – >40/1
77–98% ee
N
H
NO2
O
F
4a
Table 1. Catalytic asymmetric nitro-Mannich reaction promoted by RE/alkali metal/4a
heterobimetallic catalyst.a
RE(OiPr)3
alkali metal source 6 mol %
ligand 4a 6 mol %
3 mol %
Boc
Ph
Boc
Ph
Boc
H
NH
NH
N
+
+
Ph
THF, –40 °C
NO2
NO2
NO2
syn-3aa
1a
2a
anti-3aa
Alkali metal
source d
NaHMDS
LHMDS
Time Yielde
dr
(%) (anti/syn)
87
trace
trace
72
89
80
83
92
ee (anti)
Entry
RE(OiPr)3
(h)
21
21
21
19
19
19
19
19
(%)
0
ND
ND
7
11
8
3
1 b
2
Nd5O(OiPr)13
Nd5O(OiPr)13
Nd5O(OiPr)13
La(OiPr)3
3.7/1
ND
ND
7.2/1
3.5/1
4.4/1
5/1
c
c
c
3
4
5
6
7
8
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
Sm(OiPr)3
Gd(OiPr)3
Er(OiPr)3
Yb(OiPr)3
5.2/1
6
a 1a: 0.3 mmol, 2a: 3.0 mmol. A heterogeneous complex formed during catalyst preparation procedure
b
was isolated by centrifugation and used as catalyst. oxo-Complex of Nd(OiPr)3. The amount used was
c
calculated based on Nd. d HMDS: hexamethyldisilazane. e Determined by 1H-NMR analysis with Bn2O as
an internal standard.
Table 2. Catalytic asymmetric nitro-Mannich reaction promoted by RE/K/4a heterobimetallic catalyst.a
RE(OiPr)3
KHMDS
ligand 4a
10 mol %
20 mol %
20 mol %
Boc
Ph
Boc
Boc
H
NH
NH
N
+
+
Ph
Ph
NO2
THF, –40 °C
NO2
NO2
syn-3aa
1a
2a
anti-3aa
Time Yieldb
dr
(anti/syn)
ND
ee (anti)
Entry
RE(OiPr)3
(h)
27
27
27
27
(%)
0
66
73
66
(%)
ND
6
18
0
1
2
3
4
La(OiPr)3
Pr(OiPr)3
Sm(OiPr)3
Gd(OiPr)3
5.3/1
5.8/1
7.7/1

Molecules 2010, 15
1283
Table 2. Cont.
5
6
7
8
Dy(OiPr)3
Er(OiPr)3
Yb(OiPr)3
Yb(OiPr)3
17
17
27
17
61
68
72
78
6.7/1
9.0/1
11/1
20
51
68
55
6.6/1
a 1a: 0.1 mmol, 2a: 1.0 mmol. bDetermined by 1H-NMR analysis with Bn2O as an internal standard.
We next focused on the effect of the amide-ligand architecture on stereoselectivity. 4a was
developed in the study of the asymmetric nitroaldol reaction, and its 2-fluoro substituent on the
benzamide moiety was crucial for limiting the C–C bond rotation through the C–F---H–N hydrogen
bond (Figure 1) [39,40]. The nitro-Mannich reaction with a Yb/K catalytic system prepared from
various amide-based ligands is summarized in Table 3. A ligand lacking 2-fluoro substituent 4b and a
pyridine-type ligand 4c gave almost racemic product, suggesting that conformational restriction of the
3-hydroxybenzamide moiety was a significant factor (entries 2,3). We then examined the effect of
modifying the anilide moiety by ligands 4d and 4e. Interestingly, both the presence and the position of
the fluoro substituent affected stereoselectivity, and the catalyst derived from 4e predominantly
afforded the opposite enantiomer, presumably because the pattern of the oligomeric association of the
heterobimetallic catalyst was different (entries 4,5). Together, these data indicated that the catalyst
comprising Yb/K/4a was optimum for the present reaction; therefore, the final optimization of reaction
conditions was conducted on a Yb/K heterobimetallic system (Table 4). The ratio of Yb/K/4a was a
dominant factor for both catalytic activity and stereoselectivity, revealing that Yb/K/4a = 1/2/2 was
optimal for catalytic performance (entries 1–4). A significant solvent effect was observed, likely
because the association of the ligand through hydrogen bonding and metal coordination was
susceptible to coordinative characteristics and/or the dielectric constant of the solvents (entries 5–8)
[41]. Non-polar, non-coordinating solvents exhibited poor catalytic efficiency (entries 5,6). Lowering
the reaction temperature to –60 °C somewhat increased both diastereo- and enantioselectivity,
affording 3aa in anti/syn = 18/1 and 73% ee (anti) (entry 9).
Figure 1. Intramolecular hydrogen bond in ligand 4a.
4a
O
OH
H
HO
N
N
H
O
F
F
benzamide moiety
anilide moiety
C–F---H–N
hydrogen bond

Molecules 2010, 15
Table 3. Catalytic asymmetric nitro-Mannich reaction promoted by RE/K/4 heterobimetallic catalysts.
1284
Yb(OiPr)3
KHMDS
ligand 4
10 mol %
20 mol %
20 mol %
Boc
Boc
Boc
H
NH
NH
N
+
+
Ph
Ph
Ph
NO2
THF, –40 °C
NO2
anti-3aa
NO2
syn-3aa
1a
2a
Time Yieldc
(h)
dr
(%) (anti/syn)
ee (anti)
Entry
Amide-based ligand 4
(%)
O
F
OH
H
HO
N
1
4a
4b
27
72
88
11/1
68
N
H
O
F
O
OH
H
N
2
3
23
17
3.1/1
17
2
HO
N
H
O
O
OH
H
N
N
H
4c
91
2.9/1
N
O
OH
O
OH
H
N
HO
HO
4
5
4d
4e
23
23
68
66
4.5/1
4.5/1
19
N
H
O
O
F
O
H
N
F
31b
N
H
HO
F
b
c
a1a: 0.1 mmol, 2a: 1.0 mmol. The opposite enantiomer was obtained preferentially. Determined
by 1H-NMR analysis with Bn2O as an internal standard.
Table 4. Optimization of reaction conditions based on Yb/K/4a heterobimetallic catalyst.a
Yb(OiPr)3
KHMDS
ligand 4a
x mol %
y mol %
z mol %
Boc
Ph
Boc
Ph
Boc
H
NH
NH
N
+
+
Ph
NO2
NO2
NO2
syn-3aa
1a
2a
anti-3aa
Temp
(°C)
dr
(anti/syn
)
Time Yieldb
ee (anti)
Entry
x
y
z
Solvent
(h)
(%)
(%)
1
2
3
4
5
10
10
10
10
10
20
10
20
10
20
20
THF
THF
THF
THF
CH2Cl2
–40
–40
–40
–40
–40
27
13
13
13
12
72
23
72
62
26
11/1
68
17
4
52
4
10
10
20
20
3.8/1
2.3/1
7.6/1
4.4/1

Molecules 2010, 15
1285
Table 4. Cont.
6
7
8
9
10
10
10
10
20
20
20
20
20
20
20
20
toluene
EtOAc
tBuOMe
THF
–40
12
12
12
24
46
79
70
77
2.2/1
3.1
7.6
4
20
52
73
–40
–40
–60
18/1
a1a: 0.1 mmol, 2a: 1.0 mmol. bDetermined by 1H NMR analysis with Bn2O as an internal standard.
2.2. Scope of the Catalytic Asymmetric Nitro-Mannich Reaction with Yb/K/4a Heterobimetallic
Catalyst
With a heterobimetallic Yb/K/4a catalyst for the nitro-Mannich reaction in hand, we examined the
substrate generality of the catalytic system (Table 5). Imines bearing a 2-naphthyl or tolyl group gave
the corresponding nitro-Mannich products 3ba–3da with stereoselectivity comparable to 3aa
(entries 2–4), indicating that steric issue was not significant in stereoselectivity. On the other hand, the
stereoselectivity appeared to be dependent on the electronic nature of the aromatic group of imines 1;
an imine with electron-withdrawing substituents afforded the product in poor stereoselectivity whereas
an imine with an electron-donating substituent enhanced stereoselectivity (entries 5–7), suggesting that
a background racemic pathway was involved [42]. Diastereo- and enantioselectivity were uniform in
the course of the reaction, indicating that the possibility of retro-reaction and epimerization of the
product were neglected [43]. The nitro group of the nitro-Mannich product anti-3ea was readily
reduced to generate anti-1,2-diamine 5ea (Scheme 3), indicating the synthetic utility of the nitro-
Mannich reactions to access synthetically versatile enantioenriched 1,2-diamines.
Table 5. Substrate scope of nitro-Mannich reaction promoted by Yb/K/4a heterobimetallic catalyst.a
Yb(OiPr)3
KHMDS
ligand 4a
10 mol %
20 mol %
20 mol %
Boc
R1
Boc
R1
Boc
H
NH
NH
N
+
+
R1
NO2
THF, –60 °C
NO2
anti-3aa
Time Yieldb
NO2
1a
2a
syn-3aa
dr
ee (anti)
(%)
73
Entry
R1
Product
(h)
22
22
44
20
44
20
20
(%)
(anti/syn)
18/1
1
2
3
4
5
6
7
Ph
1a
3aa
3ba
3ca
3da
3ea
3fa
80
71
87
76
79
74
72
2-naph
4-Me
3-Me
4-OMe
4-Cl
1b
1c
1d
1e
1f
17/1
72
22/1
86
13/1
75
19/1
82
6.6/1
2.4/1
50
4-CF3
1g
3ga
14
a1a: 0.3 mmol, 2a: 3.0 mmol. b Isolated yield.

Molecules 2010, 15
1286
Scheme 3. Reduction of nitro group of the niro-Mannich product.
Boc
Boc
NiCl2•6H2O
NaBH4
NH
NH
MeOH, 0 °C, 1 h
NO2
NH2
MeO
MeO
y. 99%
3ea
5ea
3. Experimental
3.1. General
Reactions were performed in flame-dried 20 mL test tubes with a magnetic stirring bar unless
otherwise noted. The test tubes were fitted with a glass 3-way stopcock and reactions were conducted
under argon atmosphere. Air- and moisture-sensitive liquids were transferred via gas-tight syringe and
stainless-steel needle. Flash chromatography was performed using silica gel 60 (230–400 mesh)
purchased from Merck. Commercial reagents were purchased from Kojundo Chemical Co. Ltd.
(RE(OiPr)3, RE5O(OiPr)13: Stored and handled in a dry box, contact: http://www.kojundo.co.jp/
English/index.html, Fax: +81-49-284-1351, E-Mail: sales@kojundo.co.jp.), TCI (aldehydes,
nitroethane, nitropropane), and Aldrich (LHMDS (1.0 M/THF), NaHMDS (1.0 M/THF), and KHMDS
(0.5 M/toluene)). N-Boc imines 1 were prepared by following reported procedure [38]. THF was
distilled from sodium/benzophenone ketyl. Other dry solvents were used as received from KANTO
1
13
Chemical Co. Ltd. H, C NMR spectra were recorded on JEOL LA-500 or ECX–500 spectrometers
(500 MHz). Chemical shifts for protons are reported in parts per million downfield from
tetramethylsilane and are referenced to residual protium in the NMR solvent (CDCl3: δ 7.24 ppm).
Chemical shifts for carbons are reported in parts per million downfield from tetramethylsilane and are
referenced to the carbon resonances of the solvent (CDCl3: δ 77.0). Coupling constants are reported in
Hertz (Hz). Infrared (IR) spectra were obtained using a JASCO FT/IR 410 spectrophotometer. ESI
mass spectral data for new compounds were obtained using a JEOL AccuTOF JMS-T100LC mass
spectrometer. Melting point was recorded on Yamato Melting Point Apparatus Model MP-21. All the
nitro-Mannich products were reported in the literature and spectral data of them were matched to the
reported ones.
3.2. General Procedure for Catalytic Asymmetric Nitro-Mannich Reaction with Yb/K/4a
Heterobimetallic Catalyst (Table 5, Entry 1)
To a flame dried 20 mL test tube charged with ligand 4a (22.7 mg, 0.06 mmol) and dried under
vacuum at room temperature for 10 min. Ar was back-filled to the test tube, then THF (520 μL),
Yb(OiPr)3 (341 μL, 0.03 mmol, 0.0878 M/THF), and KHMDS (120 μL, 0.06 mmol, 0.5 M/toluene)
were added by well-dried syringe and needle successively at room temperature, leading to a white
suspension. The subsequent addition of nitroethane (2a, 215 μL, 3.0 mmol) at the same temperature
gave a clear catalyst solution. The test-tube was immersed to an electronically-controlled cooling bath
at −60 °C, then THF solution (300 μL) of N-Boc-imine 1a (61.5 μL, 0.30 mmol) was added to run the

Molecules 2010, 15
1287
reaction. After stirring the reaction mixture at the same temperature for 22 h, 1N HCl aq. was added
and the resulting mixture was extracted with ethyl acetate (×2). The combined organic layers were
washed with sat. aq. NaHCO3 and brine, then dried over Na2SO4. After the removal of volatiles under
1
reduced pressure, the resulting residue was analyzed by H NMR to determine diastereomeric ratio
(anti/syn = 18/1) of 3aa (PhCH(NHBoc)-: anti δ 5.18 ppm; syn δ 5.09 ppm). The residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate = 20/1 to 4/1) to give 3aa as a coloress
solid (67.5 mg, 0.241 mmol, 80% yield). Spectroscopic data of the obtained 3aa were matched to the
reported data (reg# 1001022-93-0). Enantiomeric excess was determined by HPLC analysis
(anti = 73% ee, DAICEL CHIRALPAK AD-H (φ 0.46 cm x 25 cm), 2-propanol/n-hexane 1/9, flow
rate 1.0 mL/min, detection at 210 nm, tR 8.0 min [anti minor-enantiomer: (1S,2R)] and 8.8 min [anti
major-enantiomer: (1R,2S)]. Absolute configuration was determined by comparing the reported
retention time in HPLC analysis of the stereochemically defined sample [18]. The nitro-Mannich
products 3ba–3fa are previously reported compounds. 3ba: CAS 1001023-00-2, 3ca: CAS 1001022-
97-4, ent-3da: CAS 848194-80-9, 3ea: CAS 1001022-96-3, 3fa: CAS 1187084-34-9, 3ga: CAS
10001022-98-5.
3.3. Reduction of Nitro Group of 3ea
To a stirred solution of 3ea (26.7 mg, 0.086 mmol) in MeOH (1.0 mL) were added NiCl2·6H2O
(22.0 mg, 0.092 mmol) and NaBH4 (32. 5 mg, 0.86 mmol) at 0 °C and the resulting mixture was stirred
at the same temperature for 1 h. The reaction was quenched with H2O, and the resulting biphasic
mixture was extracted with ethyl acetate (x2). The combined organic layers were washed with brine
and dried over Na2SO4. Volatiles were removed under reduced pressure and the resulting residue was
purified by silica gel column chromatography (CHCl3/MeOH = 10/1) to give tert-butyl(1S,2R)-2-
amino-1-(4-methoxyphenyl)propylcarbamate (5ea) as a colorless solid (23.9 mg, y. 99%). Colorless
solid; M.p. 101–104 °C; IR (KBr) ν 1033, 1251, 1684, 3373; 1H-NMR (CDCl3) δ 1.00 (d, J = 6.4 Hz,
3H), 1.38 (s, 9H), 3.09–3.12 (m, 1H), 3.76 (s, 3H), 4.41 (brs, 1H), 5.39 (d, J = 7.4 Hz, 1H), 6.84 (d,
J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H); 13C-NMR (CDCl3) δ 21.2, 28.3, 50.7, 55.2, 59.6, 79.2, 113.7,
127.3, 128.4, 155.4, 158.8; [α]D26 +41.0 (c 0.5, MeOH); ESI-MS m/z 303 [M+Na]+; HRMS (ESI-TOF)
Anal. calcd. for C15H24N2NaO3 [M+Na]+ m/z 303.1685, found 303.1682.
4. Conclusions
In summary, we developed a catalytic asymmetric nitro-Mannich reaction based on bifunctional
heterobimetallic catalysis exerted by a rare earth metal/alkali metal heterobimetallic catalyst. The
amide-based ligand 4a, which was effective for the catalytic asymmetric nitroaldol reaction, proved to
be a suitable platform for a Yb/K heterobimetallic catalyst in the asymmetric nitro-Mannich reaction,
affording anti-1,2-nitroamines in up to 86% ee. Facile reduction of the nitro group of the product
allowed for an efficient access to synthetically versatile enantioenriched 1,2-diamines.

Molecules 2010, 15
1288
Acknowledgements
This work was financially supported by a Grant-in-Aid for Scientific Research (S) and a Grant-in-
Aid for Innovative Areas from JSPS and MEXT. T.N. thanks JSPS for a predoctral fellowship.
References and Notes
1. Westermann, B. Asymmetric catalytic aza-Henry reactions leading to 1,2-diamines and 1,2-
diaminocarboxylic acids Angew. Chem., Int. Ed. 2003, 42, 151–153.
2. Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P. Catalytic enantioselective aza-Henry
reactions. Eur. J. Org. Chem. 2009, 2401–2420.
3. Ono, N., Ed.; The Nitro Group in Organic Synthesis; John Wiley & Sons: New York, USA, 2001.
4. Ballini, R.; Petrini, M. Recent synthetic developments in the nitro to carbonyl conversion (Nef
reaction). Tetrahedron 2004, 60, 1017–1047.
5. Czekelius, C.; Carreira, E.M. Convenient transformation of optically active nitroalkanes into
chiral aldoximes and nitriles. Angew. Chem., Int. Ed. 2005, 44, 612–615.
6. Yamada, K.I.; Harwood, S.J.; Gröger, H.; Shibasaki, M. The first catalytic asymmetric nitro-
Mannich-type reaction promoted by a new heterobimetallic complex. Angew. Chem., Int. Ed.
1999, 38, 3504–3506.
7. Yamada, K.-I.; Moll, G.; Shibasaki, M. The first enantioselective and diastereoselective catalytic
nitro-Mannich reaction: a new entry to chiral vicinal diamines. Synlett 2001, 980–982.
8. Nishiwaki, N.; Knudsen, K.R.; Gothelf, K.V.; Jørgensen, K.A. Catalytic enantioselective addition
of nitro compounds to imines – a simple approach for the synthesis of optically active α-nitro-β-
Amino Esters. Angew. Chem. Int. Ed. 2001, 40, 2992–2995.
9. Knudsen, K.R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K.V.; Jørgensen, K.A. The first catalytic
asymmetric aza-Henry reaction of nitronates with imines: a novel approach to optically active β-
nitro-α-amino acid- and α,β-diamino acid derivatives. J. Am. Chem. Soc. 2001, 123, 5843–5844.
10. Lee, A.; Kim, W.; Lee, J.; Hyeon, T.; Kim, B.M. Heterogeneous asymmetric nitro-Mannich
reaction using a bis(oxazoline) ligand grafted on mesoporous silica. Tetrahedron: Asymmetry
2004, 15, 2595–2598.
11. Anderson, J.C.; Howell, G.P.; Lawrence, R.M.; Wilson, C.S. An asymmetric nitro-Mannich
reaction applicable to alkyl, aryl, and heterocyclic imines. J. Org. Chem. 2005, 70, 5665–5670.
12. Trost, B.M.; Lupton, D.W. Dinuclear zinc-catalyzed enantioselective aza-Henry reaction. Org.
Lett. 2007, 9, 2023–2026.
13. Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. syn-Selective catalytic asymmetric
nitro-Mannich reactions using a heterobimetallic Cu−Sm−Schiff base complex. J. Am. Chem. Soc.
2007, 129, 4900–4901.
14. Yoon, T.P.; Jacobsen, E.N. Highly enantioselective thiourea-catalyzed nitro-Mannich reactions.
Angew. Chem., Int. Ed. 2005, 44, 466–468.
15. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Bifunctional-thiourea-catalyzed
diastereo- and enantioselective aza-Henry reaction. Chem. Eur. J. 2006, 12, 466–476.
16. Bode, C.M.; Ting, A.; Schaus, S.E. A general organic catalyst for asymmetric addition of
stabilized nucleophiles to acyl imines. Tetrahedron 2006, 62, 11499–11505.

Molecules 2010, 15
1289
17. Robak, M.T.; Trincado, M.; Ellman, J.A. Enantioselective aza-Henry reaction with an N-sulfinyl
urea organocatalyst. J. Am. Chem. Soc. 2007, 129, 15110–15111.
18. Wang, C.J.; Dong, X.Q.; Zhang, Z.H.; Xue, Z.Y.; Teng, H.L. Highly anti-selective asymmetric
nitro-Mannich reactions catalyzed by bifunctional amine-thiourea-bearing multiple hydrogen-
bonding donors. J. Am. Chem. Soc. 2008, 130, 8606–8607.
19. Rampalakos, C.; Wulff, W.D. A novel bis-thiourea organocatalyst for the asymmetric aza-Henry
reaction. Adv. Synth. Catal. 2008, 350, 1785–1790.
20. Takada, K.; Nagasawa, K. Enantioselective aza-Henry reaction with acyclic guanidine-thiourea
bifunctional organocatalyst. Adv. Synth. Catal. 2009, 351, 345–347.
21. Nugent, B.M.; Yoder, R.A.; Johnston, J.N. Chiral proton catalysis: a catalytic enantioselective
direct aza-Henry reaction. J. Am. Chem. Soc. 2004, 126, 3418–3419.
22. Rueping, M.; Antonchick, A.P. Brønsted-acid-catalyzed activation of nitroalkanes: a direct
enantioselective aza-Henry reaction. Org. Lett. 2007, 10, 1731–1734.
23. Palomo, C.; Oiarbide, M.; Laso, A.; López, R. Catalytic enantioselective aza-Henry reaction with
broad substrate scope. J. Am. Chem. Soc. 2005, 127, 17622–17623.
24. Gomez-Bengoa, E.; Linden, A.; López, R.; Múgica- Mendiola, I.; Oiarbide, M.; Palomo, C.
Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical
study. J. Am. Chem. Soc. 2008, 130, 7955–7966.
25. Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Doubly
stereocontrolled asymmetric aza-Henry reaction with in situ generation of N-Boc-imines
catalyzed by novel rosin-derived amine thiourea catalysts. Adv. Synth. Catal. 2009, 351,
2096–2100.
26. Nitabaru, T.; Kumagai, N.; Shibasaki, M. A catalytic asymmetric anti-selective nitroaldol reaction
with a neodymium sodium heterobimetallic complex. Tetrahedron Lett. 2008, 49, 272–276.
27. Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M. anti-Selective catalytic
asymmetric nitroaldol reaction via a heterobimetallic heterogeneous catalyst J. Am. Chem. Soc.
2009, 131, 13860–13869.
28. Yamamoto, H.; Futatsugi, K. “Designer acids”: combined acid catalysis for asymmetric synthesis.
Angew. Chem. Int. Ed. 2005, 44, 1924–1942.
29. Taylor, M.S.; Jacobsen, E.N. Asymmetric catalysis by chiral hydrogen-bond donors. Angew.
Chem. Int. Ed. 2006, 45, 1520–1543.
30. Mukherjee, S.; Yang, J.W.; Hoffmann, S.; List, B. Asymmetric enamine catalysis. Chem. Rev.
2007, 107, 5471–5569.
31. Matsunaga, S.; Shibasaki, M. Multimetallic bifunctional asymmetric catalysis based on proximity
effect control. Bull. Chem. Soc. Jpn. 2008, 81, 60–75.
32. Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Recent progress in asymmetric
bifunctional catalysis using multimetallic systems. Acc. Chem. Res. 2009, 42, 1117–1127.
33. Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. En route to an
efficient asymmetric synthesis of AS-3201. J. Am. Chem. Soc. 2007, 129, 11342–11343.
34. Mashiko, T.; Kumagai, N.; Shibasaki, M. An improved lanthanum catalytic system for
asymmetric amination; toward a practical asymmetric synthesis of AS-3201 (ranirestat). Org. Lett.
2008, 10, 2725–2728.

Molecules 2010, 15
1290
35. Nojiri, A.; Kumagai, N.; Shibasaki, M. Asymmetric catalysis via dynamic substrate/ligand rare
earth metal conglomerate. J. Am. Chem. Soc. 2008, 130, 5630–5631.
36. Nojiri, A.; Kumagai, N.; Shibasaki, M. Linking structural dynamics and functional diversity in
asymmetric catalysis. J. Am. Chem. Soc. 2009, 131, 3779–3784.
37. Mashiko, T.; Kumagai, N.; Shibasaki, M. Managing highly coordinative substrates in asymmetric
catalysis: a catalytic asymmetric amination with a lanthanum-based ternary catalyst. J. Am. Chem.
Soc. 2009, 131, 14990–14999.
38. Boc: tert-butoxycarbonyl. N-Boc imines 1 were prepared by following the reported procedure;
Kanazawa, A.M.; Denis, J.; Greene, A.E. Highly stereocontrolled and efficient preparation of the
protected, esterification-ready docetaxel (taxotere) side chain. J. Org. Chem. 1994, 59, 1238.
39. Zhao, X.; Wang, X.Z.; Jiang, X.K.; Chen, Y.Q.; Li, Z.T.; Chen, G.J. Hydrazide-based quadruply
hydrogen-bonded heterodimers. Structure, assembling selectivity, and supramolecular substitution.
J. Am. Chem. Soc. 2003, 125, 15128–15139.
40. Li, C.; Ren, S.F.; Hou, J.L.; Yi, H.P.; Zhu, S.Z.; Jiang, X.K.; Li, Z.T. F···H–N hydrogen bonding
driven foldamers: efficient receptors for dialkylammonium ions. Angew. Chem., Int. Ed. 2005, 44,
5725–5279.
41. Reichardt, C., Ed. Solvents and Solvent Effects in Organic Chemistry; Wiley-VCH: Weinheim,
Germany, 2003.
42. The attempted reaction of 1a and 2a in the absence of ligand 4a under otherwise identical
conditions (Yb(OiPr)3: 10 mol %, KHMDS: 20 mol %, THF, –60 °C, 22 h) afforded racemic 3aa
1
in 53% yield (determined by H-NMR, anti/syn = 2.6/1), strongly suggested that unidentified
achiral basic species promoted the background reaction to decrease the stereoselectivity.
43. The identical reaction in Table 5, entry 3 gave the product 3ca after 20 h in 62% yield
anti/syn = 18/1, 85% ee (anti), indicating the absence of retro-reaction and epimerization of the
product during the reaction.
Sample Availability: Amide-based ligand 4a is available from the authors.
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).