A catalytic asymmetric anti-selective nitroaldol reaction with a neodymium-sodium heterobimetallic complex

Article abstract of DOI:10.1016/j.tetlet.2007.11.055

A catalytic asymmetric anti-selective nitroaldol reaction with a neodymium-sodium heterobimetallic catalyst is described. A readily accessible amide ligand works efficiently as a chiral platform for the Nd/Na heterobimetallic catalyst in the reaction of v

Full text of DOI:10.1016/j.tetlet.2007.11.055

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Tetrahedron Letters 49 (2008) 272–276
A catalytic asymmetric anti-selective nitroaldol reaction
with a neodymium–sodium heterobimetallic complex
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
Received 18 October 2007; revised 6 November 2007; accepted 12 November 2007
Available online 17 November 2007
Abstract—A catalytic asymmetric anti-selective nitroaldol reaction with a neodymium–sodium heterobimetallic catalyst is described.
A readily accessible amide ligand works efficiently as a chiral platform for the Nd/Na heterobimetallic catalyst in the reaction of
various aldehydes and nitroethane, affording anti-1,2-nitro alkanols in good diastereo- and enantioselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
A number of enzymes contain metal cations at the active
site, which make a crucial contribution to the extraordi-
nary high catalytic activity and stereoselectivity of the
enzyme. Without exception, the enzyme works coopera-
tively with the neighboring peptide chain and its associ-
ated functional groups in a sophisticated spatial
arrangement, exhibiting a highly ordered transition state
(TS) architecture.1 In Nature, there are many combina-
tions of diverse peptide chains and metals with distinct
coordination modes. Lanthanides, characterized by a
variable coordination number (6 6 CN 6 12) and geo-
metry, seldom display simple coordination chemistry.2
Their coordination mode is not predictable and depends
largely on the ligand structure.2 We hypothesized that
the combination of a lanthanide and a simple amide
ligand with suitable functionality would mimic the
highly ordered TS exhibited by enzymes. Although
numerous asymmetric catalysts containing lanthanides
have been reported, asymmetric catalysis by lantha-
nide/amide combination has not been well explored.3
Recently, we reported that a lanthanum/amide complex
promoted the catalytic asymmetric amination of a
highly coordinative substrate, which could not be ad-
dressed by other types of asymmetric catalysts.4 In our
continuing studies of lanthanide/amide chemistry, we
aimed to expand the scope of lanthanide/amide complex
in asymmetric catalysis.
The catalytic asymmetric nitroaldol (Henry) reaction5,6
falls in a category of the most efficient carbon–carbon
bond forming reactions, in which the optically active
1,2-nitro alkanols are produced through a proton trans-
fer without waste. 1,2-Nitro alkanols have direct access
to 1,2-amino alcohols, a common structural motif that
frequently occurs in biologically active natural products,
pharmaceuticals, and chiral ligands.7 The obvious syn-
thetic utility of the product has promoted considerable
research progress in this field, leading to the develop-
ment of chiral metal catalysts and organocatalysts to
exert the asymmetric nitroaldol reaction.8 Diastereo-
selectivity in asymmetric nitroaldol reactions, however,
has been less studied and syn-selective reactions are spo-
radically reported.9 On the other hand, an anti-selective
asymmetric nitroaldol reaction remains to be developed.
Seebach et al. introduced an achiral nitroaldol reaction
via a silyl nitronate strategy, providing anti-1,2-nitro
alkanols in a highly diastereoselective manner.10,11 Mar-
uoka and co-workers elegantly applied a chiral quater-
nary ammonium bifluoride catalyst to silyl nitronate
chemistry to obtain anti-1,2-nitro alkanols with high
diastereo- and enantioselectivity.12 Another example of
this strategy was reported by Jørgensen and co-workers
using a Cu-Box catalyst with moderate enantioselectivi-
ty.13 A catalytic asymmetric anti-selective nitroaldol
reaction through proton transfer, an ideal form of the
reaction in terms of atom-economy,14 remains to be
developed.15 Quite recently, Ooi and co-workers
revealed that chiral P-spiro triaminoiminophosphorane
is an effective catalyst for the anti-selective catalytic
asymmetric nitroaldol reaction.16 In this context, the
catalytic asymmetric anti-selective nitroaldol reaction
Keywords: Nitroaldol (Henry) reaction; Neodymium; Heterobimetallic
catalyst; Asymmetric catalysis.
*
Corresponding authors. Tel.: +81 3 5841 4830; fax: +81 3 5684 5206
(M.S.); e-mail addresses: nkumagai@mol.f.u-tokyo.ac.jp;
mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.055

T. Nitabaru et al. / Tetrahedron Letters 49 (2008) 272–276
273
is still an intriguing objective to be addressed. Herein,
we report the catalytic asymmetric anti-selective nitroal-
dol reaction with a newly developed heterobimetallic
catalyst with an appropriate chiral platform would pro-
vide a suitable environment for the extended TS, where
each metal works independently as a Lewis acid for the
aldehyde and as a Brønsted base for the nitronate
formation, overriding the undesirable chelate formation.
Our initial focus was devoted to the combination of a
lanthanide metal as a Lewis acid and alkaline metal as
a Brønsted base part,19 which are assembled with amide
ligand 1a derived from L-Val.20 A bimetallic catalyst
prepared from 1a, Ln(OiPr)3 (Ln = lanthanides), and
NaHMDS in a ratio of 2/1/1 was evaluated in the nitro-
aldol reaction of benzaldehyde (2a) and nitroethane in
THF at À40 °C (Table 1). As we anticipated, the present
catalytic system displayed anti-diastereoselectivity.
Among the lanthanides examined, Nd gave the highest
diastereoselectivity (anti/syn = 85:15), although the
enantiomeric excess was not satisfactory (entry 3). Using
another alkaline metal or performing the reaction with-
out an alkaline metal resulted in inferior diastereoselec-
tivity (entries 9–11), suggesting that the Ln/Na
heterobimetallic catalyst would be preferred to form
the extended TS. Increasing the amount of NaHMDS
(Nd/Na = 1/2) significantly enhanced the catalytic
activity, affording the product in 96% yield with compa-
rable stereoselectivity (entry 12). The addition of 1 equiv
of H2O to the complex proved to be beneficial for
further improvement of stereoselectivity, affording 3a
in 83% yield with anti/syn = 91:9 and 43% ee (anti)
(entry 13).
catalyst composed of
ligand.
a neodymium/sodium/amide
On the basis of TS model, an extended TS affords anti
diastereomers whereas a cyclic TS affords the syn coun-
terparts (Fig. 1).17 The extended TS is favored in the
reaction using silyl nitronates likely due to the preferen-
tial antiparallel orientation of nitronates and alde-
hydes.10,18 In contrast, the reaction with metal cat-
alysts tends to proceed through the cyclic TS via chelate
formation, thereby predominantly affording syn
diastereomers. We hypothesized that a heterobimetallic
Next, our efforts were directed toward the modification
of the amide ligand structure. The effect of an amino
Figure 1. TS models of metal-catalyzed nitroaldol reaction.
Table 1. Catalytic asymmetric anti-selective nitroaldol reaction with Ln/Na/1a heterobimetallic complexa
Ln(OiPr)3 9 mol %
OH
OH
O
alkaline metal source 9 mol %
Ligand 1a 18 mol %
+
+
Ph
Ph
Ph
H
NO2
THF, –40 °C, 24 h
NO2
anti-3a
NO2
syn-3a
2a
Entry
Ln
Alkaline metal source
H2O (mol %)
Yieldb (%)
drc (anti/syn)
ee (anti) (%)
1
2
3
4
5
6
7
8
9
10
11
12d
13d
La
Pr
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
nBuLi
KHMDS
—
NaHMDS
NaHMDS
—
—
—
—
—
—
—
—
—
—
—
—
9
48
23
36
16
15
9
15
23
10
73
1
72/28
70/30
85/15
73/27
74/26
71/29
69/31
64/36
68/32
67/33
57/43
85/15
91/9
À4
15
35
20
22
15
4
Nd
Sm
Eu
Gd
Dy
Yb
Nd
Nd
Nd
Nd
Nd
À29
0
0
0
38
43
96
83
O
OH
H
N
HO
1a
N
H
O
a Aldehyde 0.1 mmol, nitroethane 1.0 mmol.
b Determined by 1H NMR analysis with (Me3Si)2O as internal standard.
c Determined by 1H NMR analysis.
d Nd(OiPr)3/NaHMDS/1a = 1/2/2, Nd = 9 mol %.

274
T. Nitabaru et al. / Tetrahedron Letters 49 (2008) 272–276
Table 2. Catalytic asymmetric anti-selective nitroaldol reaction with Nd/Na/1a heterobimetallic complexa
Nd(OiPr)3 9 mol %
NaHMDS 18 mol %
OH
OH
O
Ligand 1 18 mol %
+
+
Ph
Ph
Ph
H
H2O 9 mol %
THF, –40 °C, 48 h
NO2
NO2
anti-3a
NO2
syn-3a
2a
Entry
Ligand
[R
iPr
cHex
(S)-2-butyl
Bn
iBu
Ar]
Yieldb (%)
drc (anti/syn)
ee (anti) (%)
1
2
3
4
5
1a
1b
1c
1d
1e
43
79
80
83
85
91/9
43
43
24
32
59
OH
85/15
67/33
85/15
92/8
HO
6d,e
1f
iPr
43
75/25
17
tBu
HO
7d
8
1g
1h
iPr
iBu
72
82
89/11
89/11
46
51
O
R
H
N
HO
N
H
Ar
1
O
a Aldehyde 0.1 mmol, nitroethane 1.0 mmol.
b Determined by 1H NMR analysis with (Me3Si)2O as internal standard.
c Determined by 1H NMR analysis.
d 18 mol % of H2O was used.
e 9 mol % of NaHMDS was used.
Table 3. Catalytic asymmetric anti-selective nitroaldol reaction with Nd/Na/1e heterobimetallic complexa
Nd(OiPr)3 x mol %
OH
OH
NaHMDS 2x mol %
O
Ligand 1e 2x mol %
+
+
R1
R1
R1
H
H2O x mol %
THF, –40 °C
NO2
NO2
anti-3
NO2
syn-3
2
Entry
R1
x=
Product
Time (h)
Yieldb (%)
drd (anti/syn)
ee (anti) (%)
1
2
Ph
Ph
2a
2a
9
3
3a
3a
48
48
85
93c
92/8
90/10
59
57
3
2b
3
3b
48
91
96/4
80
4
5
2b
2c
3
3
3b
3c
48
48
93
90
98/2
98/2
84
84
6
2d
3
3d
48
67
97/3
79
F
Et2N
7
8
2e
2f
3
9
3e
3f
17
48
74
63
96/4
98/2
76
81
O
MeO
9
2g
3
3g
48
99c
88/12
65
O
O
a Aldehyde 0.3 mmol, nitroethane 3.0 mmol.
b Isolated yield.
c Determined by 1H NMR analysis with (Me3Si)2O as internal standard.
d Determined by 1H NMR analysis.

T. Nitabaru et al. / Tetrahedron Letters 49 (2008) 272–276
275
2006, 386, 472; (c) Sigel, R. K. O.; Pyle, A. M. Chem. Rev.
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acid residue and an aminophenol part on the stereo-
chemical outcome was examined (Table 2). Bulkier sub-
stituents on the amino acid residue gave product 3a in
lower stereoselectivity (entries 2–4), presumably because
the formation of polymetallic assembly was encumbered
and higher fraction of the reaction would proceed
through the chelated cyclic TS. Ligand 1e derived from
L-Leu performed best, affording 3a in 85% yield with
anti/syn = 92:8 and 59% ee (anti) (entry 5). Manipula-
tions of the aminophenol part had less impact on stereo-
selectivity, implying that the amino acid residue is
important for constructing a suitable chiral platform
for the present bimetallic system (entries 6–8).
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The optimized reaction conditions were evaluated with a
variety of aldehydes (Table 3). The reaction reached
completion with 3 mol % of catalyst loading without
any detrimental effects (entries 1 and 2). o-Alkyl substit-
uents on the aromatic ring of aldehyde enhanced both
diastereo- and enantioselectivity, exhibiting nearly
exclusive formation of anti-diastereomers with 76–84%
ee (entries 3–8). The reaction of aldehyde with elec-
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In summary, we developed a catalytic asymmetric anti-
selective nitroaldol reaction using a newly developed
Nd/Na/amide heterobimetallic catalyst to afford anti-
1,2-nitro alkanols, providing a facile entry to anti-1,2-
amino alcohols with significant synthetic versatility.
The catalyst worked particularly well in the reaction of
aromatic aldehydes with an o-alkyl substituent and
exhibits high diastereo- (anti/syn = 96:4–98:2) and
enantioselectivity (76–84% ee (anti)) with 3 mol % cata-
lyst loading. Investigations into the structure of the
heterobimetallic catalyst and further improvement of
enantioselectivity as well as substrate generality are
currently underway.
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Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J.
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Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.;
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Acknowledgments
This work was financially supported by Grant-in-Aid
for specially promoted research. N.K. thanks Grant-
in-Aid for Young Scientist (B). Financial support from
Toray Co Ltd is gratefully acknowledged.
Supplementary data
9. (a) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.;
Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388; (b)
Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org.
Chem. 2006, 2894; (c) Arai, T.; Watanabe, M.; Yanagis-
awa, A. Org. Lett. 2007, 9, 3595.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.055.
10. (a) Colvin, E. W.; Seebach, D. J. Chem. Soc., Chem.
Commun. 1978, 689; (b) Seebach, D.; Beck, A. K.; Lehr,
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