A modified preparation procedure for carbon nanotube-confined Nd/Na heterobimetallic catalyst for anti -selective catalytic asymmetric nitroaldol reactions

Article abstract of DOI:10.1021/jo402042s

A recyclable asymmetric metal-based catalyst is a rare entity among the vast collection of asymmetric catalysts developed so far. Recently we found that the combination of a self-assembling metal-based asymmetric catalyst and multiwalled carbon nanotubes (MWNTs) produced a highly active and recyclable catalyst in which the catalytically active metal complex was dispersed in the MWNT network. Herein we describe an improved preparation procedure and full details of a Nd/Na heterobimetallic complex confined in MWNTs. Facilitated self-assembly of the catalyst with MWNTs avoided the sacrificial use of excess chiral ligand for the formation of the heterobimetallic complex, improving the loading ratio of the catalyst components. Eighty-five percent of the catalyst components were incorporated onto MWNTs to produce the confined catalyst, which was a highly efficient and recyclable catalyst for the anti-selective asymmetric nitroaldol reaction. The requisite precautions for the catalyst preparation to elicit reproducible catalytic performance are summarized. Superior catalytic profiles over the prototype catalyst without MWNTs were revealed in the synthesis of optically active 1,2-nitroalkanols, which are key intermediates for the synthesis of therapeutics.

Full text of DOI:10.1021/jo402042s

Article
pubs.acs.org/joc
A Modified Preparation Procedure for Carbon Nanotube-Confined
Nd/Na Heterobimetallic Catalyst for anti-Selective Catalytic
Asymmetric Nitroaldol Reactions
Devarajulu Sureshkumar,† Kazuki Hashimoto,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A recyclable asymmetric metal-based catalyst is
a rare entity among the vast collection of asymmetric catalysts
developed so far. Recently we found that the combination of a
self-assembling metal-based asymmetric catalyst and multi-
walled carbon nanotubes (MWNTs) produced a highly active
and recyclable catalyst in which the catalytically active metal
complex was dispersed in the MWNT network. Herein we
describe an improved preparation procedure and full details of
a Nd/Na heterobimetallic complex confined in MWNTs.
Facilitated self-assembly of the catalyst with MWNTs avoided
the sacrificial use of excess chiral ligand for the formation of the heterobimetallic complex, improving the loading ratio of the
catalyst components. Eighty-five percent of the catalyst components were incorporated onto MWNTs to produce the confined
catalyst, which was a highly efficient and recyclable catalyst for the anti-selective asymmetric nitroaldol reaction. The requisite
precautions for the catalyst preparation to elicit reproducible catalytic performance are summarized. Superior catalytic profiles
over the prototype catalyst without MWNTs were revealed in the synthesis of optically active 1,2-nitroalkanols, which are key
intermediates for the synthesis of therapeutics.
NdO1/5(OiPr)13/5, NaHMDS, and amide-based ligand 4 in
THF formed insoluble self-assembled particles together with
INTRODUCTION
The nitroaldol reaction is widely used as a C−C bond-forming
reaction and is particularly useful for the construction of carbon
■
nitroethane 2a, and the isolated particles were used as
heterogeneous catalysts (Figure 1a).6b Recently, we reported
frameworks bearing oxygen and nitrogen functionalities in
adjacent positions (Scheme 1).1 Despite its early discovery in
that the self-assembly in a fibrous network of multiwalled
carbon nanotubes (MWNTs)10 produced Nd/Na heterobime-
tallic catalysts dispersed and confined in MWNT (Figure
Scheme 1. Nitroaldol Reaction
1b).11−13 The MWNT-confined catalyst exhibited higher
catalytic performance and allowed repetitive use. Although a
the 19th century,2 the precise control of diastereo- and
enantioselectivity in the catalytic nitroaldol reaction has been
elusive until recently. We have developed an arsenal of rare
earth metal-based asymmetric catalysts,3 and La/Li,4 Pd/La,5
Figure 1. Nd/Na/amide-based ligand 4 heterobimetallic catalyst. (a)
Isolated heterogeneous catalyst was used only once. (b) MWNT-
confined catalyst allowed repetitive use.
and Nd/Na6 heterobimetallic catalysts have been developed for
syn- and anti-selective catalytic asymmetric nitroaldol reac-
tions.7−9 Among them, Nd/Na/amide-based ligand 4 catalysts
are particularly important because of their self-assembling
property: mixing of the three catalyst components
Received: September 13, 2013
Published: October 21, 2013
© 2013 American Chemical Society
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Scheme 2. Schematic Representation of Catalyst Preparation
a
The molar ratio of Nd:Na:4 in heterobimetallic catalysts and the loading ratio of catalyst components were determined by inductively coupled
plasma atomic emission spectroscopy (ICP-AES) and X-ray fluorescence (XRF).6b The molar ratio of Nd:Na:4 in the heterobimetallic catalysts and
b
the loading ratio of catalyst components were determined by MP-AES and HPLC.27 200 wt % of MWNT relative to 4 was used. 400 wt % of
c
d
MWNT relative to 4 was used.
a
Table 1. anti-Selective Catalytic Asymmetric Nitroaldol Reaction with MWNT-Confined Nd/Na Heterobimetallic Catalyst
pretreatment
b
c
d
e
f
g
g
entry
supplier of 2a
H2O content of 2a (ppm)
dist.
MS 3A
base
time (h)
yield (%)
anti/syn
ee (%)
1
2
3
4
5
6
7
8
9
A
B
150
301
1965
13
−
−
−
−
−
−
+
−
−
−
+
−
−
−
−
−
−
−
+
4
4
8
4
4
8
8
4
8
99
96
<1
99
99
<1
<1
99
95
98/2
98/2
−
98/2
98/2
−
99
99
−
99
99
−
C
A
B
33
+
C
C
C
C
3
+
311
1423
63
−
−
+
−
99/1
−
99
−
−
+
97/3
98
a
1a: 0.2 mmol, 2a: 2.0 mmol. The same 2a was used for catalyst preparation and as substrate. Catalyst loading is noted based on the amount of
b
c
NdO1/5(OiPr)13/5 used for catalyst preparation. Determined by Karl Fischer titration. Vacuum distillation for 2a was conducted twice before use.
d
e
f
1
2a was treated with predried MS 3 Å pellets before use. 2a was treated with NaHCO3 solid before use. Determined by H NMR analysis.
g
Determined by HPLC analysis.
wide array of asymmetric catalysts has been developed to date,
the majority of them are not designed for repetitive use. In
contrast to the recyclable catalysts for nonstereoselective
chemical transformations,14 recyclable asymmetric catalysts
have been much less explored despite their huge practical
impact.15−17 Given the versatility of optically active 1,2-amino
alcohols in the synthetic point of view,18 the catalytic
asymmetric nitroaldol reaction deserves exploration as a
platform for the development of practical stereoselective
transformations promoted by recyclable catalysts. In our
continuing study directed toward the further sophistication of
recyclable MWNT-confined heterobimetallic catalysts,19 we
encountered fluctuating reaction outcomes depending on the
purity and moisture content of the reagents for catalyst
preparation. Herein we describe the requisite precautions for
the preparation of MWNT-confined Nd/Na heterobimetallic
catalysts and an improved preparation protocol that gives a
higher loading ratio onto MWNTs. The previous preparation
protocol required the sacrificial use of ligand 4 to facilitate self-
assembly. Our new protocol allowed us to prepare the
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heterobimetallic catalyst with stoichiometry identical to the
actual complex, leading to loading ratios >85%.20
sonication (Scheme 2b).27 The Nd:Na:4 ratio of 1:2.18:1.0 and
the incorporation profile of Cat. B were nearly identical to
those of the prototype Cat. A. We envisioned that the MWNT
surface might facilitate the nucleation of the heterobimetallic
catalyst even with a 1:1 ratio of NdO1/5(OiPr)13/5:4, thus
significantly improving the loading ratio of 4 onto the actual
heterogeneous catalyst. The performance of Cat. C prepared
RESULTS AND DISCUSSION
■
The preparation procedure of the prototype Nd/Na hetero-
bimetallic catalyst is outlined in Scheme 2a (Cat. A).
NdO1/5(OiPr)13/5 and then NaHMDS were added to a THF
solution of amide-based ligand 4, affording a white
suspension.6b A homogeneous solution transiently developed
upon the addition of nitroethane 2a and self-assembly of the
heterobimetallic catalyst was initiated within approximately 5
min, affording the catalyst as a white precipitate after
centrifugation. This precipitate contained 2a and the use of
2a was indispensable for self-assembly of heterogeneous
catalyst. By adding MWNTs before the addition of 2a, self-
assembly proceeded in the fibrous network of MWNTs to
produce the MWNT-confined catalyst (Scheme 2b, Cat. B).11
For operational simplicity, 2a was used as received from the
commercial suppliers. In a test reaction using 3,5-diiodoben-
zaldehyde 1a and nitroethane 2a with Cat. B, significantly
different reaction outcomes were produced depending on the
supplier of 2a (Table 1). When 2a from suppliers A and B was
used for the catalyst preparation and as a substrate, high
catalytic efficiency and stereoselectivity were observed.21
However, the reaction with 2a from supplier C barely
proceeded under identical conditions (entries 1−3).22 The
moisture content of 2a was analyzed for each sample and the
poor reaction with 2a from supplier C seemed to be caused by
its excessively high moisture content. Therefore, 2a from each
supplier was desiccated with predried MS 3 Å pellets and these
dried samples of 2a were evaluated in the nitroaldol reaction.23
Unexpectedly, desiccation of 2a from each supplier made no
difference in reaction outcomes (entries 4−6). HPLC analysis
of the desiccated 2a samples revealed that those from supplier
C contained several unidentified impurities, which might
interfere with the formation of the Nd/Na heterogeneous
catalysts and/or nitroaldol reaction itself.24 Thus, 2a from
supplier C was double distilled but still the reaction progress
was negligible (entry 7). Eventually, we found that when 2a
from supplier C was pretreated with NaHCO3 powder, the
efficient reaction progress was observed,25 suggesting that some
acidic impurities contaminated 2a from supplier C that could
not be efficiently removed by distillation (entry 8,9). Reaction
reached completion irrelevant of the treatment with MS 3 Å
and the reaction with untreated 2a exhibited a marginally
higher reaction rate.
with the reduced amount of 4 (1 equiv to NdO1/5(OiPr)13/5
)
under otherwise identical conditions as for Cat. B (Scheme 2c)
was evaluated in the nitroaldol reaction of 1a and pretreated 2a
with low catalyst loadings (0.25 mol%). As shown in Figure 2,
Figure 2. Reaction profile of the reaction promoted by Cat. A−C.
Nitroethane 2a (supplier A) was pretreated with MS 3 Å pellets.
Conversion and diastereo- and enantioselectivity were determined by
HPLC analysis. Catalyst loading is noted based on the amount of
NdO1/5(OiPr)13/5 used for catalyst preparation.
Cat. B and C exhibited nearly identical catalytic efficiency with
high stereoselectivity, and the reaction rates with these
MWNT-confined catalysts were much higher than those with
Cat. A, as expected from the previous study. The quantitative
analysis of Cat. C was in line with its catalytic performance; the
incorporated amounts of Nd, Na, and 4 were nearly identical
for Cat. B and C, and 89% of 4 was incorporated to constitute
the heterobimetallic complex in Cat. C. The Nd:Na:4 ratio for
Cat. A, B, and C was consistently ca. 1:2:1 (Scheme 2),
suggesting that the microscopic structure of the catalytically
active complex was uniform for each catalyst and the higher
catalytic performance of Cat. B and C was ascribed to the
increased surface area of the catalyst after dispersion in the
MWNT network. By comparing the results in entries 8 and 9 of
Table 1, the moisture content of 2a had some influence on
catalytic efficiency. To clarify the optimum range for moisture
content, the nitroaldol reaction of 1a was conducted with
nitroethane 2a containing varied amounts of water (Figure 3).
The presence of some water in the reaction mixture was
beneficial, whereas excessive moisture content led to a sharp
decrease in reaction progress. 2a with 600−2000 ppm of water
and free from any acidic impurities could produce sufficient
catalytic efficiency.28 Cat. C could be stored at −25 °C for 1
week without any loss in catalytic efficiency.29
An obvious drawback of Cat. A and Cat. B was the sacrificial
use of excess amounts of amide-based ligand 4. To prepare the
heterobimetallic catalyst, two molar equivalents of 4 relative to
NdO1/5(OiPr)13/5 were required, whereas quantitative elemen-
tal analysis of Cat. A revealed that the molar ratio of Nd:4 in
the catalyst is nearly 1:1, indicating that 61% of 4 remained
uncomplexed in the supernatant (Scheme 2a).6b,26 The 1:1
molarity of Nd and 4 in the complex led us to prepare the
catalyst with a 1:1 ratio of NdO1/5(OiPr)13/5:4; however, these
attempts resulted in poor nucleation of the heterogeneous
complex with low reproducibility.6b For the MWNT-confined
Cat. B, for which preparation included the addition of MWNT
200 wt % relative to 4 under otherwise identical conditions, Nd
and Na contents were determined using microwave plasma
atomic emission spectroscopy (MP-AES) after complete
decomposition and elution of the heterobimetallic catalyst
confined in MWNT by treatment with 5% HNO3 aq. under
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received. The optimum range of moisture content was
identified (600−2000 ppm) for which higher reaction rates
were observed than for the reaction under dry conditions. With
MWNTs, sacrificial use of 4 was avoided in the formation of the
heterobimetallic catalyst. The optimal catalyst was prepared
from NdO1/5(OiPr)13/5/NaHMDS/4 in a ratio 1/2/1, which is
identical to the observed ratio of components (Nd/Na/4) in
the heterobimetallic catalyst. The loading ratio of the catalyst
components onto MWNT reached >85%,20 and high catalytic
performance and reusability offer broad synthetic utility.
Implementation of a continuous-flow reaction system using
the MWNT-confined catalyst for catalytic asymmetric nitro-
aldol reaction is currently under way.
EXPERIMENTAL SECTION
■
General Procedures. Catalytic asymmetric nitroaldol reaction was
performed in a flame-dried 20 mL glass test tube with a Teflon-coated
magnetic stirring bar unless otherwise noted. Flasks or test tubes were
fitted with a 3-way glass stopcock and reactions were run under Ar
atmosphere. Air- and moisture-sensitive liquids were transferred via a
gastight syringe and a stainless steel needle. All workup and
purification procedures were carried out with reagent-grade solvents
under ambient atmosphere. Flash chromatography was performed
using silica gel 60 (230−400 mesh). Chemical shifts for protons are
reported as δ in units of parts per million downfield from
tetramethylsilane and are referenced to residual protons in the NMR
solvent (CDCl3: δ 7.26 ppm). For 19F NMR, chemical shifts are
reported in the scale relative to trifluoroacetic acid (76.5 ppm) as an
external reference. NMR data are reported as follows: chemical shifts,
multiplicity (s: singlet, d: doublet, dd: doublet of doublets, t: triplet, q:
quartet, sep: septet, m: multiplet, br: broad signal), coupling constant
(Hz), and integration. Optical rotation was measured using a 2 mL cell
with a 1.0 dm path length. Compounds 3a, 3b, 3c, and 3d are reported
compounds.
Figure 3. Reaction profile depending on the H2O content of
nitroethane 2a. 2a (supplier A) with varied H2O content was prepared
by treatment with MS 3 Å pellets followed by the arbitrary addition of
H2O. Each 2a was used for catalyst preparation and as substrate.
Conversion was determined by HPLC analysis. Diastereo- and
enantioselectivity of each reaction were similar, anti/syn = 97/3 and
98% ee on average. Catalyst loading is noted based on the amount of
NdO1/5(OiPr)13/5 used for catalyst preparation.
General Procedure for anti-Selective Catalytic Asymmetric
Nitroaldol Reaction (Table 1, Cat. B, entry 1). A flame-dried 20
mL test tube equipped with a magnetic stirring bar and a 3-way glass
stopcock was charged with ligand 4 (9.1 mg, 0.024 mmol) and dried
under vacuum for ca. 5 min. Ar was backfilled to the test tube, after
which dry THF (400 μ L, 2 ppm on average) and 0.2 M THF solution
of NdO1/5(OiPr)13/5 (60 μL, 0.012 mmol, 6 mol %, based on Nd) were
added via a gastight syringe with a stainless steel needle under an Ar
atmosphere at 0 °C. After stirring the mixture at room temperature for
30 min, the slightly cloudy solution was cooled to 0 °C. 1.0 M THF
solution of NaHMDS (24 μL, 0.024 mmol) was added via syringe at 0
°C to form a white suspension. After stirring at room temperature for
1 h, carbon nanotubes (Baytubes C 70P, 18 mg) was added.
Nitroethane (2a) (supplier A, 86 μL, 1.2 mmol, moisture content 150
ppm) was added via syringe at room temperature. After stirring at
room temperature for 2 h, the resulting whole black suspension was
transferred to Eppendorf safe-lock tube (2 mL volume) with THF
washing (ca. 1.2 mL). The tube was centrifuged (ca. 104 rpm, 15 s).
The supernatant was decanted and dry THF (1.5 mL) was added. The
tube was agitated by vortex mixer for 20 s (and occasional finger
tapping, if necessary) and centrifuged again (washing process). After
the supernatant was decanted, the resulting precipitate was agitated
with dry THF (0.7 mL) and the resulting suspension was divided into
6 portions (1 mol % each) and was transferred to a flame-dried 20 mL
test tube. Nitroethane (2a) (supplier A, 142 μL, 2.0 mmol, 10 equiv,
moisture content 150 ppm) were added via a syringe at room
temperature. The resulting black suspension was cooled to −60 °C. A
solution of 3,5-diiodobenzaldehyde (1a) (72 mg, 0.2 mmol) in THF
(0.6 mL) was added dropwise via a syringe over 1 min. The resulting
suspension was stirred at −60 °C for 4 h under Ar and quenched with
0.2 M THF solution of AcOH (300 μL). After stirring at −60 °C for 1
h, the reaction mixture was warmed to room temperature. Then 1 N
HCl aq. (1 mL) was added. The resulting biphasic mixture was
filtrated through a syringe filter (0.2 μm) and washed with AcOEt. The
The synthetic utility of the MWNT-confined catalyst was
exemplified by higher catalytic efficiency than the prototype
Cat. A as well as reusability. The reaction of 1a and 2a could be
promoted with as little as 0.25 mol% of Cat. C to reach
completion and to afford anti-3a almost exclusively in 98% ee,
which is a key intermediate to the enantioselective synthesis of
anacetrapib, a promising drug candidate for hypercholester-
olemia (Scheme 3a).11,30,31 An anti-1,2-amino alcohol motif is
embedded in a wide variety of medicinally significant
compounds, e.g., β-adrenoceptor agonists (ritodrine, 5),32
prophylactic agent 6,33 and zanamivir;34 and the present
protocol was utilized for the enantioselective delivery of their
intermediates 3b−d (Scheme 3b−d). In all cases, the MWNT-
confined Cat. B and C outperformed the prototype Cat. A in
terms of catalytic efficiency. Reuse of the MWNT-confined Cat.
C for 6 cycles in the reactions of aldehyde 1b is worthy of
notice (Scheme 3b).35 Stereoselective synthesis of 3d, a key
intermediate for enantioselective synthesis of zanamivir,36 was
performed on 1.0 g scale. Catalyst recycling could be possible
using Cat. C in this challenging combination of functionalized
aldehyde 3d and 4-nitrobut-1-ene 2b (Scheme 3d).35,37
CONCLUSION
■
We have improved the preparation protocol of MWNT-
confined Nd/Na/amide-based ligand 4 heterobimetallic cata-
lysts for the anti-selective asymmetric nitroaldol reaction.
Precautions for reagents and the effect of moisture content in
eliciting optimal catalytic performance were thoroughly
investigated. Commercial nitroethane 2a free from acidic
impurities and excess amount of moisture can be used as
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Scheme 3. Enantioselective Synthesis of Key Intermediates for Therapeutics
a
Catalysts were prepared by following the procedures shown in Scheme 2. Catalyst loading is noted based on the amount of NdO1/5(OiPr)13/5 used
1
for catalyst preparation. Diastereoselectivity was determined by H NMR analysis or HPLC analysis. Enantioselectivity was determined by HPLC
analysis. 2a (supplier A, 2087 ppm H2O) was used for catalyst preparation and as substrate. 2a (supplier A, 1992 ppm of H2O) was used for
catalyst preparation and as substrate 2a (supplier A, 356 ppm of H2O) was used for catalyst preparation and as substrate. 2a (supplier A, 133 ppm
of H2O) was used for catalyst preparation and as substrate. Catalyst was prepared with ent-4 and 2a (supplier A, 1992 ppm H2O). Catalyst was
b
c
d
e
f
g
h
i
prepared with ent-4 and 2a (supplier A, 1992 ppm H2O). H2O content was 33 ppm. 0.4 mmol scale.
filtrate was extracted with AcOEt and the combined organic extracts
were washed successively with saturated aqueous NaHCO3 aq., water,
and sat. NaCl aq. and then dried over Na2SO4. After evaporation of
volatiles under reduced pressure, the crude mixture was submitted to
1H NMR analysis to determine chemical yield (98%) with DMF as an
mmol) was added via syringe at 0 °C to form white suspension. After
stirring at room temperature for 30 min, carbon nanotubes (Baytubes
C 70P, 220 mg) was added. Nitroethane (2a) (supplier A, 86 μL, 1.2
mmol, moisture content 1977 ppm) was added via syringe at room
temperature. After stirring at room temperature for 2 h, the resulting
whole black suspension was transferred to centrifuge tube (2 mL
volume) with THF washing (ca. 6.0 mL). The tube was centrifuged
(ca. 5000 rpm, 2 min). The supernatant was decanted and dry THF
(12 mL) was added. The tube was agitated by vortex mixer for 20 s
(and occasional finger tapping, if necessary) and centrifuged again
(washing process). The supernatant was decanted. After additional
three-cycles of washing procedure, the resulting precipitate was
agitated with THF (18 mL) and was transferred to a flame-dried 100
mL test tube under an Ar atmosphere. 4-Nitrobut-1-ene (2b) (1.5 mL,
14.55 mmol, 3 equiv, moisture content 33 ppm) were added via a
syringe at room temperature. The resulting black suspension was
cooled to −60 °C. The solution of (E)-4-((4-methoxybenzyl)oxy)but-
2-enal (1d) (1000 mg, 4.85 mmol) in THF (0.6 mL) was added
dropwise via a syringe over 10 min. The resulting suspension was
stirred at −60 °C for 30a6 h under Ar and quenched with 0.2 M THF
solution of AcOH (5 mL). After stirring at −60 °C for 1 h, the
internal standard. The anti/syn ratio and enantioselectivity were
determined to be 98/2 and 99% ee, respectively, by chiral-stationary-
phase HPLC analysis [Daicel CHIRALPAK IC, ϕ 0.46 cm × 25 cm,
detection at 254 nm, n-hexane/iPrOH/TFA = 19/1/0.02, flow rate
=1.0 mL/min] tR = 10.0 min (anti/minor), tR = 11.0 min (anti/major).
General Procedure for anti-Selective Catalytic Asymmetric
Nitroaldol Reaction (Cat. C, Scheme 3d). A flame-dried 30 mL
round-bottom flask equipped with a magnetic stirring bar and a 3-way
glass stopcock was charged with ligand ent-4 (derived from D-Leu, 55
mg, 0.15 mmol) and dried under vacuum for ca. 5 min. Ar was
backfilled to the test tube, after which dry THF (5 mL, 2 ppm on
average) and 0.2 M THF solution of NdO1/5(OiPr)13/5 (727 μL, 0.15
mmol, 3 mol %, based on Nd) were added via a gastight syringe with a
stainless steel needle under an Ar atmosphere at 0 °C. After stirring
the mixture at room temperature for 1 h, the slightly cloudy solution
was cooled to 0 °C. 1.0 M THF solution of NaHMDS (291 μL, 0.29
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reaction mixture was warmed to room temperature. The resulting
mixture was filtrated through a pad of Celite and dilute with AcOEt.
The resulting mixture was washed sat. NH4Cl aq., water and dried over
Na2SO4. After evaporation of volatiles under reduced pressure, the
crude mixture was purified by silica gel column chromatography (95:5
to 1:1 n-hexane/ethyl acetate) to give the desired product 3d (1250
mg, 84% yield). The anti/syn ratio and enantioselectivity were
determined to be 89/11 by 1H NMR and 94% ee by chiral-stationary-
phase HPLC analysis,36 respectively [Daicel CHIRALPAK AD-H, ϕ
0.46 cm × 25 cm, detection at 254 nm, n-hexane/iPrOH = 9/1, flow
rate = 1.0 mL/min] tR = 13.4 min (anti/major), tR = 15.5 min (anti/
minor).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JST, ACT-C, and
KAKENHI (No. 25713002). D.S. thanks the JSPS for the
Postdoctoral Fellowship for Foreign Researchers.
General Procedure for anti-Selective Catalytic Asymmetric
Nitroaldol Reaction (repetitive use of Cat. C, Scheme 3d). A
flame-dried 20 mL test tube equipped with a magnetic stirring bar and
a 3-way glass stopcock was charged with ligand ent-4 (derived from D-
Leu, 9.1 mg, 0.024 mmol) and dried under vacuum for ca. 5 min. Ar
was backfilled to the test tube, after which dry THF (400 μL, 2 ppm
on average) and 0.2 M THF solution of NdO1/5(OiPr)13/5 (120 μL,
0.024 mmol, 6 mol %, based on Nd) were added via a gastight syringe
with a stainless steel needle under an Ar atmosphere at room
temperature. After stirring the mixture at room temperature for 30
min, the slightly cloudy solution was cooled to 0 °C. 1.0 M THF
solution of NaHMDS (48 μL, 0.048 mmol) was added via syringe at 0
°C. After stirring for 30 min at room temperature, carbon nanotubes
(Baytubes C 70P, 18 mg) was added. Nitroethane (supplier A, 80 μL,
moisture content 133 ppm) was added via syringe at room
temperature. After stirring at room temperature for 2 h, the resulting
whole black suspension was transferred to Eppendorf safe-lock tube
(2.0 mL volume) with THF washing (ca. 1 mL). The tube was
centrifuged (ca. 104 rpm, 15 s). The supernatant was decanted and dry
THF (1 mL) was added. The tube was agitated by vortex mixer for 30
s and centrifuged (washing process). The supernatant was decanted.
After additional two-cycles of washing procedure, the resulting
precipitate was agitated with dry THF (1.0 mL) and the resulting
suspension was transferred to a flame-dried 20 mL test tube under an
Ar atmosphere. THF (1.5 mL) and 4-nitrobut-1-ene (2b) (124 μL, 1.2
mmol, 3 equiv, moisture content 33 ppm) were added via a syringe at
room temperature. The resulting black suspension was cooled to −60
°C. The solution of (E)-4-((4-methoxybenzyl)oxy)but-2-enal (1d)
(82.4 mg, 0.4 mmol) in THF (0.5 mL) was added dropwise via a
syringe over 1 min. The resulting suspension was stirred at −60 °C for
48 h under Ar. The test tube was cool down to −78 °C (dry ice/
acetone bath) and the tube was quickly centrifuged (ca. 104 rpm, 5 s).
The separated supernatant was immediately decanted and quenched
by transferring into another test tube containing 0.2 M THF solution
of AcOH (300 μL) at −78 °C. The test tube containing the catalyst
was placed to the cooling bath at −60 °C again and the catalyst was
used for next cycle by repeating same procedure mentioned above.
The quenched reaction mixture was warmed to room temperature and
sat. NH4Cl aq. (1 mL) was added. The resulting biphasic mixture was
filtrated with Celite pad under reduced pressure and washed with
AcOEt. The filtrate was extracted with AcOEt and then dried over
Na2SO4. After evaporation of volatiles under reduced pressure, the
crude residue was obtained which was directly subjected to NMR
analysis. Yields of 3d were calculated based on 1H NMR using DMF as
an internal standard. The anti/syn ratio and enantioselectivity were
determined by 1H NMR and 94% ee by chiral-stationary-phase HPLC
analysis,36 respectively [Daicel CHIRALPAK AD-H, ϕ 0.46 cm × 25
cm, detection at 254 nm, n-hexane/iPrOH = 9/1, flow rate =1.0 mL/
min] tR = 13.5 min (anti/major), tR = 15.6 min (anti/minor).
REFERENCES
■
(1) For recent reviews, see: (a) Shibasaki, M.; Groger, H. In
̈
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. III, pp
1075−1090. (b) Luzzio, F. A. Tetrahedron 2001, 57, 915. (c) Palomo,
C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442.
(d) Shibasaki, M.; Groger, H.; Kanai, M. In Comprehensive Asymmetric
̈
Catalysis, Supplement 1; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Hidelberg, Germany, 2004; pp 131−133. (e) Boruwa,
J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006,
17, 3315. (f) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2007, 2561. (g) Blay, G.; Hernan
2011, 1195.
(2) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
(3) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236. (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002,
102, 2187. (c) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N.
Acc. Chem. Res. 2009, 42, 1117. (d) Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2013, 52, 223.
(4) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418. (b) Sasai, H.; Tokunaga, T.; Watanabe, S.;
Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388.
(5) (a) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 3230. (b) Sohtome, Y.;
Kato, Y.; Handa, S.; Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki,
M. Org. Lett. 2008, 10, 2231.
́
dez-olmos, V.; Pedro, J. R. Synlett
(6) (a) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett.
2008, 49, 272. (b) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860.
(7) For syn-selective catalytic asymmetric nitroaldol reactions:
(a) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem.
2006, 2894. (b) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett.
2007, 9, 3595. (c) Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.;
Iguchi, T.; Nagasawa, K. Chem. Asian. J. 2007, 2, 1150. (d) Arai, T.;
Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2008, 73, 4903. (e) Yoshimoto, J.; Sandoval, C. A.; Saito, S. Chem. Lett.
2008, 37, 1294. (f) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682.
(g) Jin, W.; Li, X.; Wan, B. J. Org. Chem. 2011, 76, 484. (h) White, J.
D.; Shaw, S. Org. Lett. 2012, 14, 6270. For partially successful
examples of syn-selective catalytic asymmetric nitroaldol reaction, see:
(i) Lang, K.; Park, J.; Hong, S. J. Org. Chem. 2010, 75, 6424. (j) Zhou,
Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem. 2011, 76, 588.
(k) Chougnet, A.; Zhang, G.; Liu, K.; Haussinger, D.; Kagi, A.;
̈
̈
Allmendinger, T.; Woggon, W.-D. Adv. Synth. Catal. 2011, 353, 1797.
(8) For an anti-selective catalytic asymmetric nitroaldol reactions:
(a) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129,
12392. (b) Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem., Int. Ed.
2010, 49, 7562. (c) Lang, K.; Park, J.; Hong, S. Angew. Chem., Int. Ed.
2012, 51, 1620. (d) Xu, K.; Lai, G.; Zha, Z.; Pan, S.; Chen, H.; Wang,
Z. Chem.Eur. J. 2012, 18, 12357. For partially successful (moderate
́
stereoselectivity) examples: (e) Blay, G.; Domingo, L. R.; Hernandez-
ASSOCIATED CONTENT
■
S
* Supporting Information
Olmos, V.; Pedro, J. R. Chem.Eur. J. 2008, 14, 4725. (f) Ube, H.;
Terada, M. Bioorg. Med. Chem. Lett. 2009, 19, 3895. (g) Noole, A.;
Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75,
Additional notes and HPLC charts for nitroethane 2a and
nitroaldol products 3a-d. This material is available free of
charge via the Internet at http://pubs.acs.org.
́
1313. (h) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Org. Lett. 2010,
11499
dx.doi.org/10.1021/jo402042s | J. Org. Chem. 2013, 78, 11494−11500

The Journal of Organic Chemistry
Article
12, 3058. (i) Ji, Y. Q.; Qi, G.; Judeh, Z. M. A. Tetrahedron: Asymmetry
2011, 22, 2065. (j) Ji, Y. Q.; Qi, G.; Judeh, Z. M. A. Eur. J. Org. Chem.
2011, 4892. (k) Yao, L.; Wei, Y.; Wang, P.; He, W.; Zhang, S.
Tetrahedron 2012, 68, 9119. (l) Boobalan, R.; Lee, G.-H.; Chen, C.
Adv. Synth. Catal. 2012, 354, 2511.
(9) For anti-selective nitroaldol reaction of benzaldehyde catalyzed
by hydroxynitrile lyase, see: (a) Purkarthofer, T.; Gruber, K.; Gruber-
Khadjawi, M.; Waich, K.; Skranc, W.; Mink, D.; Griengl, H. Angew.
Chem., Int. Ed. 2006, 45, 3454. (b) Gruber-Khadjawi, M.; Purkarthofer,
T.; Skranc, W.; Griengl, H. Adv. Synth. Catal. 2007, 349, 1445.
(10) Iijima, S. Nature 1991, 354, 56.
(24) Several unidentified peaks appeared in a reverse-phase HPLC
trace of nitroethane 2a from supplier C. See Supporting Information.
(25) Commercial powdered NaHCO3 was suspended with 2a for 1 h
at room temperature, then filtered. See Supporting Information.
(26) The use of supernatant as a catalyst resulted in poor
stereoselectivity (see ref 6b), presumably because some defective
complexes promoted the reaction in much less stereoselective fashion.
(27) See Supporting Information for details.
(28) Under the reaction conditions for Figure 2, ca. 2000 ppm of
H2O corresponds to an equimolar amount of H2O to
NdO1/5(OiPr)13/5
.
(29) In the reaction of 1a and 2a under 1 mol% conditions (−60 °C,
5 h), 3a was obtained in 99% yield (anti/syn = 98/2, 99% ee).
(30) (a) Tall, A. R.; Jiang, X.; Luo, Y.; Silver, D. Arterioscler. Thromb.
Vasc. Biol. 2000, 20, 1185. (b) Thompson, A.; Di Angelantonio, E.;
Sarwar, N.; Erqou, S.; Saleheen, D.; Dullaart, R. P.; Keavney, B.; Ye, Z.;
Danesh, J. JAMA 2008, 299, 2777.
(31) (a) Smith, C. J.; Ali, A.; Hammond, M. L.; Li, H.; Lu, Z.;
Napolitano, J.; Taylor, G. E.; Thompson, C. F.; Anderson, M. S.;
Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D. P.; Sparrow,
C. P.; Wright, S. D.; Cumiskey, A.-M.; Latham, M.; Peterson, L. B.;
Rosa, R.; Pivnichny, J. V.; Tong, X.; Xu, S. S.; Sinclair, P. J. J. Med.
Chem. 2011, 54, 4880. (b) Gutstein, D. E.; Krishna, R.; Johns, D.;
Surks, H. K.; Dansky, H. M.; Shah, S.; Mitchel, Y. B.; Arena, J.;
Wagner, J. A. Clin. Pharmacol. Ther. 2012, 91, 109.
(11) Ogawa, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed.
2013, 52, 6196.
(12) For reviews of self-assembly: (a) Whitesides, G. M.; Mathias, J.
P.; Seto, C. T. Science 1991, 254, 1312. (b) Lehn, J.-M. Supramolecular
Chemistry: Concepts and Perspectives; Wiley-VCH, Weinheim, 1995.
(c) Lehn, J.-M. Science 2002, 295, 2400. (d) Whitesides, G. M.;
Grzybowski, B. Science 2002, 295, 2418. (e) Chakrabarty, R.;
Mukherjee, P. S.; Stang, P. Chem. Rev. 2011, 111, 6810.
(13) For examples of immobilization of asymmetric catalysts
infibrous network; (a) Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y.
Nature 1956, 178, 323. (b) Akamatsu, A.; Izumi, Y.; Akabori, S. Bull.
Chem. Soc. Jpn. 1961, 35, 1706. (c) Ikawa, T.; Sajiki, H.; Hirota, K.
Tetrahedron 2005, 61, 2217.
(14) (a) Handbook of Heterogeneous Catalysis, 2nd ed.; Ertl, G.,
(32) (a) Tanaka, N.; Tamai, T.; Mukaiyama, H.; Hirabayashi, H.;
Muranaka, M.; Sato, M.; Akahane, M. Patent WO00/02846, 1999.
(b) Tanaka, N.; Tamai, T.; Mukaiyama, H.; Hirabayashi, A.;
Muranaka, H.; Ishikawa, T.; Kobayashi, J.; Akahane, S.; Akahane, M.
J. Med. Chem. 2003, 46, 105. (c) Tanaka, T.; Tamai, T. JP Patent
JP2002−64840. See also ref 5a.
Knozinger, H., Schuth, F., Weitkamp, J., Eds.; Wiley-VCH; Weinheim,
2008. (b) Modeling and Simulation of Heterogeneous Catalytic Reactions;
Deutschmann, O., Ed.; Wiley-VCH; Weinheim, 2011.
(15) Reviews on asymmetric heterogeneous catalysis: (a) Thomas, J.
M.; Raja, R.; Lewis, D. W. Angew. Chem., Int. Ed. 2005, 44, 6456.
(b) Heitbaum, M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006,
̈
̈
(33) Ooi, T.; Uraguchi, D. JP Patent JP2013−71892.
45, 4732. (c) Baleizao, C.; Garcia, H. Chem. Rev. 2006, 106, 3987.
̃
(34) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J.
C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Woods, J. M.;
Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature
1993, 363, 418.
(35) Decrease in catalytic activity was observed, which would be
ascribed to mechanical damage of the nanotube catalyst and leaching
of the catalyst during the reaction. This problem would be addressed
by implementation of the MWNT-confined catalyst to a continuous-
flow system.
(36) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed.
2012, 51, 1644.
(37) Use of nitroethane 2a was essential for the preparation of self-
assembling of heterobimetallic catalyst. Contamination of the
nitroaldol product derived from 2a was negligible due to the presence
of large excess amount of 2b in the reaction mixture.
(d) Mallat, T.; Orglmeister, E.; Baiker, A. Chem. Rev. 2007, 107, 4863.
(e) Handbook of Asymmetric Heterogeneous Catalysis; Ding, K.,
Uozumi, Y., Eds.; Wiley-VCH: Weinheim, 2008. (f) Wang, Z.; Chen,
G.; Ding, K. Chem. Rev. 2009, 109, 322.
(16) A review on facile non-covalent immobilization of asymmetric
catalysts: Fraile, J. M.; García, J. I.; Mayoral, J. A. Chem. Rev. 2009, 109,
360.
(17) Recent examples of noncovalent immobilization of asymmetric
catalysts: (a) Yasukawa, T.; Miyamura, H.; Kobayashi, S. J. Am. Chem.
Soc. 2012, 134, 16963. (b) Tan, Y.-X.; He, Y.-P.; Zhang, J. Chem.
Mater. 2012, 24, 4711. (c) Jin, R.; Liu, K.; Xia, D.; Qian, Q.; Liu, G.;
Li, H. Adv. Synth. Catal. 2012, 354, 3265. (d) Li, Z.-H.; Zhou, Z.-M.;
Hao, X.-Y.; Zhang, J.; Dong, X.; Liu, Y.-Q. Chirality 2012, 24, 1092.
(e) Xu, Y.; Cheng, T.; Long, J.; Liu, K.; Qian, Q.; Gao, F.; Liu, G.; Li,
H. Adv. Synth. Catal. 2012, 354, 3250.
(18) For reviews on asymmetric synthesis of 1,2-amino alcohols, see:
(a) Kolb, H. C.; Sharpless, K. B. In Transition Metals in Organic
Synthesis; Beller, M., Bolm. C., Eds.; Wiley-VCH: Weinheim, 1998; pp
243. (b) Reetz, M. T. Chem. Rev. 1999, 99, 1121. (c) Bergmeier, S. C.
Tetrahedron 2000, 56, 2561.
(19) Use of carbon nanotubes in asymmetric catalysis: Chen, Z.;
Guan, Z.; Li, M.; Yang, Q.; Li, C. Angew. Chem., Int. Ed. 2011, 50,
4913.
(20) Incorporation ratio: Nd = 88%, Na = 85%, ligand 4 = 89%.
(21) Nitroethane 2a purchased from TCI Co. Ltd. (supplier A) and
Wako Pure Chemical Co. Ltd. (supplier B) could be used as received
in this reaction under 1 mol% catalyst conditions.
(22) When nitroethane 2a purchased from Sigma-Aldrich (supplier
C, without treatment with NaHCO3) was used for catalyst preparation
or as substrate, no reaction proceeded in our hands. Trace amount of
acidic impurity might interfere the self-assembly of the catalyst and
decompose the catalyst (prepared from 2a from suppliers A or B)
during the reaction.
(23) Long-term contact with dried MS 3Å and 2a led to the
accumulation of unidentified impurities in HPLC analysis, probably
because of gradual decomposition. Separation of 2a from MS 3Å is
recommended after 1 h.
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