Asymmetric conjugate addition of α-keto esters to nitroolefins catalyzed by chiral CuII hydroxo complexes

Article abstract of DOI:10.1016/j.tetasy.2010.04.009

As a part of our research project on hard anion-late transition metal complexes as mild acid-base catalysts, we describe herein that Cu^II hydroxo complexes having chiral N-substituted-diaminocyclohexanes are mild and selective catalysts, which are applicable to the catalytic asymmetric conjugate addition of α-keto esters to nitroolefins. The reaction proceeded diastereoselectively without the detectable formation of self-aldol products, affording the corresponding coupling products with anti-stereochemistry in an enantioselective manner.

Full text of DOI:10.1016/j.tetasy.2010.04.009

Tetrahedron: Asymmetry 21 (2010) 1682–1687
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric conjugate addition of
by chiral CuII hydroxo complexes
a-keto esters to nitroolefins catalyzed
Ayako Nakamura a,b,c, Sylvain Lectard a, Ryo Shimizu a,b, Yoshitaka Hamashima a, Mikiko Sodeoka a,
*
a RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
b Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
c Exploratory Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of our research project on hard anion-late transition metal complexes as mild acid–base cata-
lysts, we describe herein that CuII hydroxo complexes having chiral N-substituted-diaminocyclohexanes
are mild and selective catalysts, which are applicable to the catalytic asymmetric conjugate addition of a-
keto esters to nitroolefins. The reaction proceeded diastereoselectively without the detectable formation
of self-aldol products, affording the corresponding coupling products with anti-stereochemistry in an
enantioselective manner.
Received 22 March 2010
Accepted 12 April 2010
Available online 18 May 2010
Dedicated to Professor H. Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
silanes, and nitromethane to the keto group have been well inves-
tigated.6 In contrast, they have rarely been used as a pronucleo-
The development of environmentally friendly atom-economical
organic transformations is an important goal in the field of current
synthetic organic chemistry. Direct in situ activation of acidic com-
pounds and its application to asymmetric catalysis have witnessed
great progress in the last decade,1 and various C–C bond-forming
reactions without pre-activation of substrates have been devel-
oped using novel chiral Lewis acid catalysts, basic metal catalysts,
enamine catalysis, and Brønsted acid catalysts.2–4 However, we be-
lieve that further studies to create mild and selective catalysts are
necessary in order to expand the scope of available substrates as
well as to develop novel catalytic reactions.
phile,7 although pyruvic acid, a representative 1,2-dicarbonyl
compound, is an important donor unit in biosynthesis. This is prob-
ably because the high reactivity as an electrophile may limit their
use as a pronucleophile, and because they are considered to be less
acidic than 1,3-dicarbonyl compounds. However, strongly basic
catalysts would induce undesired side reactions such as self-aldol
condensation reactions. Therefore, the development of selective
catalysts with mild reactivity is desirable. To this end, we thought
that our acid–base catalysis using basic charged anion-coordinat-
ing transition metal complexes would be effective to achieve selec-
tive transformations of a-keto esters.
We have been working on asymmetric catalysis under proton-
transfer conditions and unique C–C bond-forming reactions, haloge-
nation reactions, and aza-Michael reactions have been developed.5
During these studies, we found that charged anionic-ligands such
as a hydroxide ion on late transition metals can act as a mild endog-
enous base. Since monomeric Pd hydroxo complexes dissociated
2. Results and discussion
To test our hypothesis, we selected the catalytic asymmetric con-
jugate addition of a-keto esters to nitroolefins as a model reaction,
which should be useful for the synthesis of highly functionalized
compounds.8,9 It is noteworthy that a catalytic version of this type
of reactions had not been reported before our recent work.10 Only
one example using a nearly stoichiometric amount of strongly basic
t-BuOK (0.9 equiv) has been reported,11 but the chemical yield of the
desired product was less than 50%. Based on our previous studies,5
we first tested the Pd l-hydroxo complexes 1. However, all reactions
examined were sluggish, and the desired product was obtained in
less than 15% yield (48 h, rt). This may be due to that the Pd hydroxo
complex is not sufficiently basic to abstract the
strate (see Scheme 1).
from Pd l-hydroxo complexes 1 can function as both a Lewis acid
and a Brønsted base, the reactions with 1,3-dicarbonyl compounds
such as b-keto esters and malonates give chiral bidentate Pd eno-
lates cleanly. As a part of our research project on hard anion-late
transition metal complexes as mild acid–base catalysts, we herein
describe that CuII hydroxo complexes having chiral diamines are
effective acid–base catalysts, being applicable to a novel catalytic
asymmetric reaction of
a-keto esters.
Because -keto esters are versatile building blocks, asymmetric
a
a-proton of the sub-
addition reactions of dialkylzinc reagents, arylboronic acids, enol
To overcome this problem, we planned to investigate a Cu hy-
droxo complex. We expected that it should show stronger basicity
than the palladium complex 1, judging from their electronegativity
* Corresponding author. Tel.: +81 48 467 9373; fax: +81 48 462 4666.
E-mail address: sodeoka@riken.jp (M. Sodeoka).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.009

A. Nakamura et al. / Tetrahedron: Asymmetry 21 (2010) 1682–1687
1683
H
O
18 h
+
Pd
+
Pd
+
Pd
H
O
P
P
P
P
OH
P
P
N
N
+
Cu
OH
X-
N
N
+
Cu
*
*
*
*
Brønsted base
*
6
*
O
H
1
n
2TfO-
TfO-
X-
Lewis acid
EtOHa CuX
filtration
O2
7
&
n = 2 or 3
P
P
39~96%
concentration
= BINAP derivatives
6a: R1 = Me, R2 = Me
6b: R1 = Me, R2 = Bn
6c: R1 = H, R2 = Bn
N
OH
X
R1 R2
Cu
*
N
N
6d: R1 = H, R2 = 2-MeO-C6H4CH2
6e: R1 = H, R2 = 4-MeO-C6H4CH2
6f: R1 = H, R2 = 2-CF3-C6H4CH2
N
Scheme 1. Transition metal hydroxo complexes as acid–base catalysts.
R1 R2
6g: R1 = H, R2 = 2,4,6-Me3-C6H2CH2
6h: R1 = H, R2 = 2,4,6-(i-Pr)3-C6H2CH2
6
(Pd: 2.2, Cu: 1.9).12 The following facts discussed in the literature
also support our idea: (1) In Glaser–Hay dimerization reactions
of terminal alkynes, Cu acetylides are formed as a result of depro-
tonation by the Cu hydroxo complex.13 (2) In oxidative coupling
reactions of naphthols, an acid–base reaction of the Cu hydroxo
complex gives a Cu naphthoxide as a key intermediate.14 To our
Scheme 3. Preparation of Cu hydroxo complexes. aTHF was used in the case of
Cu(CH3CN)4(PF6).
Table 1
Catalyst screening
delight, the reaction of
ciently promoted by 10 mol % of known [(TMEDA)Cu(
a
-keto ester 2 with nitroolefin 3 was effi-
-OH)]2Cl2
l
CO2t-Bu
HO
5 [TMEDA = tetramethylethylenediamine].15 While the reactions
in normal organic solvents such as THF, toluene, CH2Cl2, and
CH3CN resulted in only modest yield (<25% yield), the reaction in
2-propanol proceeded smoothly to give the desired product 4a at
a synthetically useful level (68% yield after 19 h) (Scheme 2).
Cu complex 7
(9 mol%)
O
Ph
Bn
Ph
NO2
2
+
O2N
+
CO2t-Bu
2-propanol
rt
Ph
3
Ph
4a
NO2
8
Entry
Catalyst 7
[diamine, X]
Time (h)
4aa Yield % (% ee)
8 Yielda % (% ee)
10 mol%
2 Cl-
H
O
O
N
N
N
N
+
+
Cu Cu
1b
2b
3b
4
5
6
6a, X = Cl
6b, X = Cl
6c, X = Cl
6d, X = Cl
6e, X = Cl
6f, X = Cl
6g, X = Cl
6g, X = Cl
6g, X = Br
6g, X = I
10
47
10
2
10
27
6
72
24
6
52
178
6
59 (0)
12 (0)
6 (37)
10
27
35 (39)
30
36
31
10 (66)
14
21
36
Ph
CO2t-Bu
O
H
O
Ph
2
5
O2N
+
CO2t-Bu
14 (40)
17 (41)
31 (56)
73 (76)
42 (84)
45 (75)
24 (41)
44 (77)
38 (80)
79 (80)
2-propanol (1.0 M)
rt, 19 h
NO2
Ph
Ph
4a
(dl)
7
3
single isomer (anti)
8c
9
68%
10
11
12
13
Scheme 2. Conjugate addition of 2a–3a catalyzed by [(TMEDA)Cu(l-OH)]2Cl2.
6g, X = OTf
6g, X = PF6
6h, X = Cl
13
14
6 (11)
This result prompted us to investigate an asymmetric version of
this reaction. Chiral Cu hydroxo complexes having optically active
N-substituted diaminocyclohexane derivatives were prepared
according to the reported procedure14–16 (Scheme 3). It was re-
ported that the resulting Cu complex exists as its dimer or trimer
in a solid phase, depending on the amount of substitution at the
nitrogen atom. However, it is generally considered that they are
in equilibrium with the monomer in the solution, which partici-
pates in the reaction as the active species.14 Therefore, we describe
the Cu complex 7 as a monomer and calculated it on the basis of
the formula of [(diamine)Cu(OH)Cl], although the exact structure
is unclear at present.
Results of the catalyst screening are summarized in Table 1.
Although Cu complexes having N,N,N0,N0-tetraalkyl-substituted dia-
minocyclohexanes 6a and 6b as a chiral ligand could promote the
model reaction, negligible asymmetric induction was observed.
Moreover undesired cyclic compound 8 which arose from over-
reaction with a second nitroolefin was also formed in an appreciable
amount (entries 1 and 2). In contrast, modest to good enantioselec-
tivities (37–56%) were observed using secondary amine ligands
(entries 3–6). However, in these reactions, the chemical yield of 4a
was less than 20%, accompanied with the compound 8 in 31–36%
yield.
a
b
c
Yield based on 2.
0.4 M.
0 °C.
Additionally, such bulky ligands might improve the chiral environ-
ment of the putative Cu enolate of 2a, allowing for better enantiose-
lectivity. As we hoped, the chemical yield and the ee of the product
were greatly improved, when bulkier 6g was used as a ligand.
Although the best enantioselectivity of 84% was achieved at 0 °C,
the reaction became slow (entry 8). Further studies on the influence
of counter anions revealed that chloride ion gave the best results
(entries 9–12). In entry 13, the catalyst having a much bulkier 6h
gave a slightly better ee. The reaction was complete within 6 h to af-
ford 4a in 79% yield and with 80% ee. Interestingly, the ee of 8 was
decreased dramatically compared to that of the parent compound
4a in this reaction (vide infra).
As in the case of the Cu complex 5, 2-propanol was the best sol-
vent for this asymmetric reaction, and other usual organic solvents
gave low chemical yields. The reaction was always anti-selective,
and only a trace amount of syn-epimer was detected. The relative
and absolute stereochemistries of 4a and 8 were determined by
comparing the reported analytical data.10 Interestingly, the Cu cat-
alyst 7 gave the opposite enantiomer of the product obtained from
Ni(OAc)2–6c complex that has been recently developed by us,10
even though both diamine ligands were synthesized from the same
chiral source. It should be noted that the diastereoselectivity of this
We speculated that a Cu nitronate intermediate generated in the
first conjugate addition reacted directly with the remaining nitro-
olefin to give 8. If this was the case, it was expected that the
over-reaction would be minimized by employing bulkier diamine li-
gands to prevent the nitroolefin from approaching the Cu nitronate.

1684
A. Nakamura et al. / Tetrahedron: Asymmetry 21 (2010) 1682–1687
O
reaction is complementary to the syn-selectivity generally ob-
R1
R2
Cu complex 7h
served in organocatalytic reactions of aldehydes and ketones.8
Under the optimized conditions, the scope of the reaction was
investigated (Scheme 4). Thus, the reactions were carried out in
2-propanol (1 M) at room temperature in the presence of 9 mol %
of 7h (X = Cl). As shown in Scheme 4, this reaction was applicable
O
CO2t-Bu
(9 mol%)
O2N
+
CO2t-Bu
2-propanol, rt
R1
4
NO2
R2
to various substrates in respect to both a-keto esters and nitroole-
O
O
Ph
O
Ph
Ph
fins. Regardless of the size and electronic properties of the sub-
strates, all reactions examined reached completion within 8 h,
affording the corresponding products in good yield with good to
high enantioselectivity (63–83% ee). Since the reaction conditions
are mild, various functional groups including ethers, halogens,
and the acid-sensitive furan ring were tolerant. Like 4a, these reac-
tions proceeded in a highly diastereoselective manner. Notably, the
starting materials and the solvent could be used without purifica-
tion, and no precaution to remove moisture was necessary.
O2N
O2N
O2N
CO2t-Bu
CO2t-Bu
CO2t-Bu
Me
BnO
4b
8 h, 86% (83% ee)
4c
4d
8 h, 79% (78% ee)
8 h, 84% (75% ee)
O
O
O
Ph
Ph
O
O2N
CO2t-Bu
O2N
CO2t-Bu
O
O2N
CO2t-Bu
3. Mechanistic considerations
Cl
MeO
Bn
4e
4f
4g
A proposed catalytic cycle of the present reaction is outlined in
Scheme 5. The Cu hydroxo complex 7h would react with a-keto es-
6 h, 45% (71% ee)
6 h, 75% (76% ee)
6 h, 80% (68% ee)
ters to give the corresponding chiral Cu enolates. Since CuII usually
takes a square planar geometry,17 we assume that a bidentate eno-
late 9 is formed. The C–C bond-forming event would occur through
the coordination of the nitoolefins to the Cu ion. Although an acy-
clic transition state model B cannot be ruled out, the excellent dia-
stereoselectivity observed in this reaction can be explained by
assuming a cyclic transition state model A. Based on molecular
modeling studies and the reported X-ray structure of similar Cu–
diamine complexes,18 it is most likely that the aryl groups of the
diamine ligands are located at the pseudo-equatorial position, cre-
ating a C2 symmetric chiral environment. Therefore, the ester
OMe
Br
O
O
O
O
O2N
CO2t-Bu
O2N
O2N
CO2t-Bu
CO2t-Bu
Bn
Bn
Bn
4h
4i
4j
8 h, 75% (64% ee)
8 h, 80% (76% ee)
8 h, 61% (71% ee)
Scheme 4. Catalytic asymmetric conjugate addition of various
a
-keto esters to
nitroolefins.
H
R2
O
N
N
+
Cu
O
*
O2N
CO2t-Bu
n
Cl-
R1
O
R1
4
CO2t-Bu
N
OH
Cl-
+
Cu
*
O2N
R2
N
H2O
H2O
7h
O-
O-
R2
R1
R1
N+
H
H
N
+
Cu
O
O
CO2t-Bu
N
+
O
O
H
*
R1
R2
N+ O-
O
Cu
*
O
N
Ot-Bu
[Cu]
Cl-
N
Ot-Bu
Cl-
R2
Cu enolates 9
NO2
C
NO2
R2
O
N
H
i-Pr
i-Pr
O
i-Pr
HO CO2t-Bu
N
N
O
R1
NO2
Cu
i-Pr
H
R2
R1
O
i-Pr
i-Pr
R2
R2
O
NO2
t-Bu
A
8
H
N
i-Pr
i-Pr
i-Pr
N
O
Cu
i-Pr
H
O
i-Pr
i-Pr
1
H
R
O
NO2
t-Bu
R2
H
B
Scheme 5. Assumed catalytic cycle.

A. Nakamura et al. / Tetrahedron: Asymmetry 21 (2010) 1682–1687
1685
group of the substrate points away to avoid steric repulsion with
the aryl group. Since the re face of the enolate is blocked by the
t-butyl ester and the aryl group of the ligand, the reaction occurs
at the si face of the enolate preferentially. The absolute and relative
stereochemistry of the product can be predicted using this model.
Based on the fact that the N–H bond within the ligand plays an
important role for asymmetric induction (see Table 1, entries 1–
3), we assume that hydrogen bonding between the nitro group
and the N–H group is also operative in controlling the geometry
of the nitroolefins. Finally, protonation of the resulting Cu nitro-
nate C followed by dissociation of the desired product completes
the catalytic cycle. The bulky ligands seem to be the factor in sup-
pressing the undesired over-reaction of the intermediate C. In the
meantime, when the Cu catalyst is sterically less hindered, the
remaining nitroolefin can react with the Cu nitronate, affording
the cyclic compound 8 as a major product.
Unlike 7c, the ee of 8 obtained from the bulky 7h was much
lower than that of the parent compound 4a as shown in entry 13
of Table 1. We assume that the bulky diamine 6h is relatively easy
to dissociate from the Cu catalyst because of the steric repulsion,
which might promote less enantioselective conjugate addition of
2 as well as the second conjugate addition of 4a. A control experi-
ment indicated that the diamine ligand alone could catalyze the
reaction, affording the opposite enantiomers ent-4a and ent-8 with
moderate enantioselectivity (Eq. 1). The difference in the ees be-
tween 4a and 8 might arise from the kinetic resolution in the sec-
ond conjugate addition.
the product selectivity was observed. Further studies to improve
the reaction efficiency are under way in our laboratory.
5. Experimental section
5.1. General
NMR spectra were recorded on a JEOL JNM-LA400 spectrometer
operating at 400 MHz for 1H NMR and 100.4 MHz for 13C NMR.
Chemical shifts were reported downfield from TMS (=0) for 1H
NMR. For 13C NMR, chemical shifts were reported using the solvent
signal as an internal reference. FAB-LRMS and HRMS were taken on
JEOL Mstation JMS-700 using m-nitrobenzyl alcohol (mNBA) as
matrix. ESI-LRMS and HRMS were taken on JMS T100LP using
H2O/acetonitrile (contained with 0.05% of formic acid) as mobile
phase. Optical rotations were measured on a JASCO DIP-370 polar-
imeter. IR was measured on Thermo Nicolet AVATAR 370 FT-IR
equipped with DuraScope™ or PerkinElmer Spectrum 100. Melting
points were measured using Yamaco MP-J3. Precoated TLC plates
(Silica Gel 60 F254, 0.25 mm) were used for the TLC analysis. Flash
column chromatography was performed with silica gel N 60
(40–100 lm) or NH silica gel (100–200 mesh). In some cases, puri-
fication was carried out using Yamazen medium-pressure liquid
chromatography (MPLC) systems [pump, 580-D; UV-detector,
prepUV-10VW; column, Yamazen HI-FLASH™]. The enantiomeric
excesses (ees) were determined by chiral HPLC analysis, which
6h
(9 mol %)
2
+
3
ent-4a
+
ent-8
2-propanol
rt, 6 h
35%, 52% ee
15%, 37% ee
ð1Þ
HO CO2t-Bu
R2
R1
NO2
O
O
6h
6h
NO2
O2N
R1
CO2t-Bu
R2
R2
CO2t-Bu
R1
NO2
R2
R2
NO2
As for the desired compound 4, high enantioselectivity was
achieved (Table 1, entry 13). This may be attributed to the Cu-cat-
alyzed conjugate addition reaction being faster than that by the
diamine. In contrast, the Cu- and the diamine-involved pathways
to 8 might be retarded due to the steric interaction. Consequently,
both routes are likely to contribute to the formation of 8 compara-
bly, resulting in the drastic loss of the ee. On the contrary, the sim-
ilar ees were observed in the case of 7c (entry 3). This is probably
because the Cu-involved pathway to give 8 prevailed, and because
the dissociation of the ligand was minimized.25 In addition, the
reactivity of 4 and ent-4 in the Cu- or diamine-catalyzed second
conjugate addition as well as the reactivity of two diastereomeric
isomers of the intermediate C in the reaction with the nitroolefins
may be different. It is also necessary to consider such kinetic reso-
lution for a further understanding of the reaction mechanism.
was performed on JASCO Borwin Ver.1.5 systems consisting of
the following: pump, PU-2080 Plus; detector, CD-2095 Plus mea-
sured at 254 nm or 280 nm; column, DAICEL CHIRALPAK AD-H,
IC, and DAICEL CHIRALCEL OD-H; mobile phase, n-hexane/2-propa-
nol (IPA), n-hexane/IPA/ethyl acetate, or n-hexane/ethanol. Sol-
vents used in this paper were purchased and used directly. Other
reagents were purified by usual methods. (R,R)-1,2-Diaminocyclo-
hexane was purchased from commercial source and was used as
received. Known chiral ligands, a-keto esters, and nitroolefins were
prepared according to the literature procedures.
5.2. Ligand
Diamines 6a,19 6b,19 6c,20 6d,21,22 6e,22,23 6f,22 and 6g24 are
known compounds. The compound 6h was synthesized as de-
scribed below.
4. Conclusion
5.2.1. (1R,2R)-N,N0-Bis[(2,4,6-triisopropylphenyl)methyl]-1,2-
diaminocyclohexane 6h
To a suspension of K2CO3 (2.21 g, 16.0 mmol) and (R,R)-1,2-
diaminocyclohexane (456 mg, 4.00 mmol) in DMF (10 mL) was
added 2,4,6-triisopropylbenzyl chloride (2.02 g, 8.00 mmol) in
DMF (20 mL). After stirring at room temperature for 2 h, at 50 °C
for 1 h, and at 100 °C for 3 h, the reaction mixture was quenched
In conclusion, we have demonstrated that the Cu hydroxo com-
plexes having N-substituted diaminocyclohexane derivatives can
be used as mild acid–base catalysts for catalytic asymmetric conju-
gate addition of
a-keto esters to nitroolefins. The reactions pro-
ceeded smoothly in a product-selective manner, and the desired
products with anti-stereochemistry were obtained in good yield
with up to 84% ee. In addition, a unique ligand effect in controlling

1686
A. Nakamura et al. / Tetrahedron: Asymmetry 21 (2010) 1682–1687
with water (40 mL). The resultant mixture was extracted with Et2O
(20 mL ꢀ 3), and the combined organic layers were washed with
water (40 mL). The organic layer was dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (NH silica gel, n-hexane/Et2O = 15:1) to give
6h in 45% yield as a colorless solid (981 mg).
5.4.5. (3S,4S)-tert-Butyl 3-(40-methoxybenzyl)-5-nitro-2-oxo-4-
phenylpentanoate 4e10
CHIRALCEL OD-H, n-hexane/2-propanol = 90:10, flow rate
1.0 mL/min, k = 254 nm, smajor 29.9 min, sminor 35.5 min;
½
a 2D9
ꢂ
¼ ꢁ19:7 (c 1.06, CHCl3) (76% ee).
Mp 59–61 °C; IR (neat)
m
3307, 2958, 2924, 2865, 1608, 1458,
5.4.6. (3S,4S)-tert-Butyl 3-(40-chlorobenzyl)-5-nitro-2-oxo-4-
phenylpentanoate 4f10
1261, 1114, 876 cmꢁ1 1H NMR (400 MHz, CDCl3) d 6.88 (s, 4H),
;
3.93 (d, J = 11.5 Hz, 2H), 3.41 (d, J = 11.5 Hz, 2H), 3.21–3.06 (m,
4H), 2.91–2.75 (m, 2H), 2.35–2.19 (m, 4H), 1.78 (d, J = 8.1 Hz,
2H), 1.43–1.04 (m, 28H), 0.98 (d, J = 6.8 Hz, 12H); 13C NMR
(100 MHz, CDCl3) d 147.2, 147.1, 132.0, 120.6, 63.0, 43.7, 34.3,
31.8, 29.1, 25.1, 24.8, 24.3, 24.2, 24.1; LRMS (ESI) m/z 547
[M+H]+; HRMS (ESI) calcd for C38H63N2 547.49912 [M+H]+, found
CHIRALCEL OD-H, n-hexane/2-propanol = 90:10, flow rate
1.0 mL/min, k = 254 nm, smajor 26.0 min, sminor 29.9 min;
½
a 2D9
ꢂ
¼ ꢁ15:2 (c 1.07, CHCl3) (68% ee).
5.4.7. (3S,4S)-tert-Butyl 4-(30,40-methylenedioxyphen)-3-benzyl-
5-nitro-2-oxopentanoate 4g
547.49915; ½a 2D7
ꢂ
¼ ꢁ56:5 (c 1.01, CHCl3).
Mp 92–94 °C; IR (neat)
m 2981, 1722, 1552, 1487, 1247,
1038 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.29–7.23 (m, 2H), 7.23–
;
7.16 (m, 1H), 7.15–7.09 (m, 2H), 6.70 (d, J = 1.7 Hz, 1H), 6.70 (d,
J = 8.1 Hz, 1H), 6.65 (dd, J = 8.7, 1.7 Hz, 1H), 5.92 (d, J = 1.5 Hz,
1H), 5.91 (d, J = 1.5 Hz, 1H), 4.76 (dd, J = 12.7, 5.1 Hz, 1H), 4.67
(dd, J = 12.7, 9.5 Hz, 1H), 4.20–4.11 (m, 1H), 3.83 (apparent td,
J = 9.5, 5.1 Hz, 1H), 2.98 (apparent d, J = 8.3 Hz, 2H), 1.30 (s, 9H);
13C NMR (100 MHz, CDCl3) d 196.2, 159.0, 148.0, 147.3, 136.9,
130.1, 128.9, 128.7, 126.9, 121.6, 108.6, 108.4, 101.2, 84.2, 78.1,
50.8, 45.6, 36.1, 27.5; LRMS (FAB) m/z 450 [M+Na]+; HRMS (FAB)
calcd for C23H25NaNO7 450.1529 [M+Na]+, found 450.1531; CHIR-
ALPAK IC, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min,
5.3. Complex 7a–7h (X = Cl)
Complexes 7a–7h were prepared according to the literature
procedure.15
A mixture of the ligand of interest and CuCl (1 equiv) in ethanol
(95%) was stirred at room temperature for 18 h under O2 atmo-
sphere. The resulting solution was filtered through filter paper
and concentrated under reduced pressure. The obtained green so-
lid was used without further purification.
k = 254 nm, smajor 14.5 min, sminor 20.2 min; ½a D29
¼ ꢁ16:1 (c 0.63,
ꢂ
5.4. General procedure for the catalytic asymmetric conjugate
CHCl3) (71% ee).
addition of
a-keto esters to nitroolefin
5.4.8. (3S,4S)-tert-Butyl 3-benzyl-4-(40-bromophenyl)-5-nitro-2-
oxopentanoate 4h10
The Cu
l
-hydroxo complex 7h (9 mol %) and an
a-keto ester
(0.1 mmol) were combined under N2 atmosphere in 2-propanol
(0.1 mL) at room temperature. A trans-b-nitroolefin (0.1 mmol)
was added to the resulting solution and the mixture was stirred for
6–8 h. After dilution with ethyl acetate, the solution was passed
through a pad of SiO2 and concentrated under reduced pressure. Fur-
therpurificationbyMPLC(n-hexane/ethyl acetate = 9:1)wascarried
out to give the pure product. The ee of the product was determined
by chiral HPLC analysis. The absolute stereochemistry of the prod-
ucts was assigned by analogy to that of the compound 4a.10
CHIRALCEL OD-H, n-hexane/2-propanol/ethyl acetate = 90:7:3,
flow rate 1.0 mL/min, k = 280 nm, smajor 22.1 min, sminor 72.7 min;
½
a 2D9
ꢂ
¼ ꢁ12:7 (c 1.30, CHCl3) (64% ee).
5.4.9. (3S,4S)-tert-Butyl 3-benzyl-4-(40-methoxyphenyl)-5-nitro-
2-oxopentanoate 4i10
CHIRALCEL OD-H, n-hexane/2-propanol/ethyl acetate = 90:7:3,
flow rate 1.0 mL/min, k = 254 nm, smajor 26.3 min, sminor 65.7 min;
½
a 2D9
ꢂ
¼ ꢁ21:2 (c 1.05, CHCl3) (76% ee).
5.4.10. (3S,4S)-tert-Butyl 3-benzyl-4-(furan-20-yl)-5-nitro-2-
oxopentanoate 4j10
5.4.1. (3S,4S)-tert-Butyl 3-benzyl-5-nitro-2-oxo-4-
phenylpentanoate 4a10
CHIRALCEL OD-H, n-hexane/2-propanol/ethyl acetate = 90:7:3,
flow rate 1.0 mL/min, k = 254 nm, smajor 14.2 min, sminor 30.1 min;
CHIRALCEL OD-H, n-hexane/2-propanol = 90:10, flow rate
1.0 mL/min, k = 254 nm, smajor 22.8 min, sminor 59.6 min;
a 2D7
ꢂ
¼ þ3:8 (c 0.73, THF) (71% ee).
½
a 2D8
ꢂ
¼ ꢁ28:0 (c 1.03, CHCl3) (80% ee).
½
Acknowledgments
5.4.2. (3S,4S)-tert-Butyl 3-methyl-5-nitro-2-oxo-4-
phenylpentanoate 4b10
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Area (No. 19028065, ‘Chemistry of Concert Catal-
ysis’) and Project Funding from RIKEN.
CHIRALPAK IC, n-hexane/ethanol = 98:2, flow rate 1.0 mL/min,
k = 280 nm, smajor 12.8 min, sminor 22.3 min; ½a D27
¼ ꢁ8:5 (c 1.01,
ꢂ
acetone) (83% ee).
References
5.4.3. (3S,4S)-tert-Butyl 3-(20-nitro-10-phenylethyl)-2-oxohex-5-
enoate 4c10
1. Handbook of C–H Transformations, Vols. 1 and 2; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005.
2. Modern Aldol Reactions, Vols. 1 and 2; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
2004.
3. Multimetallic Catalysis in Organic Synthesis; Shibasaki, M., Yamamoto, Y., Eds.;
Wiley-VCH: Weinheim, 2004.
CHIRALPAK IC, n-hexane/2-propanol = 98:2, flow rate 1.0 mL/
min, k = 254 nm, smajor 13.1 min, sminor 23.6 min; ½a D28
¼ ꢁ1:8 (c
ꢂ
1.00, CHCl3) (78% ee).
4. Berlessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005.
5. (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240–
11241; (b) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 14530–14531; (c) Hamashima, Y.; Somei, H.; Shimura, Y.;
Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861–1864; (d) Hamashima, Y.;
Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.,
Int. Ed. 2005, 44, 1525–1529; (e) Hamashima, Y.; Suzuki, T.; Takano, H.;
Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164–10165; (f)
5.4.4. (3S,4S)-tert-Butyl 3-[20-(benzyloxy)ethyl]-5-nitro-2-oxo-4-
phenylpentanoate 4d10
CHIRALPAK AD-H, n-hexane/2-propanol = 90:10, flow rate
1.0 mL/min, k = 254 nm, smajor 14.0 min, sminor 15.1 min;
½
a 2D9
ꢂ
¼ þ6:4 (c 1.15, CHCl3) (75% ee).

A. Nakamura et al. / Tetrahedron: Asymmetry 21 (2010) 1682–1687
1687
Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2006, 128,
14010–14011; (g) Sodeoka, M.; Hamashima, Y. Pure Appl. Chem. 2006, 78, 477–
494; (h) Hamashima, Y. Chem. Pharm. Bull. 2006, 54, 1351–1364; (i) Sodeoka,
M.; Hamashima, Y. Pure Appl. Chem. 2008, 80, 763–776; (j) Sodeoka, M.;
Hamashima, Y. Chem. Commun. 2009, 5787–5798.
Organometallics 2002, 21, 4513–4522; (c) Li, X.; Hewgley, J. B.; Mulrooney, C.
A.; Yang, J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500–5511; (d) Hewgley, J.
B.; Stahl, S. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 12232–12233.
15. We prepared [(TMEDA)Cu(l-OH)]2Cl2 complex according to the following
papers: (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35, 7983–
7984; (b) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001, 66,
7892–7897 and references cited therein.
6. For recent selected examples: (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett.
2002, 4, 3781–3784; (b) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451–
3453; (c) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 5489–5492; (d) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. F. J.
Am. Chem. Soc. 2006, 128, 6532–6533; (e) Mikami, K.; Kawakami, Y.; Akiyama,
K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950–12951; (f) Duan, H.-F.;
Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2008, 47,
4351–4353.
16. Ferraro, J. R.; Walker, W. R. Inorg. Chem. 1965, 4, 1382–1386.
17. (a) Cotton, F. A.; Wilkinson, G.; Gauss, P. L. Basic Inorganic Chemistry, 3rd ed.;
John Wiley & Sons: New York, 1995; (b) Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J.
Org. Chem. 2005, 70, 3712–3715; (c) Christensen, C.; Juhl, K.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875–4881.
18. Nguyen, Q. T.; Jeong, J. H. Polyhedron 2008, 27, 3227–3230; For related NiBr2–
diaminocyclohexane complex: Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc.
2007, 129, 11583–11592.
19. Arjan, H.; Boyd, E.; Coumbarides, G. S.; Eames, J.; Jones, R. V. H.; Stenson, R. A.;
Suggate, M. J. Tetrahedron Lett. 2005, 46, 1921–1925.
20. Denmark, S. E.; Stadler, H.; Dorow, R. L.; Kim, J.-H. J. Org. Chem. 1991, 56, 5063–
5079.
21. Jones, V. A.; Sriprang, S.; Thornton-Pett, M.; Kee, T. P. J. Organomet. Chem. 1998,
567, 199–218.
22. Kylmälä, T.; Kuuloja, N.; Xu, Y.; Rissanen, K.; Franzén, R. Eur. J. Org. Chem. 2008,
23, 4019–4024.
23. Roh, S. G.; Yoon, J. U.; Jeong, J. H. Polyhedron 2004, 23, 2063–2067.
24. (a) Desimoni, G.; Faita, G.; Righetti, P. P.; Sardone, N. Tetrahedron 1996, 52,
12019–12030; racemic: (b) De la Cruz, A.; Koeller, K. J.; Rath, N. P.; Spilling, C.
D.; Vasconcelos, I. C. F. Tetrahedron 1998, 54, 10513–10524.
25. The reaction catalyzed by the diamine ligand 6c gave a racemic product.
7. For a-ketoesters and a-ketoanilides: (a) Juhl, K.; Gathergood, N.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2001, 40, 2995–2997; (b) Juhl, K.; Jørgensen, K. A. J. Am.
Chem. Soc. 2002, 124, 2420–2421; (c) Lu, G.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 6847–6850; (d) Xu, Y.; Lu, G.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 3353–3356.
8. For general reviews on asymmetric conjugate addition reactions to
nitroolefins: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877–1894; (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716; (c) Doyle, A.
G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
9. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH, 2001.
10. Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.; Sodeoka, M., J. Am.
Chem. Soc. doi:10.1021/ja909457b.
11. Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314–2315.
12. Encyclopedia of Inorganic Chemistry; King, R. B., Ed.; Wiley: Chichester, 1994.
13. Hay, A. S. J. Org. Chem. 1962, 27, 3320–3321.
14. (a) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J.
Org. Chem. 1999, 64, 2264–2271; (b) Kozlowski, M. C.; Li, X.; Carrol, P. J.; Xu, Z.