Catalytic enantioselective conjugate addition of diethylzinc to chalcones using chiral amino alcohol-nickel complexes

Article abstract of DOI:10.1016/S0040-4020(02)00994-8

A series of chiral β-amino alcohols derived from (S)-leucine, valine, and phenylalanine were examined as chiral ligand in nickel-catalyzed conjugate addition of diethylzinc to chalcones. The (S)-valine-derived amino alcohol 1d possessing a piperidine ring

Full text of DOI:10.1016/S0040-4020(02)00994-8

Tetrahedron 58 (2002) 8095–8097
Catalytic enantioselective conjugate addition of diethylzinc to
chalcones using chiral amino alcohol–nickel complexes
a
Izumi Wakimoto, Yuko Tomioka and Yasuhiro Kawanami
b
a,*
a
Department of Biochemistry and Food Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795, Japan
Department of Chemistry, Faculty of Education, Kagawa University, Takamatsu, Kagawa 760-8522, Japan
b
Received 2 July 2002; accepted 7 August 2002
Abstract—A series of chiral b-amino alcohols derived from (S)-leucine, valine, and phenylalanine were examined as chiral ligand in nickel-
catalyzed conjugate addition of diethylzinc to chalcones. The (S)-valine-derived amino alcohol 1d possessing a piperidine ring and two
flexible phenethyl groups was found to be an efficient ligand to catalyze the conjugate addition with high enantioselectivity (up to 92%
ee). q 2002 Elsevier Science Ltd. All rights reserved.
2
1
. Introduction
tivity, where flexible moieties (R ) should relay and amplify
the stereochemical information of the stereogenic center of
1
Catalytic enantioselective conjugate additions of organo-
metallic reagents to enones have been intensively investi-
gated as synthetic methods for chiral carbon–carbon bond
the amino acid residue (R ) as shown in Fig. 1. This
prompted us to employ this series of b-amino alcohols as
chiral ligand in nickel-catalyzed conjugate addition to
chalcones as shown in Scheme 1. In this paper, we report
the enantioselective conjugate addition of diethylzinc to
acyclic chalcones, which was realized by optimizing chiral
amino alcohol ligands, the solvent, and the amount of ligand
and Ni(acac)2.
1
formation. Recently, Feringa and co-workers reported that
copper-catalyzed conjugate addition of diethylzinc using
chiral phosphoramidite proceeded with good to excellent
enantioselectivity for acyclic chalcones (up to 89% ee) and
2
cyclic enones (up to 98% ee). A variety of chiral amino
3
alcohols such as ephedrine derivatives, chiral pyridine
6
derivatives, borneol derivatives, proline derivatives,
4
5
7
8
pyrrolidine derivatives, and others has been also used in
nickel-catalyzed conjugate addition of diethylzinc to
chalcones. Quite recently, we reported that chiral b-amino
alcohol derived from (S)-leucine bearing two flexible
phenethyl groups catalyzed the addition of diethylzinc to
aldehydes with excellent enantioselectivity (up to 97% ee).
Moreover, the systematic studies of the substituent effect
and nonlinear effect revealed that ‘chiral relay’ system
played an important role in controlling the enantioselec-
2. Results and discussion
The ligands 1a–f were easily prepared from commercially
available (S)-leucine, valine, and phenylalanine ester via
addition of various Grignard reagents to the (S)-amino acid
esters and alkylation with 1,5-diiodopentane as described
previously. We examined the enantioselective conjugate
addition of diethylzinc to chalcone as a model substrate with
9
1
0
9
1
6 mol% of the chiral ligands 1a–f and 7 mol% of
Figure 1.
Keywords: conjugate addition; asymmetric synthesis; enantioselection;
chiral relay; amino alcohol.
*
Corresponding author. Tel.: þ81-87-891-3088; fax: þ81-87-891-3021;
e-mail: kawanami@ag.kagawa-u.ac.jp
Scheme 1. The nickel-catalyzed conjugate addition and chiral ligands.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00994-8

8096
I. Wakimoto et al. / Tetrahedron 58 (2002) 8095–8097
Table 1. Enantioselective conjugate addition of diethylzinc to chalcone
using ligands 1a–f
a
Entry
Ligand
Yield (%)
ee (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
71
91
48
65
50
91
37
74
22
87
34
74
Scheme 2.
1 mol% resulted in the increase of the enantioselectivity
and the decrease of the chemical yield (entry 7). Finally,
1.5 mol% of Ni(acac) and 20 mol% of chiral ligand 1d
2
were found to be the best reaction conditions, producing
(S)-1,3-diphenylpentan-1-one with 91% ee in 71% yield
All reactions were carried out with 7 mol% Ni(acac)
in MeCN at 2308C.
2
and 16 mol% ligand
a
Determined by HPLC analysis using DAICEL Chiralcel OD. The
absolute configurations of the resulting adducts were determined to be S
4a
by comparison of the retention time.
(entry 8).
3
c
Ni(acac)2 in acetonitrile at 2308C. These results are
summarized in Table 1.
In addition, we examined the conjugate addition to the
substituted chalcones using the optimal experimental
conditions (Scheme 2). Chalcone 2b with an electron-
donating group (OMe) at 4-position afforded the highest
enantioselectivity (92% ee, entry 10) and chalcone 2c with
an electron-withdrawing group (Cl) gave slightly lower
enantioselectivity (86% ee, entry 12). This substituent effect
on the enantioselectivity is identical to that of the conjugate
Comparison between the amino alcohol ligands 1a, 1c, and
1
e (entries 1, 3, and 5) and ligands 1b, 1d, and 1f (entries 2,
, and 6), reveals that the ligands with a flexible phenethyl
4
2
group as the relay group (R ) afford good yields and higher
enantioselectivites in the conjugate addition of diethylzinc
to chalcone. These results are the same trend as were
observed with the ligands derived from (S)-leucine for its
8
b
additions catalyzed by pyrrolidine derivative and is
8e
9
b
addition to aldehydes. However, with respect to the
1
chiral group (R ), the use of isopropyl group derived from
contrast to that of N-trityl aziridine derivative. Since the
electronic effect of chalcones was not significantly impor-
tant for the enantioselectivity of the copper-catalyzed
(S)-valine provided the highest enantioselectivity (entry 4).
Thus, the amino alcohol 1d was found to be the most
2
conjugate addition, it might be an alternative explanation
efficient ligand in the conjugate addition to chalcone.
that the observed poor solubility of 4-chlorochalcone 2c in
propionitrile at 2308C might affect the enantioselectivity of
the nickel-catalyzed conjugate addition.
Next, the effects of additive, solvents, and the amount of
Ni(acac) and ligand were examined as shown in Table 2.
2
Addition of 2,2-bipyridine did not improve the enantio-
selectivity as observed in the conjugate addition using
ephedrine derivatives and Ni(II) (entry 2). On the other
hand, the solvent significantly affected the enantioselec-
tivity of the conjugate addition and propionitrile afforded
the slightly high enantioselectivity at lower Ni(II) loading
Although the actual active species are unclear, the following
transition state model (Fig. 2) is suggested, based on the
reaction mechanism for the nickel- and copper-catalyzed
2
conjugate addition. Chiral amino alcohol ligand 1d might
3
5c
form the similar nickel complex to ethylzinc complex in the
addition of diethylzinc to aldehydes, in which one of the
phenethyl groups should locate in a pseudo-axial position.
Furthermore, we assume that acyclic chalcones would
coordinate to the nickel in the s–cis conformation as shown
in Fig. 2, where the carbonyl oxygen of chalcones and the
oxygen of chiral amino alcohol would locate in a trans
position. Thus, the chalcones might be attacked on its Si
face at the upper side of the square planar nickel complex to
produce the corresponding (S)-adduct. This is consistent
with the observed enantioselection.
(
selectivity was also observed in the conjugate addition
entries 3–6). The similar solvent effect on the enantio-
5
b
catalyzed by cis-endo-N,N-dimethyl-3-aminoborneol.
Furthermore, decreasing the amount of Ni(acac)2 to
Table 2. Enantioselective conjugate addition of diethylzinc to chalcones
2a–c using ligands 1d
a
Entry Substrate Solvent Ni/ligand (mol%) Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
1
1
1
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
MeCN
MeCN
MeCN
EtCN
7:16
7:16
2:16
2:16
65
79
76
82
61
78
64
71
80
65
86
57
87
85
86
88
77
80
90
91
83
92
79
86
b
3. Conclusion
n-PrCN 2:16
We have demonstrated that the chiral amino alcohol derived
from (S)-valine, which possesses a piperidine ring and
two phenethyl groups, catalyzed the conjugate addition of
i-PrCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
2:16
1:16
1.5:20
2:16
1.5:20
2:16
1.5:20
0
1
2
Reactions were carried out at 2308C.
Determined by HPLC analysis using DAICEL Chiralcel OD and OD-H.
a
The absolute configurations of the resulting adducts 3b and 3c were
determined to be S by comparison of the optical rotations.
Additive, 2,2-bipyridine (7 mol%), was used.
8e
b
Figure 2. The transition state model.

I. Wakimoto et al. / Tetrahedron 58 (2002) 8095–8097
8097
8
e
diethylzinc to acyclic chalcones with high enantioselec-
tivity. Thus, we clearly indicated that chiral relay system of
these amino alcohol ligands is also operative in the nickel-
catalyzed conjugate addition. Further studies are underway
to apply to other related asymmetric reactions.
(c 1.85, EtOH), OD-H column (0.25% i-PrOH in hexane,
flow rate: 0.5 ml/min, (S)-enantiomer: 35 min, (R)-enantio-
mer: 37 min). For 3-(4-methoxyphenyl)-1-phenylpentan-1-
2
5
8e
one; [a] ¼þ14.5 (c 4.01, EtOH), OD column (0.25%
D
i-PrOH in hexane, flow rate: 1.0 ml/min, (S)-enantiomer:
28 min, (R)-enantiomer: 25 min).
4
. Experimental
IR spectra were determined using a Shimadzu IR-435
Acknowledgements
1
13
spectrophotometer. H NMR and C NMR spectra were
recorded at 400 and 100 MHz using a JEOL JNM-A400
spectrometer, respectively. Mass spectra were recorded on a
JEOL JMS-SX102A mass spectrometer. Optical rotations
were determined on a Yanagimoto OR-50 polarimeter. The
HPLC analysis was carried out using a DAICEL Chiralcel
OB or OD column (0.46£25 cm) with a Shimadzu LC-6A.
Acetonitrile, propionitrile, n-butyronitrile, and i-butyro-
nitrile were dried over MS 4A. TLC was carried out on
Merck glass plates precoated with silica gel 60F-254
We are grateful to Professor Tsutomu Katsuki (Kyushu
University) for helpful discussion.
References
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9
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4.1. Typical procedure for enantioselective conjugate
addition of diethylzinc to chalcones
4
(
0
.1.1. (S)-1,3-diphenylpentan-1-one. A solution of 1d
75.9 mg, 0.2 mmol, 20 mol%) and Ni(acac)2 (3.9 mg,
.015 mmol, 1.5 mol%) in propionitrile (2 ml) was stirred
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(
208.3 mg, 1.0 mmol) was added. The mixture was stirred
and cooled to 2308C. Diethylzinc (1.0 M solution in
hexane, 1.5 ml, 1.5 mmol) was added (the color changed
from a clear green to dark brown) and stirring was continued
at 2308C for 2 h (the color changed to pale yellow). The
reaction mixture was quenched with aqueous 1N HCl
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solution, extracted with ether, dried (MgSO ), and concen-
4
trated. The residue was purified by flash column chroma-
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2
5
phenylpentan-1-one (168.3 mg, 71%); [a] ¼þ9.4 (c 2.47,
D
1
1
EtOH), (lit. [a] ¼þ10.5 (c 2.5, EtOH)). The ee was
D
determined to be 91% by HPLC analysis using a DAICEL
Chiralcel OD column (0.25% i-PrOH in hexane, flow rate:
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4a
1
.0 ml/min, (S)-enantiomer: 17 min, (R)-enantiomer: 20 min).
2
11. Brienne, M. J.; Ouannes, C.; Jacques, C. Bull. Soc. Chim. Fr.
1967, 613.
5
For 3-(4-chlorophenyl)-1-phenylpentan-1-one; [a] ¼þ6.2
D