Chiral calcium catalysts with neutral coordinative ligands: Enantioselective 1,4-addition reactions of 1,3-dicarbonyl compounds to nitroalkenes

Article abstract of DOI:10.1002/anie.200902902

Salt of the earth: The first chiral, coordinate alkaline earth metal catalysts have been developed. These catalysts effectively promote catalytic asymmetric additions of ss-dicarbonyl compounds to nitroalkenes in high yields with high enantioselectivities

Full text of DOI:10.1002/anie.200902902

Angewandte
Chemie
DOI: 10.1002/anie.200902902
Asymmetric Catalysis
Chiral Calcium Catalysts with Neutral Coordinative Ligands:
Enantioselective 1,4-Addition Reactions of 1,3-Dicarbonyl Compounds
to Nitroalkenes**
Tetsu Tsubogo, Yasuhiro Yamashita, and Shu¯ Kobayashi*
Alkaline earth metals are among the most promising metallic
species in organic synthesis owing to their abundance and low
toxicity. Since the first report of their use as a chiral catalyst in
1998,[1] there have been several reports of their use in
asymmetric catalysis;[2–4] however, their reactivity and selec-
tivity are lower in most cases compared with those of other
chiral metal-catalyzed reactions. Recently, we developed the
1,4-addition and the [3+2]-cycloaddition reactions of glycine
Schiff bases using chiral calcium catalysts.[5] We also reported
the chiral strontium-catalyzed Michael reactions of malonates
with chalcone derivatives,[6] in which high reactivities and
selectivities were attained. Salt formation is essential in the
construction of chiral alkaline earth metal catalysts; it is
required to successfully connect chiral ligands to the metal
centers (Scheme 1). However, in those systems shown in
Scheme 1, the Brønsted basicity of the catalyst is sometimes
decreased owing to the acidic nature of the chiral ligands.
During the course of our investigations to develop more
efficient catalysts, we envisioned that a complex between an
alkaline earth metal base and a chiral coordinative ligand
might act as a stronger chiral Brønsted base species, although
such examples have not been reported.[7] Herein, we describe
the use of chiral calcium catalysts, with neutral coordinative
ligands, in 1,4-addition reactions of 1,3-dicarbonyl compounds
to nitroalkenes.
Asymmetric 1,4-addition reactions of 1,3-dicarbonyl com-
pounds to nitroalkenes are one of the most important
methods for the preparation of chiral g-nitro carbonyl
compounds, which can be converted into various chiral
amines by subsequent reduction.[8,9] We began by investigat-
ing the reaction of malonate 4a with b-nitrostyrene (5a) in
the presence of chiral catalysts, prepared from alkaline earth
metal alkoxides and chiral ligands (Table 1). Although
calcium complex of box ligand 1,[5] and strontium complex
of bis(sulfonamide) 2[6] unexpectedly gave very low enantio-
selectivities (Table 1, entries 1 and 2; Scheme 2), calcium
pybox complex (pybox = pyridinebisoxazoline; 3a), a chiral
complex with a neutral coordinative ligand, gave the desired
Table 1: Optimization of reaction conditions.
Entry Ligand
M(OR)2
Conditions
Yield [%] ee [%]
Scheme 1. Chiral alkaline earth metal salt catalysts; coordinative
ligands, such as solvents, are omitted for clarity.
1
2
3
4
5
6
7
8
1
2
Ca(OiPr)2
Sr(OiPr)2
Ca(OiPr)2
Mg(OtBu)2
Sr(OiPr)2
Ba(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
THF, 08C
Toluene, 208C
Toluene, 08C
Toluene, 08C
Toluene, 08C
Toluene, 08C
THF, 08C
49
88
70
32
32
35
54
33
43
53
45
84
27
72
94
0
À8
44
2
8
3
18
51
28
32
4
91
19
50
91
96
96[b]
3a
3a
3a
3a
3a
3a
3a
3b
3c
[*] T. Tsubogo, Dr. Y. Yamashita, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science and Graduate School of
Pharmaceutical Sciences, The University of Tokyo,
The HFRE Division ERATO, Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Ether, 08C
DCM, 08C
9
10
11
12
13
14
15
16
17
Toluene, 08C
Toluene, 08C
Toluene, 08C
Toluene, 08C
Toluene, 08C
Toluene, 08C
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), the University of Tokyo,
and MEXT (Japan). T.T. thanks the JSPS Research Fellowship for
Young Scientists.
anti-3e Ca(OiPr)2
3d
syn-3e
anti-3e Ca(OAr)2
anti-3e Ca(OAr)2
anti-3e Ca(OAr)2
Ca(OiPr)2
Ca(OiPr)2
[a]
[a]
[a]
Toluene, À208C 80
Toluene, À308C 68
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902902.
[a] Ar=p-MeOC6H4. [b] 48 h.
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Table 2: Substrate scope for malonates and nitroalkenes.
Entry
R1
R2
Product
Yield [%]
ee [%]
1
2
3
4
Me
Et
iPr
Ph
Ph
Ph
Ph
6a
6b
6c
6d
6 f
6g
6h
6i
80 (quant.)[a]
95
91
50
95
92
quant.
97
93
96 (94)[a]
92
87
18
93
94
94
65
93
94
tBu
Me
Me
Me
Me
Me
Me
Me
5[b]
6[b]
7[b]
8[b]
9
p-MeOC6H4
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-BrC6H4
2-furyl
Cy
Scheme 2. Chiral ligands that are employed herein.
6j
6k
6l
10
96
73
1,4-addition product 6a with moderate enantioselectivity
(Table 1, entry 3). Among the alkaline earth metal alkoxides
examined, calcium showed the highest enantioselectivity
(Table 1, entries 3–6). We also examined the effect of solvent
on the reaction, and found that the best result was obtained
using toluene (Table 1, entries 3,7–9). To consider the effect
of the chiral ligand, several pybox ligands, prepared from
chiral amino alcohols, were synthesized and tested.[10]
Although pybox ligands 3a–3c gave low enantioselectivities
(Table 1, entries 3,10, and 11), anti-5,4-diphenyl pybox (anti-
3e) afforded the product in high ee (91%; Table 1, entry 12).
We also conducted the reaction using syn-5,4-diphenyl pybox
(syn-3e) and 5-phenyl pybox (3d) to examine the effect of
placing substituents at the 5-positions on the two oxazoline
rings. Interestingly, although a very low enantioselectivity was
obtained using 3d (19%; Table 1, entry 13), syn-3e afforded a
more moderate ee value (50%; Table 1, entry 14). These
results show that substituents with an anti configuration at the
4- and 5-positions of the oxazoline ring are very important for
high enantioselectivity, and that the phenyl group at the 5-
position has a significant influence on the structure of the
calcium pybox complex. Furthermore, the yield improved
when Ca(OAr)2 (Ar= p-MeOC6H4) was used instead of
Ca(OiPr)2 (Table 1, entry 15). The reactions at lower temper-
atures gave higher enantioselectivities (Table 1, entries 16
and 17), although the rate of reaction decreased at À308C
(Table 1, entry 17).
We then investigated the substrate scope of the 1,4-
addition reaction using our optimized reaction conditions
(Table 2). The malonate methyl ester gave the highest
enantioselectivity of those tested (Table 2, entries 1–4).
Impressively, it was found that nitroalkenes with substituted
phenyl groups reacted with methyl malonate smoothly, to
afford the desired 1,4-adducts in high yields, with high
enantioselectivities (Table 2, entries 5–7,9). Substituted aro-
matic nitroalkenes bearing either electron-donating or elec-
tron-withdrawing groups reacted without any significant loss
of enantioselectivity. In the case of an ortho-substituted
nitroalkene (Table 2, entry 8), the enantioselectivity was
moderate, presumably owing to steric constraints imposed
by the aromatic moiety. Nitroalkenes bearing heteroaromat-
ics (Table 2, entry 10), or an aliphatic ring (Table 2, entry 11)
11[c]
87
[a] 1.0 mol%, 0.6m. 18 days. [b] 48 h. [c] 72 h.
also worked well. The reaction proceeded smoothly even in
the presence of only 1.0 mol% of catalyst (Table 2, entry 1, in
the parenthesis); the reaction time was 18 days.
We also investigated other 1,3-dicarbonyl compounds as
nucleophiles under the same conditions (Table 3). b-Ketoest-
ers afforded both high yields and high enantioselectivities
Table 3: Substrate scope for 1,3-dicarbonyl compounds.
Entry
R1
R2
R3
Product
Yield [%]
ee[a] [%]
1
OMe
OMe
OtBu
Me
OEt
OMe
OMe
Me
Me
Me
OEt
OMe
H
H
H
H
Me
OMe
6a
6m
6n
6o
6p
6q
80
90
91
54
quant.
84
96
93 (93)
90 (90)
78
2[b]
3[c]
4[d]
5[e]
6[e]
87
87
[a] Parentheses indicate ee of minor distereoisomer. [b] d.r.=51:49.
[c] d.r.=76:24. [d] À458C, 72 h. [e] 72 h.
(Table 3, entries 2 and 3). However, the reaction involving a
b-diketone, namely acetylacetone, proceeded with lower yield
and enantioselectivity, even at À458C (Table 3, entry 4). a-
Methyl malonate and a-methoxy malonate reacted with 5a to
afford their corresponding adducts in high yields, and with
high enantioselectivities (Table 3, entries 5 and 6).
Neutral coordinative ligands worked well in these reac-
tions, with a noticeably faster rate of reaction relative to the
ligand-free system clearly observed (Table 4). In the absence
of any other ligands, Ca(OiPr)2 and Ca(OAr)2 (Ar= p-
MeOC6H4) both furnished the desired product 6 in 40%
9118
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Table 4: Effect of ligand.
tion of other reactions using alkaline earth metal coordinative
ligand complexes are now in progress.
Received: May 30, 2009
Revised: August 7, 2009
Published online: October 28, 2009
Entry
Metal
Ligand
none
iPr-pybox
none
Yield [%]
ee [%]
Keywords: 1,4-addition · asymmetric catalysis · calcium ·
N,O ligands · nitroalkenes
.
1
2
3
4
Ca(OiPr)2
Ca(OiPr)2
Ca(OAr)2
Ca(OAr)2
40
70
74
quant.
–
44
–
iPr-pybox
54
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Communications
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