Strontium-catalyzed highly enantioselective Michael additions of malonates to enones

Article abstract of DOI:10.1021/ja710332h

A novel catalyst system based on a chiral strontium complex which promotes the catalytic asymmetric Michael addition reactions of malonates to enones has been developed. The conjugate addition reactions proceeded smoothly in the presence of 5 mol % of the

Full text of DOI:10.1021/ja710332h

Published on Web 02/05/2008
Strontium-Catalyzed Highly Enantioselective Michael Additions of Malonates
to Enones
Magno Agostinho and Shuj Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The UniVersity of
Tokyo, The HFRE DiVision, ERATO, JST, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received November 14, 2007; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Table 1. Effect of Metal Sources and Chiral Ligandsa
Strontium is the fifteenth most abundant element in the earth’s
crust (384 ppm),1 it commonly occurs in nature as the form of the
sulfate mineral celestite (SrSO4) and the carbonate strontianite
(SrCO3). Despite its availability, there are few reports of its use as
catalyst in organic transformations.2 Herein we describe the first
report of an asymmetric strontium catalyst.
The catalytic asymmetric Michael reaction is one of the most
powerful carbon-carbon bond-forming reactions, which enables
access to a variety of optically active building blocks from catalytic
amounts of chiral information.3 There are several reports of the
catalytic asymmetric conjugate addition of malonates to enones,
where different types of catalysts such as chiral metal complexes,4
chiral ionic liquids,5 phase-transfer catalysts,6 organocatalysts,7 and
L-proline salts8 have been employed. However, when chalcone
derivatives are used, there are only a few reports enjoying limited
success. High selectivity was achieved by Maruoka et al.6a using
an N-spiro quaternary ammonium salt as a phase-transfer catalyst;
however, an excess of malonate (4 equiv) was used. Using a
cinchona thiourea organocatalyst, Wang et al.7a reported excellent
selectivities, but also in this case an excess of malonate was used
(5.6 equiv) and longer reaction times (from 72 to 144 h) were
needed. Therefore, development of a truly efficient catalyst that
provides a solution to these problems is a goal of considerable
importance.
We have recently reported the asymmetric 1,4-addition reactions
of glycine derivatives with R,â-unsaturated carbonyl compounds
catalyzed by a chiral calcium complex featuring bisoxazoline ligand
I.9 Our first attempts to extend this system to the Michael addition
of diethyl malonate (1b) to chalcone (2a) were unsuccessful (Table
1, entry 1). After careful screening of ligands, we found that a
complex prepared from Ca(O-i-Pr)2 and the sulfonamide ligand III10
in toluene afforded the desired Michael adduct in moderate
selectivity (entry 4). To our delight, changing the metal alkoxide
to Sr(O-i-Pr)2 gave the desired product in high yield with excellent
enantioselectivity (entry 5).
Next we explored the scope of the reaction under the optimized
reaction conditions. First, we examined the effect of the ester
substituent (R) of the malonates (Table 2). The results show that
the reactions proceeded smoothly in high yields with good to
excellent enantioselectivities. We found that di-n-propyl malonate
was an optimal Michael donor both in terms of reactivity and
selectivity (entry 3). Investigation of the effect of the catalyst
loading (entries 3-6) revealed that even with only 0.5 mol % of
the catalyst the reaction proceeded to afford the product in good
yield with excellent selectivity (72% yield, 97% ee, entry 6).
With these results in hand, we next surveyed the R,â-unsaturated
ketone substrates. As shown in Table 3, the strontium-catalyzed
conjugate addition reaction was also applicable to a wide variety
of chalcones 2b-u in high yields with excellent ee values.12
The system tolerated electron-withdrawing (entries 1-3, 5-7,
and 10-14), electron-donating (entries 4 and 15), or both substit-
time
(h)
yield
(%)b
ee
entry
metal (x mol %)
ligand
solvent
(%)c
1d
2d
3d
4e
5e
6e
7e
8e
9d
Ca(O-i-Pr)2 (10%)
Ca(O-i-Pr)2 (10%)
Ca(O-i-Pr)2 (10%)
Ca(O-i-Pr)2 (5%)
Sr(O-i-Pr)2 (5%)
Ba(O-i-Pr)2 (5%)
Ba(O-t-Bu)2 (5%)
Ba(O-t-Bu)2 (5%)
Mg(O-t-Bu)2 (10%)
I
II
THF
THF
THF
toluene
toluene
toluene
toluene
THF
24
24
24
18
18
18
18
18
18
47
47
89
58
91
80
82
15
9
4
49
52
65
97
76
70
33
30
III
III
III
III
III
III
III
toluene
a The catalyst was prepared at room temperature for 2 h and then the
substrates (0.3 mmol of 2a and 1.2 equiv of 1b) were added without removal
of volatiles. MS ) molecular sieves. b Isolated yields. c Determined by chiral
HPLC analysis (see Supporting Information). d Reaction run at 0 °C.
e Reaction run at 25 °C.
Table 2. Conjugate Addition Reactions of Malonates 1a-1f to 2aa
Sr(O-i-Pr)2
(mol %)
time
(h)
yield
(%)b
ee (%)c
entry
R
(configuration)
1
2
3
5
5
5
2.5
1
0.5
5
5
Me
Et
24
18
7
7
9
24
21
3
65
91
92
90
70
72
83
85
85
94 (S)d
97 (S)d
99
99
97
97
89
96
84
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
n-Bu
Bn
4
5e
6f
7
8
9
5
18
a Unless otherwise stated, see footnote in Table 1. b Isolated yields.
c Determined by chiral HPLC analysis. d Absolute configuration was
determined by comparison of the optical rotation with the value previously
reported.4k,11 e Reaction conducted with 0.75 mmol of 2a and 1.2 equiv of
1c. f Reaction conducted with 1.5 mmol of 2a and 1.2 equiv. of 1c, 0.2 M
concentration in toluene.
uents (entries 8 and 9) in the aromatic groups R1 and R2, with little
effect on the yield or the selectivity. High selectivity was also
obtained in the reactions with heteroaromatic substituents (entries
16-18). The use of N-acylpyrrole 2s afforded the Michael adduct
with remarkable selectivity (99% ee, entry 18), thus giving an access
9
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J. AM. CHEM. SOC. 2008, 130, 2430-2431
10.1021/ja710332h CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Conjugate Addition Reactions of 1c to Enones 2b-ua
strontium complex. This catalyst effectively promoted the conjugate
addition of malonates to a wide variety of chalcone derivatives,
providing an access to several useful synthetic building blocks with
high optical purity. Moreover, in contrast to previous reports, this
reaction system does not require an excess amount of nucleophile
or long reaction times, the reactions are performed at room
temperature and the catalyst loading can be reduced to 0.5 mol %.
Further investigations to clarify the exact catalyst structure, as well
as to further expand the substrate scope, are now in progress in
our laboratories.
yield
(%)b
ee
(%)c
entry
R1
R2
adduct
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18e
19f
20f
2-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
3cb
3cc
3cd
3ce
3cf
3cg
3ch
3ci
76
93
92
80
98
94
91
81
61
97
80
90
98
92
85
73
71
93
97
62
92
97
98
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-NO2C6H4
3-NO2C6H4
4-FC6H4
4-MeOC6H4
3,4-di-MeOC6H3
4-ClC6H4
2-ClC6H4
4-FC6H4
Ph
>99
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Science Research from the Japan Society for the
Promotion of Science (JSPS). Dr. Susumu Saito and Dr. Uwe
Schneider are acknowledged for fruitful discussions.
96
94
96
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-MeC6H4
4-ClC6H4
4-FC6H4
4-MeOC6H4
2-thienyl
Ph
>99
3cj
3ck
3cl
96
97
93
98
99
99
99
97
96
99
86
97
Supporting Information Available: Experimental procedures and
product characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
3cm
3cn
3co
3cp
3cq
3cr
3cs
3ct
Ph
Ph
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Scheme 1
to an important enantiopure chiral building block that can be further
transformed.4a In addition, when trans,trans-dibenzylideneacetone
(2t) or cinnamylideneacetophenone (2u) were used, the adduct
resulting from one single Michael addition was obtained exclusively,
even when 2.2 equiv of dipropyl malonate were employed (entries
19 and 20). The product can thus be further functionalized at the
unreacted double bond.12
To elucidate the structure of the catalyst, we have conducted
NMR spectroscopic studies. Sr(O-i-Pr)2 (0.15 mmol) was reacted
with 1 equiv of ligand III in deuterated THF (0.75 mL) for 2 h
(Scheme 1). After this time, the 13C{1H} NMR spectrum shows
evidence of the coordination of the ligand, and appearance of free
i-PrOH. At room temperature, the peaks corresponding to the
strontium bis(sulfonamide) complex A are considerably broadened,
indicating a possible conformational equilibrium,13 whereas the
peaks of the free i-PrOH are sharp (see Supporting Information).
After that, 1 equiv of dimethyl malonate (1a) was added, and the
mixture was stirred overnight. After this time the 13C{1H} spectrum
shows three new peaks resonating at δ 174.6, 64.6, and 49.7, which
are consistent with those of coordinated dimethyl malonate to Sr.14
In summary, we have developed a novel strontium based catalyst,
prepared from readily available Sr(O-i-Pr)2 and a simple bis-
sulfonamide type ligand. To the best of our knowledge, this is the
first example of an asymmetric transformation catalyzed by a chiral
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