Primary β-amino acid salt-catalyzed asymmetric Michael addition of benzoylacetates to cyclic enones and its application for the synthesis of enantioenriched 1,5-diketones

Article abstract of DOI:10.1246/cl.2013.180

The asymmetric Michael addition of benzoylacetates to cyclic enones was successfully carried out by using a primary β-amino acid salt catalyst. The reactions proceeded under mild reaction conditions to produce Michael adducts in high yields and with high enantioselectivities. The obtained Michael adducts were converted into β-benzoylmethylated cyclic ketones by decarboxylation without a significant loss of enantiomeric excess.

Full text of DOI:10.1246/cl.2013.180

doi:10.1246/cl.2013.180
180
Published on the web February 2, 2013
Primary ¢-Amino Acid Salt-catalyzed Asymmetric Michael Addition of Benzoylacetates
to Cyclic Enones and Its Application for the Synthesis of Enantioenriched 1,5-Diketones
Masanori Yoshida,*1,2 Ami Kubara,2 and Shoji Hara1,2
1Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University,
Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628
2Molecular Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering,
Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628
(Received November 7, 2012; CL-121128; E-mail: myoshida@eng.hokudai.ac.jp)
The asymmetric Michael addition of benzoylacetates to
are scarce. For example, the enantioselective synthesis of 3-(2-
oxo-2-phenylethyl)cyclohexanone, which can be converted into
a synthetically useful bicyclo[2.2.2]oct-5-en-2-one,11 has been
achieved by only two methods: a retro-aldol reaction of 6-
hydroxy-6-phenylbicyclo[2.2.2]octan-2-one12 and a Michael
addition reaction of ¢-ketosulfones to 2-cyclohexen-1-one
followed by removal of the sulfonyl group.13
The Michael addition of ¢-ketoesters to enones and
subsequent decarboxylation would be an attractive method
for obtaining 1,5-diketones, since decarboxylation from a ¢-
ketoester moiety is a fundamental reaction in organic synthesis;
however, only one successful example regarding the asymmetric
Michael addition of benzoylacetates to cyclic enones has been
reported other than our briefly noted preliminary results
presented in our previous paper,6c,14 and there has been no
report regarding the synthesis of ¢-benzoylmethylated cyclic
ketones through the decarboxylation of Michael adducts
obtained from ¢-ketoesters and enones.
cyclic enones was successfully carried out by using a primary
¢-amino acid salt catalyst. The reactions proceeded under mild
reaction conditions to produce Michael adducts in high yields
and with high enantioselectivities. The obtained Michael adducts
were converted into ¢-benzoylmethylated cyclic ketones by
decarboxylation without a significant loss of enantiomeric
excess.
The Michael addition reaction of ¢-dicarbonyl compounds
to ¡,¢-unsaturated carbonyl compounds is one of the most
important reactions in organic synthesis, since it is not only a
powerful tool for creating new carbon-carbon bonds to construct
desired structures, but also a simple method for introducing
synthetically useful carbonyl groups for further transformation
reactions. In terms of carrying out a Michael addition reaction
enantioselectively, organocatalysis has become a strong candi-
date as a result of remarkable growth in this field in the past
decade.1,2 In pioneering works on the organocatalytic asymmet-
ric Michael addition of carbon nucleophiles to ¡,¢-unsaturated
carbonyl compounds, Yamaguchi and co-workers reported that
the rubidium salt of L-proline promoted the asymmetric Michael
addition of malonates to enones via the formation of an
iminium-enamine intermediate,3 and some successful results
have been obtained by organocatalysis using amino acid salt
catalysts.4
We recently reported that readily obtainable primary ¡-
amino acid salts were effective asymmetric catalysts for the
Michael addition of ¡-branched aldehydes to nitroalkenes to
obtain £-nitroaldehydes having a quaternary carbon center at the
¡-position5 and for the Michael addition of various nucleophiles
to enones to obtain functionalized ketones.6 Through our
continuous investigation of organocatalysis using primary amino
acid catalysts, a mixed catalyst consisting of a primary ¢-amino
acid and its lithium salt was found to be more effective than a
primary ¡-amino acid salt catalyst for the Michael addition of
malonates to enones to obtain 1,5-ketoesters.7
In this letter, we present the highly enantioselective Michael
addition reaction of benzoylacetates to cyclic enones catalyzed
by a primary ¢-amino acid salt, and the transformation of the
obtained Michael adducts into ¢-benzoylmethylated cyclic
ketones.
Initially, we chose ethyl benzoylacetate (1a) and 2-cyclo-
hexen-1-one (2a) as model substrates for optimization of the
reaction conditions. Solvent screening was then carried out in
the presence of O-tert-butyldiphenylsilyl-(S)-¢-homoserine lith-
ium salt (3), which was an effective catalyst for the Michael
addition reaction of malonates to enones in our previous work
(Table 1).7 The Michael addition of 1a to 2a proceeded
smoothly and homogeneously with or without solvents to give
the desired Michael adduct 4a in good yield (Entries 1-10).
Because of the remaining acidic proton on the ¢-ketoester
moiety, the product 4a was obtained as a 1:1 mixture of
diastereomers having the same enantiomeric excess. As for the
enantioselectivity, it was found that high-polarity solvents such
as DMSO and DMF gave better results than the other solvents
examined in the screening. Fortunately, we found that a mixed
solvent system consisting of DMSO and CH2Cl2 gave better
results in terms of both chemical and optical yields than did a
simple solvent system, as was the case for the Michael addition
of malonates to enones in our previous works (Entries 11-
14).6a,7 By carrying out careful tuning of the mixed solvent, a 3:2
mixture of DMSO/CH2Cl2 was found to be an appropriate
solvent for further investigation (Entry 13).
For the formation of a 1,5-diketone from an enone,
conjugate addition with silyl enol ethers, which is known as
the Mukaiyama-Michael reaction, is often considered as the first
choice.8 Various 1,5-diketones including enantioenriched mate-
rials can be synthesized through this powerful methodology;9
however, to the best of our knowledge, the enantioselective
Mukaiyama-Michael reaction of an acetophenone-derived silyl
enol ether to cyclic enones has never been reported.10 In this
context, effective methods for the enantioselective synthesis of
cyclic ketones having a benzoylmethyl group at the ¢-position
After optimization of the amount of catalyst loading, we
studied the effects of additives on the Michael addition of 1a to
2a (Table 2). In the absence of any additives, the Michael
Chem. Lett. 2013, 42, 180-182
© 2013 The Chemical Society of Japan
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181
Table 1. Solvent screen for Michael addition of 1a to 2aa
Table 3. Substrate scopea
O
O
O
O
O
O
R1
O
3
R1
3
O
Ph
+
Ph
*
+
CO2R2
( )n
( )n
Ph
CO2t-Bu
Solvent
CO2Et
1a
Ph
1
2
4
2a
4a
1
2
1b
2b
: n=1
: R = Me, R = Et
CO2Et
1c: R1 = H, R2 = i-Pr 2c: n=3
1d: R1 = H, R2 = t-Bu 2d: n=4
1e: R1 = H, R2 = Bn
LiO2C
OTBDPS
Catalyst:
NH2
3
Time Yieldb
eec
/%
Entry
Solvent
Yield/%b
ee/%c
Entry
Michael adduct 4
/h
/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
DMF
MeOH
MeCN
THF
58
92
94
86
87
91
95
89
85
91
98
98
97
88
71
70
18
21
37
14
28
44
51
22
72
73
80
79
O
73/56
dr =
O
1
48
47d
1.1/1e
*
Ph
*
CO2Et
Et2O
4b
Benzene
CH2Cl2
CHCl3
none
O
O
2
3
24
24
98
99
93
95
*
Ph
DMSO/CH2Cl2 (1:1)
DMSO/CH2Cl2 (1:2)
DMSO/CH2Cl2 (3:2)
DMSO/CH2Cl2 (2:1)
CO2i-Pr
4c
O
O
aThe reactions were carried out with 1a (1.0 mmol), 2a
(0.5 mmol), and 3 (0.15 mmol) in a solvent (1 mL) at 25 °C for
24 h. Isolated yield of 4a based on 2a. Determined by chiral
HPLC analysis.
O
b
c
Ph
CO2t-Bu
4d
Table 2. Additive screen for Michael addition of 1a to 2aa
O
3
4
5
24
72
97
93
92
30
*
1a
+
2a
4a
Ph
DMSO/CH2Cl2
Additive
CO2Bn
4e
Entry
Additive (equiv)
Yield/%b
ee/%c
O
1
2
3
4
5
6
7
8
9
none
82
89
85
89
91
91
93
92
94
85
85
84
85
81
87
88
91
89
O
AcOH (0.2)
PhCO2H (0.2)
Pyridine (0.2)
Et3N (0.2)
H2O (0.2)
H2O (1.0)
H2O (5.0)
H2O (10.0)
*
Ph
CO2t-Bu
4f
O
O
Ph
6
7
24
24
92
93
97
98
CO2t-Bu
CO2t-Bu
4g
O
aThe reactions were carried out with 1a (1.0 mmol), 2a
(0.5 mmol), 3 (0.10 mmol), and additive in DMSO/CH2Cl2
(3:2, 1 mL) at 25 °C for 24 h. bIsolated yield of 4a based on 2a.
cDetermined by chiral HPLC analysis.
Ph
*
O
4h
aThe reactions were carried out with 1 (1.0 mmol), 2 (0.5
mmol), 3 (0.10 mmol), and H2O (2.5 mmol) in DMSO/CH2Cl2
(3:2, 1 mL) at 25 °C. bIsolated yield of 4 based on 2.
cDetermined by chiral HPLC analysis. dConversion: 76%.
eDetermined by 1H NMR analysis of the crude product. Unless
otherwise mentioned, the Michael adducts 4 were obtained as a
1:1 mixture of diastereomers.
addition reaction provided 4a in 82% yield with 85% ee
(Entry 1). Although the addition of a catalytic amount of acid
or base did not greatly affect the yield or enantioselectivity,
the addition of water improved both the results slightly (Entries
2-6). Examination of the effects of different amounts of water
added indicated that a small excess amount of water was
Chem. Lett. 2013, 42, 180-182
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

182
References and Notes
1
O
O
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O
O
TFA
*
*
CH2Cl2
r.t., 16 h
( )n
( )n
Ph
CO2t-Bu
: n=1 (95% ee)
4g: n=2 (97% ee)
4h
Ph
4d
5a
(3R): n=1 (73%, 94% ee)
5b (3R): n=2 (56%, 96% ee)
5c
2
: n=3 (98% ee)
: n=3 (70%, 96% ee)
Scheme 1. Synthesis of 5 by decarboxylation of 4.
3
4
5
necessary to obtain 4a in high yield with high enantioselectivity
(Entry 8).
Under the optimized reaction conditions, we investigated
the substrate scope with various benzoylacetates and cyclic
enones (Table 3). Unfortunately, the Michael addition of ethyl
2-methylbenzoylacetate (1b) to 2a was very slow, and gave
the corresponding Michael adduct 4b as a 1.1:1 mixture of
diastereomers with moderate enantioselectivity (Entry 1). Study
of the substituent effect on the alkoxycarbonyl group of the
benzoylacetates indicated that a bulky substituent provides better
enantioselectivity of the Michael addition reaction (Entries 2-4).
Thus, the reaction of tert-butyl benzoylacetate (1d) to 2a gave
the Michael adduct 4d in 99% yield with 95% ee (Entry 3). As
for the cyclic enones, cycloheptenone (2c) and cyclooctenone
(2d) were also good substrates for the Michael addition reaction
with 1d, although the reaction of cyclopentenone (2b) resulted in
low enantioselectivity (Entries 5-7).15,16
6
7
8
9
Finally, we examined the synthesis of ¢-benzoylmethylated
cyclic ketones 5 from Michael adducts 4d, 4g, and 4h through a
decarboxylation reaction (Scheme 1).16 Under common condi-
tions for the deprotection of tert-butyl esters using trifluoroacetic
acid, the decarboxylation of these Michael adducts proceeded
smoothly to give the corresponding ¢-benzoylmethylated cyclic
ketones 5a-5c in moderate yields without significant loss of
enantiomeric excess, although the generation of minor by-
products was observed by TLC analysis in each reaction.
In conclusion, we carried out the Michael addition reaction
of tert-butyl benzoylacetate to cyclic enones successfully by
using a primary ¢-amino acid salt catalyst to give Michael
adducts in high yields and with high enantioselectivities. By
subjecting the Michael adducts to common conditions for the
deprotection of tert-butyl esters, we succeeded in obtaining ¢-
benzoylmethylated cyclic ketones with high enantioselectivity.
Further optimization of the reaction conditions for the decar-
boxylation reaction and application of the results of the present
study to the synthesis of various 1,5-diketones are underway in
our group.
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This work was supported in part by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan and
the MEXT (Japan) program “Strategic Molecular and Materials
Chemistry through Innovative Coupling Reactions” of Hokkaido
University.
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references cited therein.
16 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2013, 42, 180-182
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/