Asymmetric Michael addition of malonates to enones catalyzed by a siloxy amino acid lithium salt

Article abstract of DOI:10.1016/j.tetlet.2009.10.033

Siloxy amino acid lithium salt, O-tert-butyldiphenylsilyl l-serine lithium salt, was found to be an effective catalyst for the asymmetric Michael addition reaction of malonates to enones.

Full text of DOI:10.1016/j.tetlet.2009.10.033

Tetrahedron Letters 50 (2009) 7297–7299
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric Michael addition of malonates to enones catalyzed by a siloxy
amino acid lithium salt
*
Masanori Yoshida , Mao Narita, Keisuke Hirama, Shoji Hara
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Siloxy amino acid lithium salt, O-tert-butyldiphenylsilyl L-serine lithium salt, was found to be an effective
Received 10 September 2009
Revised 6 October 2009
Accepted 8 October 2009
Available online 13 October 2009
catalyst for the asymmetric Michael addition reaction of malonates to enones.
Ó 2009 Elsevier Ltd. All rights reserved.
Organocatalysis has been recognized as an important synthetic
methodology for constructing an enantiomeric carbon center in
organic synthesis.1 In organocatalysis based on the formation of
iminiums or enamines from carbonyl compounds with optically
reaction of isobutyraldehyde with nitroalkenes.7 The reaction is
promoted by the formation of an enamine from the catalyst and
isobutyraldehyde; that is, the reaction proceeds on the basis of
activation of a Michael donor. We then turned our attention to a
catalytic asymmetric Michael addition reaction by activation of a
Michael acceptor. Thus, we planned the Michael addition reaction
of malonates to enones via the formation of imines using a primary
amino acid lithium salt as a catalyst. The catalytic use of amino
acid alkali metal salts was first reported by Yamaguchi’s group in
1991.3j They later succeeded in the asymmetric Michael addition
active amines, secondary amines, especially L-proline and its deriv-
atives, have generally been employed as catalysts. Within common
natural amino acids, however, only a few secondary amino acids
are available, while more than 20 types of primary amino acids
are readily obtainable from a commercial source. Although the
use of primary amines as asymmetric catalysts is quite primitive,
several successful works have been published in recent years.2
of malonates to enones using L
-proline rubidium salt.3g,i Quite
The Michael addition of malonates to
a
,b-unsaturated carbonyl
recently, Yamamoto’s group reported that asymmetric intramolec-
ular Robinson annulation was catalyzed effectively by a primary
amino acid salt.8
compounds is one of the most important carbon-carbon bond for-
mation reactions, and many catalytic asymmetric syntheses have
been achieved by using amine catalysts,3 quaternary ammonium
catalysts,4 thiourea catalysts,5 and metal complex catalysts.6 Zhao
and Yang accomplished the reaction of dibenzyl malonate with
cyclic or acyclic enones to give Michael adducts in very high yields
(up to 99%) with excellent enantioselectivity (up to >99%ee) by
Table 1
Michael addition of dimethyl malonate with 1a using Phe-OLia
using a primary-secondary diamine catalyst derived from L-trypto-
CO2Li
Ph
phan.3a They explained that the reaction proceeds via the iminium
catalysis: the primary amine moiety activates an enone via the for-
mation of an iminium ion and the secondary amine moiety acti-
vates a malonate. To the best of our knowledge, this is one of the
most successful reports about a catalytic asymmetric Michael addi-
tion of malonates to enones using organocatalysts or metal cata-
lysts.3–6 This indicates that primary amines have much potential
as asymmetric catalysts as well as secondary amines and may be-
come a leading candidate for asymmetric catalysts in the near
future.
O
O
NH2
+ CH2(CO2Me)2
Solvent
CH(CO2Me)2
2a
1a
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
DMSO
64
40
86
80
38
45
17
2
DMF
DMSO/H2Od
MeOH
Recently, we reported that a lithium salt of a primary amino
acid was an effective catalyst for the asymmetric Michael addition
a
The reaction was carried out with dimethyl malonate (1.0 mmol), 1a
(0.5 mmol), and Phe-OLi (0.1 mmol) in a solvent (1 mL) at 25 °C for 36 h.
b
Isolated yield of 2a based on 1a.
c
Determined by Chiral HPLC analysis with a Daicel CHIRALPAK AS-H column.
* Corresponding author. Tel./fax: +81 11 706 6557.
E-mail address: myoshida@eng.hokudai.ac.jp (M. Yoshida).
d
H2O (5 mmol) was added.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.033

7298
M. Yoshida et al. / Tetrahedron Letters 50 (2009) 7297–7299
Table 3
First, we examined the Michael addition of dimethyl malonate
with 2-cyclohexen-1-one (1a) in the presence of -phenylalanine
Optimization of siloxy amino acid alkali metala
L
lithium salt, Phe-OLi (Table 1). The reaction proceeded well in a
high-polar solvent, DMSO or DMF, to give the Michael adduct 2a
with moderate enantioselectivity (Table 1, entries 1 and 2). The
addition of water enhanced the reaction rate and increased the
yield of 2a; however, the enantioselectivity was significantly de-
creased (Table 1, entry 3). The Michael addition reaction smoothly
proceeded in MeOH; however, the product 2a was obtained as a
racemate (Table 1, entry 4). As the result of further solvent screen-
ing, it was found that the Michael addition reaction did not pro-
ceed well in low-polar solvents, CH2Cl2, CHCl3, toluene, CH3CN,
Et2O, and THF, giving only a trace amount of 2a due to the low sol-
ubility of Phe-OLi in these solvents. To investigate the reaction
using an amino acid lithium salt in a low-polar solvent, we synthe-
sized a lipophilic amino acid lithium salt, O-tert-butyldiphenylsilyl
Catalyst
1a
2a
+
CH2(CO2Me)2
DMSO/CH2Cl2
Entry
Catalystb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12e
13f
Thr(O-TBDPS)-OLi
Tyr(O-TBDPS)-OLi
Hyp(O-TBDPS)-OLi
Ser(O-TBS)-OLi
65
80
73
52
63
76
68
76
77
77
Trace
59
73
68
44
44
59
67
69
43
29
16
26
—
Ser(O-TIPS)-OLi
Ser(O-TBDPS)-OLi
Ser(O-TBDPS)-ONa
Ser(O-TBDPS)-OK
Ser(O-TBDPS)-ORb
Ser(O-TBDPS)-OCs
Ser(O-TBDPS)-OH
Ser(O-TBDPS)-OLi
Ser(O-TBDPS)-OLi
L
-serine lithium salt [Ser(O-TBDPS)-OLi].9a–d As shown in Table 2,
70
62
the Michael addition reaction with Ser(O-TBDPS)-OLi could be car-
ried out in various low-polar solvents. The reactions were carried
out with 30 mol % of catalyst to consume substrates satisfactory.
A solvent screen revealed that DMSO gave a relatively high yield
and that CH2Cl2 and DMF gave better enantioselectivity than the
other solvents (Table 2, entries 1–8). After further solvent screen-
ing, we found that a 1:1 mixed solvent of DMSO and CH2Cl2 gave
the best result (Table 2, entry 9).
a
The reaction was carried out with dimethyl malonate (0.6 mmol), 1a
(0.5 mmol), and a catalyst (0.15 mmol) in DMSO/CH2Cl2 (1:1, 1 mL) at 25 °C for
24 h.
b
TBDPS = tert-butyldiphenylsilyl, TIPS = tri-iso-propylsilyl, TBS = tert-butyldi
methylsilyl.
c
Isolated yield of 2a based on 1a.
d
Determined by Chiral HPLC analysis with a Daicel CHIRALPAK AS-H column.
The reaction was carried out in DMSO/CH2Cl2 (1:1, 5 mL).
The reaction was carried out in DMSO/CH2Cl2 (1:1, 0.5 mL).
e
f
We then synthesized a variety of siloxy amino acid alkali metal
salts from
(Hyp), and
L
-threonine (Thr),
L-tyrosine (Tyr), 4-hydroxy L-proline
L
-serine (Ser) to find a suitable catalyst (Table 3).9 As
selectivity was observed when the reaction was carried out in a di-
luted condition (Table 3, entry 12).
for an amino acid, Ser and Thr showed better enantioselectivity than
Tyr and Hyp (Table 3, entries 1–3 and 6). Since Ser gave a better yield
of 2a than Thr, Ser was selected as a basic amino acid and was used
for further modification of the catalyst. Next, we examined the steric
effect of the silyl group of Ser(O-silyl)-OLi and found that a bulkier
silyl group gave better yield and enantioselectivity (TBDPS > TIPS
> TBS) (Table 3, entries 4–6). Finally, we examined the effect of alkali
metals of Ser(O-TBDPS)-OM and found that the enantioselectivity of
the reaction greatly depends on the type of alkali metal (Table 3, en-
tries 6–10).10 The amino acid Ser(O-TBDPS)-OH did not work well as
a catalyst and afforded only a trace amount of the Michael adduct
(Table 3, entry 11). Since a lithium salt of Ser(O-TBDPS) gave the best
result, Ser(O-TBDPS)-OLi was selected as the catalyst for the Michael
addition of malonates with enones. In addition, a slightly better
Next, we carried out reactions of various malonates with enone
1a to examine the steric effects of malonates (Table 4, entries 1–5).
The reaction of dimethyl and diethyl malonate with 1a gave the
Michael adduct 2a (77%, 69% ee) and 2b (61%, 76% ee), respectively
(Table 4, entries 1 and 2). A moderately bulky malonate, di-iso-pro-
pyl malonate, afforded the Michael adduct 2d in 69% yield with
80% ee; however, di-tert-butyl malonate was found to be too bulky
to react with 1a (Table 4, entries 4 and 5). By increasing the
Table 4
Michael addition of various malonates with enones using Ser(O-TBDPS)-OLia
CO2Li
TBDPSO
R1
O
R1
O
NH2
+ CH2(CO2R3)2
Table 2
R2
R2
DMSO
/CH2Cl2
Solvent screen for Michael addition of dimethyl malonate with 1a using
n equiv.
*
Ser(O-TBDPS)-OLia
CH(CO2R3)2
2
1
CO2Li
TBDPSO
Entry
R1
R2
R3
n (equiv)
Yieldb (%)
eec (%)
NH2
1a
+
CH2(CO2Me)2
2a
1
2
3
4
5
(CH2)3, 1a
1a
1a
1a
1a
1a
1a
1a
(CH2)4, 1b
(CH2)2, 1c
trans-Ph, 1d
trans-Ph, 1e
Me
Et
Bn
1.2
1.2
1.2
1.2
1.2
2.0
3.0
2.0
2.0
2.0
2.0
2.0
77, 2a
61, 2b
77, 2c
69, 2d
Trace
83, 2d
88, 2d
92, 2d
96, 2e
47, 2f
63, 2g
47, 2h
69 (S)
76 (S)
66 (S)
80 (S)
—
79 (S)
76 (S)
79 (S)
87 (S)
55 (S)
70 (R)
10 (R)
Solvent
Yieldb (%)
Entry
Solvent
eec (%)
iso-Pr
tert-Bu
iso-Pr
iso-Pr
iso-Pr
iso-Pr
iso-Pr
iso-Pr
iso-Pr
1
2
3
4
5
6
7
8
DMSO
DMF
CH2Cl2
CHCl3
Et2O
THF
Toluene
Cyclohexane
DMSO/CH2Cl2
DMF/CH2Cl2
76
59
49
44
61
41
67
69
76
65
55
65
65
59
58
60
57
55
69
69
6
7
8d
9d
10e
11e
12e
Me
Ph
9d
10d
a
The reaction was carried out with a malonate (n equiv), 1 (0.5 mmol), and
Ser(O-TBDPS)-OLi (0.15 mmol) in DMSO/CH2Cl2 (1:1, 5 mL) at 25 °C for 72 h.
Isolated yield of 2 based on 1.
Determined by Chiral HPLC analysis with a Daicel CHIRALPAK AS-H or AD-H
column. Absolute configuration of 2 is shown in parentheses.
a
b
The reaction was carried out with dimethyl malonate (0.6 mmol), 1a
(0.5 mmol), and Ser(O-TBDPS)-OLi (0.15 mmol) in a solvent (1 mL) at 25 °C for 24 h.
c
b
Isolated yield of 2a based on 1a.
c
d
Determined by Chiral HPLC analysis with a Daicel CHIRALPAK AS-H column.
The reaction was carried out for 96 h.
The reaction was carried out for 7 days.
d
e
1:1 mixed solvent of DMSO/CH2Cl2 or DMF/CH2Cl2.

M. Yoshida et al. / Tetrahedron Letters 50 (2009) 7297–7299
7299
Supplementary data
O
O
O
O
H
H
O
O
Li
Li
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.033.
Si
Si
N
N
References and notes
1. For reviews see: (a) MacMillan, D. W. C. Nature 2009, 455, 304; (b) Pellissier, H.
Tetrahedron 2007, 63, 9267; (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138; (d) Houk, K. N.; List, B., Ed. A special issue on asymmetric
organocatalysis; Acc. Chem. Res. 2004, 37, 487; (e) Asymmetric Organocatalysis;
Berkessel, A., Gröger, H., Eds.; Wiley-VCH: Weinheim, 2005.
2. For reviews on organocatalysis using a primary amines, see: (a) Xu, L.-W.; Luo,
J.; Lu, Y. Chem. Commun. 2009, 1807; (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047; (c) Chen, Y.-C. Synlett 2008, 1919.
3. (a) Yang, Y.-Q.; Zhao, G. Chem. Eur. J. 2008, 14, 10888; (b) Wascholowski, V.;
Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Eur. J. 2008, 14, 6155; (c) Wang,
Y.; Li, P.; Liang, X.; Ye, J. Adv. Synth. Catal. 2008, 350, 1383; (d) Ma, A.; Zhu, S.;
Ma, D. Tetrahedron Lett. 2008, 49, 3075; (e) Palomo, C.; Landa, A.; Mielgo, A.;
Oiarbide, M.; Puente, Á.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431; (f)
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661;
(g) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520; (h)
Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805; (i) Yamaguchi, M.;
Shiraishi, T.; Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1176; (j)
Yamaguchi, M.; Yokota, N.; Minami, T. J. Chem. Soc., Chem. Commun. 1991, 1088.
4. (a) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett. 2005, 7, 3195; (b)
Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299.
Figure 1. Plausible reaction intermediate.
amount of di-iso-propyl malonate to 2 equiv to enone 1a, the yield
of 2d was improved to 83% without a significant loss of selectivity
(Table 4, entry 6). The Michael addition reaction of di-iso-propyl
malonate with 1a was completed within 96 h to give the product
2d in 92% yield with 79% ee (Table 4, entry 8). Cycloheptenone
(1b) also gave the Michael adduct 2e in a good yield with high
enantioselectivity (96%, 87% ee) (Table 4, entry 9). Although the
reaction of cyclopentenone (1c) was not completed within 7 days,
moderate selectivity was observed (Table 4, entry 10).11 Michael
addition reactions of acyclic enones, benzalacetone (1d), and chal-
cone (1e) with di-iso-propyl malonate proceeded slowly to afford
the products 2g (63%, 70% ee) and 2h (47%, 10% ee) with polar
by-products, respectively (Table 4, entries 11 and 12). Probably,
chalcone could not efficiently form an imine with the catalyst.
A plausible reaction intermediate for the Michael addition reac-
tion using 1a is shown in Figure 1. As previously reported for
imine-based primary amine catalysis,2a,c the present Michael addi-
tion of malonates with enones also proceeds via the formation of
imine. Although (E)- and (Z)-stereoisomers of imine can be formed,
a relatively bulky methylene group comes to the less-hindered side
rather than the vinyl group. The Lewis acidic lithium cation coordi-
nates with the nitrogen atom of imine to reduce the electron den-
sity of the b-carbon and to hold the side chain of the amino acid on
the Re-face of the imine. Therefore, a malonate attacks from the Si-
face of the imine to give (S)-Michael adduct selectively. Probably, a
small and Lewis acidic lithium cation can coordinate more strongly
with the nitrogen atom than can other alkali metal cations.
In summary, we found that a primary amino acid lithium salt
worked as a catalyst for the asymmetric Michael addition of
malonates to enones. A lipophilic amino acid lithium salt, Ser(O-
TBDPS)-OLi, was found to be an effective catalyst, and various
1,5-ketoesters were synthesized in good yields with moderate to
high enantioselectivity.
5. (a) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Org. Lett. 2009,
11, 753; (b) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am.
Chem. Soc. 2006, 128, 12652.
6. (a) Chen, D.; Chen, Z.; Xiao, X.; Yang, Z.; Lin, L.; Liu, X.; Feng, X. Chem. Eur. J.
2009, 15, 6807; (b) Kobayashi, S.; Yamaguchi, M.; Agostinho, M.; Schneider, U.
Chem. Lett. 2009, 38, 296; (c) Kantam, M. L.; Ranganath, K. V. S.; Mahendar, K.;
Chakrapani, L.; Choudary, B. M. Tetrahedron Lett. 2007, 48, 7646; (d) Park, S.-Y.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 2815; (e)
Mori, K.; Oshiba, M.; Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. New J. Chem.
2006, 30, 44; (f) Guo, R.; Chen, X.; Elpelt, C.; Song, D.; Morris, R. H. Org. Lett.
2005, 7, 1757; (g) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127,
516; (h) Annamalai, V.; DiMauro, E. F.; Carroll, P. J.; Kozlowski, M. C. J. Org.
Chem. 2003, 68, 1973; (i) Velmathi, S.; Swarnalakshmi, S.; Narasimhan, S.
Tetrahedron: Asymmetry 2003, 14, 113; (j) Prabagaran, N.; Sundararajan, G.
Tetrahedron: Asymmetry 2002, 13, 1053; (k) Jha, S. C.; Joshi, N. N. Tetrahedron:
Asymmetry 2001, 12, 2463; (l) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.
Tetrahedron Lett. 2001, 42, 8515; (m) Minickam, G.; Sundararajan, G.
Tetrahedron: Asymmetry 1997, 8, 2271; (n) Arai, T.; Sasai, H.; Aoe, K.;
Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. 1996, 35, 104.
7. Sato, A.; Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242.
8. Li, P.; Yamamoto, H. Chem. Commun. 2009, 5412.
9. (a) Teo, Y.-C.; Lau, J.-J.; Wu, M.-C. Tetrahedron: Asymmetry 2008, 19, 186; (b)
Teo, Y.-C.; Chua, G.-L. Tetrahedron Lett. 2008, 49, 4235; (c) Wu, X.; Jiang, Z.;
Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812; (d) Cheng, L.; Wu, X.; Lu, Y.
Org. Biomol. Chem. 2007, 5, 1018; (e) Aratake, S.; Itoh, T.; Okano, T.; Nagae, N.;
Sumiya, T.; Shoji, M.; Hayashi, Y. Chem. Eur. J. 2007, 13, 10246; (f) Itagaki, N.;
Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185.
10. Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim,
2000.
11. The imine-based catalytic asymmetric Michael addition reaction of malonates
to cyclopentenone usually resulted in lower yields and selectivity than
cyclohexenone or cycloheptenone. See Ref. 3b,h.
Acknowledgment
This work was partly supported by the Global COE Program
(Project No. B01: Catalysis as the Basis for Innovation in Materials
Science) from the Ministry of Education, Culture, Sports, Science
and technology, Japan.