A ternary complex reagent for an asymmetric Michael reaction of lithium ester enolates with enoates

Article abstract of DOI:10.1016/j.tetlet.2008.05.101

A lithium ester enolate was activated by both a chiral etheral ligand and a lithium amide to form a ternary complex reagent that reacted with enoates giving the corresponding Michael addition products in reasonably high enantioselectivity of up to 97% ee.

Full text of DOI:10.1016/j.tetlet.2008.05.101

Tetrahedron Letters 49 (2008) 4582–4584
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Tetrahedron Letters
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A ternary complex reagent for an asymmetric Michael reaction
of lithium ester enolates with enoates
*
Yasutomo Yamamoto, Hirokazu Suzuki, Yorinobu Yasuda, Akira Iida, Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A lithium ester enolate was activated by both a chiral etheral ligand and a lithium amide to form a ternary
complex reagent that reacted with enoates giving the corresponding Michael addition products in rea-
sonably high enantioselectivity of up to 97% ee.
Received 16 April 2008
Revised 20 May 2008
Accepted 22 May 2008
Available online 27 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The activation of nucleophilic reagents1 has been the major
challenge of organic chemistry. Lewis basic chiral ethereal or ami-
no molecules are used as external ligands for preparation of active
nucleophiles in asymmetric reaction.2 We have developed a variety
of chiral organic ligands for the activation of organometallics.3
Among these organoligands a chiral diether 1 has been shown to
mediate an asymmetric Mannich reaction of lithium ester enolate
with imines by forming a ternary complex reagent comprised of
lithium enolate-1-lithium amide.4 Since the successful enantiose-
lective asymmetric Michael reactions of unstabilized lithium eno-
lates are quite limited in the number,5 we applied the ternary
complex reagent into the Michael reaction of lithium ester enolates
with unactivated simple enoates.6 We describe herein the highly
enantioselective Michael reaction of a ternary complex reagent of
a lithium ester enolate with enoates affording the Michael adducts
in high enantioselectivity of up to 97% ee.
We began our studies with the Michael reaction of isobutyrate 2
with crotonate 3a in the presence of a chiral etheral ligand 1 in tol-
uene (Table 1). The lithium enolate 4,7 generated from 2 by treat-
ing with an equivalent of lithium diisopropylamide (LDA), reacted
at À78 °C for 0.5 h to give the desired Michael adduct 5a with 60%
ee quantitatively (entry 1). The same level of enantioselectivity,
65% and 63% ee, obtained by using lithium isopropylcyclohexyla-
mide (LICA) and dicyclohexylamide (LDCA) as a lithiating base,
suggests that the presence of an amine does not affect the
enantioselectivity.
Table 1
Chiral ligand control in asymmetric Michael addition
Lithium
OLi
1.3 eq
amide
Me
Me
Me
(iPr)2HCO
(iPr)2HCO2C
2 1.3 eq
Me
amine
4 1.3 eq
Ph
Ph
Me
MeO
OMe
1
(iPr)2HCO2C
CO2t-Bu
1.7 eq
CO2t-Bu
+
Me
Me Me
toluene
—78 °C, 0.5 h
3a
5a
Entry
Lithium amide
Yield (%)
ee (%)
1
2
3
LDA
LICA
LDCA
99
93
94
60
65
63
Dramatic improvement in enantioselectivity was observed by
using 2 equiv of LDA as a lithiating agent to give 5a with 94% ee
in 78% yield (Table 2, entry 1). The enantioselectivity was highly
dependent on a lithium amide used ranging from 94% ee to 68%
ee (entries 1–4). It is worthy to note that the existence of an equi-
molar amount of a lithium amide afforded 5a with higher enanti-
oselectivity relative to those obtained in the absence of a lithium
amide.
The higher reactivity of a ternary complex of lithium enolate, 4–
1-lithium amide, became apparent from the reaction with cinna-
mate 3b at À78 °C for 0.5 h to give 5b with 78% ee in 81% yield
(Scheme 1). The absence of LDA resulted in the poorer reactivity
to give 4% yield of 5b with 12% ee. A LDA assisted lithium enolate
4 was also powerful to give racemic 5b in 72% yield.8
LDA
LICA
LDCA
LDEA
N
Li
N
N
N
Li
Li
Li
* Corresponding author. Tel.: +81 75 753 4553; fax: +81 75 753 4604.
E-mail address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.101

Y. Yamamoto et al. / Tetrahedron Letters 49 (2008) 4582–4584
4583
Table 2
Table 3
Both of chiral ligand and lithium amide control in asymmetric Michael reaction of
lithium enolate
Lithium amide dependency of reaction efficiency
OLi
Me
Lithium
OLi
2.6
eq
(iPr)2HCO
CO2t-Bu
(iPr)2HCO
amide
Ph
Ph
Me
Me
Me
Me
1.3 eq
(iPr)2HCO2C
CO2t-Bu
3b 1.0 eq
(iPr)2HCO2C
2 1.3 eq
4
Me
Me Me
toluene
—78 °C, 0.5 h
amine
+
4 1.3 eq
1 1.7 eq
+
5b
Lithium
1.3 eq
amide
Lithium
1.3 eq
amide
+
Ph
Ph
Entry
Lithium amide
Yield (%)
ee (%)
Me
MeO
OMe
1
1
2
3
LDA
LICA
LDCA
81
95
96
78
90
93
(iPr)2HCO2C
CO2t-Bu
1.7 eq
CO2t-Bu
+
Me
Me Me
toluene
3a
5a
—78 °C, 0.5 h
Entry
Lithium amide
Yield (%)
ee (%)
Ph
Me
Ph
1
2
3
4
LDA
78
63
74
73
94
83
71
68
S
1. 10% HCl/dioxane
2. BH3-Me2S/THF
3. n-BuLi/THF
LICA
LDCA
LDEA
(iPr)2HCO2C
CO2t-Bu
Me
O
Me Me
O
63%
6
(S)- 90% ee
5b 90% ee
[α]25D —62.7
(c 2.04, CHCl3)
Ph
The selection of a lithium amide was also found to be important
for the realization of high enantioselectivity (Table 3). A ternary
complex reagent 4–1-LDCA gave 5b with 93% ee in 96% yield (entry
3).
The absolute configuration of 5b was unambiguously deter-
mined by correlating 5b and 6 with (R)-79 of the established con-
figuration (Scheme 2). Other Michael products are assigned
tentatively by analogy.
R
Ph
1. LDA, MeI/THF
Me
R
2. LDA, MeI, HMPA/THF
22%
Me
O
O
O
O
(R)-7 20% ee
6
(R)- 20% ee
α 25
D —11.7
(c 1.74, CHCl3)
[ ] D —1.17
α 25
[
]
(c 4.29, CHCl3)
The promisingly high efficiency of the ternary complex of the
lithium enolate was also confirmed by the reaction with 3d to give
the corresponding Michael adduct 5d in high enantioselectivity of
Scheme 2. Correlation of 5b and 6 with 7.
97% ee (Table 4, entry 5). The Michael addition with
a, b, c, d-
Table 4
unsaturated ester 3c was 1,4-selective to give 5c with 93% ee in
Asymmetric Michael reaction
90% yield (entry 2).
OLi
A lithium enolate 8 derived from acetate, the most fundamental
of alkanoates, was applicable in the Michael reaction as a ternary
complex reagent (Table 5). The reaction with tert-butyl crotonate
3a proceeded to give 10a (R1 = Me) with 62% ee in 20% yield (entry
1). A decreasing yield was attributable to the conjugate addition of
Me
CO2t-Bu
(iPr)2HCO
R
R
Me
1.3 eq
(iPr)2HCO2C
CO2t-Bu
3c,d 1.0 eq
toluene
78 °C, 0.5-1.5 h
4
Me Me
+
—
LDA3b and
c-deprotonation of 3a. Replacement of tert-butyl ester
1 1.7 eq
+
5c,d
with a bulky and much more electron-withdrawing BHA (3,5-di-
tert-butyl-4-hydroxyanisyl) ester 9 improved the reaction effi-
ciency. The reaction with crotonate 9a (R1 = Me, R2 = BHA) pro-
Lithium
1.3 eq
amide
ceeded even in the absence of
quantitative yield of 11a (R = Me), however, with only 19% ee (en-
try 2). A ternary reagent using LDA as a lithium amide gave 11a
a
lithium amide to give
a
Entry
3
R
Lithium amide
LDA
LICA
LDCA
LDA
5
Yield (%)
ee (%)
1
2
3
4
5
6
3c
3c
3c
3d
3d
3d
MeCH@CH
MeCH@CH
MeCH@CH
iPr
iPr
iPr
5c
5c
5c
5d
5d
5d
85
90
83
63
82
62
88
93
91
91
97
88
LICA
LDCA
Ph
CO2t-Bu
(iPr)2HCO2C
Ph
CO2t-Bu
3b 1.0 eq
4
1
LDA
+
+
Me Me
1.3 eq
1.7 eq 1.3 eq
toluene
with 64% ee in unsatisfactory 31% yield, again due to the
c
-depro-
—78 °C, 0.5 h
5b
tonation (entry 3). Finally, the use of LHMDS as a poor nucleophilic
and basic lithium amide was found to improve the chemical yield
to 94% of Michael adduct 11a with 77% ee (entry 4). Other two eno-
ates 9c, d were converted to Michael adducts 11c, d with 69% and
60% ee quantitatively (entries 5 and 6). For the reaction with cinna-
mate 9b a bulky lithium amide was the best to give 11b with 81%
ee (entry 7).
81%, 78% ee
4
1
+
4%, 12% ee
72%
1.3 eq
1.7 eq
4
LDA
+
1.3 eq
1.3 eq
The absolute configuration of 11a(R1 = Me) was unambiguously
determined by correlating with (S)-1210 of the established config-
Scheme 1. Higher reactivity of lithium enolate assisted by chiral ligand and lithium
amide.

4584
Y. Yamamoto et al. / Tetrahedron Letters 49 (2008) 4582–4584
Table 5
Acknowledgments
Asymmetric Michael reaction of acetate
OLi
This research was partially supported by the 21st Century Cen-
CO2R2
R1
3a
ter of Excellence Program ‘Knowledge Information Infrastructure
for Genome Science’ and a Grant-in-Aid for Young Scientist (B)
from JSPS, a Grant-in-Aid for Scientific Research on Priority Areas
‘Advanced Molecular Transformations’ from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and ‘Targeted
Proteins Research Program’ from Japan Science and Technology
Agency.
(iPr)2HCO
8
R1
R
1 = Me, R2 = t-Bu
2 = BHA
toluene
(iPr)2HCO2C
CO2R2
+
1
9a-d
R
+
Lithium
amide
10a R1 = Me, R2 = t-Bu
11a-d R2 = BHA
Entry
3/9
R
Lithium
amide
Temperature
(°C)
Time
(h)
Yield
(%)
ee
(%)
References and notes
1
2
3
4
5
6
7
3a
9a
9a
9a
9c
9d
9b
Me
Me
Me
Me
MeCH@CH
iPr
LDA
None
LDA
LHMDS
LHMDS
LHMDS
TMSBnNLi
À78
À40
À78
À40
À40
À40
À78
0.5
4
16
4
18
16
1
20
99
31
94
99
99
28
62
19
64
77
60
69
81
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Ph
Me
1. CAN/aq MeCN
2. BH3-Me2S/THF
3. KOH/aq MeOH
4. benzene reflux
S
Me
(iPr)2HCO2C
11a
CO2BHA
O
O
(S)-
12
44%
[α]27
(c 1.87, CHCl3)
—15.8
70% ee
D
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Scheme 3. Correlation of 11a with (S)-12.
uration (Scheme 3). The same sense of enantiofacial differentiation
of enolates 4 and 8 implies the operation of similar stereochemical
control of ternary complex reagent.
In summary, the ternary complex reagent of a lithium ester
enolate, comprised of
a lithium ester enolate-chiral diether
ligand–lithium amide, was found to be the most reactive than
the binary reagent and to be the efficient Michael donor giving
the corresponding adduct in reasonably high enantioselectivity of
up to 97% ee.