C2-symmetrie chiral malonamides for asymmetric Michael reaction

Article abstract of DOI:10.1246/cl.2008.432

Described is the design and preparation of chiral C₂-symmetric malonamides and their application to asymmetric conjugate addition to enone. The mechanism of partial racemization observed in the course of hydrolysis-decarboxylation step is also

Full text of DOI:10.1246/cl.2008.432

432
Chemistry Letters Vol.37, No.4 (2008)
C2-Symmetric Chiral Malonamides for Asymmetric Michael Reaction
Sung-Ji Kim,1 Kyoungyim Lee,1 Sang-sup Jew,1 Hyeung-geun Park,ꢀ1 and Byeong-Seon Jeongꢀ2
1Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
2College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
(Received December 19, 2007; CL-071409; E-mail: hgpk@snu.ac.kr, jeongb@ynu.ac.kr)
O
O
O
Described is the design and preparation of chiral C2-sym-
BnO2C
RO2C
CO2Bn
CO2R
O
O
DEPC, Et3N
+
CO2Bn
H HCl
N
N
metric malonamides and their application to asymmetric conju-
gate addition to enone. The mechanism of partial racemization
observed in the course of hydrolysis–decarboxylation step is also
elucidated.
N
DMF, rt, 12 h, 95%
HO
OH
5
6
7
O
H2, Pd/C
MeOH, rt, 2 h, 99%
ROH, DCC, DMAP
CH2Cl2, rt, 12 h
Diacid
N
N
8
9, R = Et (85%)
10, R = t-Bu (82%)
The Michael reaction is one of the most efficient C–C bond-
forming reactions by virtue of its simple, efficient, and atom-eco-
nomical property.1 Malonyl functionality is an efficient and
readily available source of carbon nucleophile since it can form
its enolate under mild reaction conditions, which is due to effec-
tive stabilization of the enolate by two neighboring carbonyl
moieties. Many efforts have been made on the asymmetric Mi-
chael reaction of malonyl carbanion to various ꢀ,ꢁ-unsaturated
systems.2 Optically pure proline has shown its highly versatile
talents in a variety of asymmetric organic reactions and is now
thought to be one of the most essential elements to design new
asymmetric organic transformations.3 To date, proline by itself
or proline-derived catalysts or additives have been used for the
asymmetric Michael addition of malonates to electron-deficient
olefins.4
The feature of our strategy to this goal lies in an employment
of chiral malonyl anion as a Michael donor which is expected to
stereoselectively attack ꢁ-carbon of ꢀ,ꢁ-unsaturated carbonyls.
For this purpose, we adopted the advantages of proline to design
chiral malonyl nucleophile (Scheme 1). Two identical optically
pure proline moieties were fused into malonyl skeleton through
amide-bond affording chiral C2-symmetric malonamide 1. We
envisaged that stereoselectivity would be achieved in conjugate
addition of 1 to enone 2 through the proposed transition state
shown in Figure 1.
Scheme 2. Preparation of C2-symmetric chiral malonamides.
O
O
EtO2C
CO2Et
O
N
O
N
O
O
EtO2C
CO2Et
LiBr, Et3N, CH2Cl2
+
N
N
Conditions
2
9
11 (90-95%)
O
, p-TsOH
OH
HO
1) 6 M-HCl, reflux, 14 h
O
O
2) CH2N2, Et2O, 0 °C, 10 min
87% (2 steps)
Toluene, reflux, 1 h, 95%
CO2Me
CO2Me
12
13
Scheme 3. Asymmetric Michael addition of chiral malonyl
nucleophile to enone.
ester variant 9 to the asymmetric conjugate addition to (E)-3-
penten-2-one (2) (Scheme 3). The reaction was performed with
chiral nucleophile 9 (1.0 equiv) and enone 2 (2.0 equiv) in the
presence of triethylamine (1.0 equiv) and lithium bromide (5.0
equiv) in dichloromethane affording 11 in 90–95% yields. De-
tachment of the proline moieties from the Michael adduct 11
and subsequent decarboxylation of the resulting 1,3-dicarboxylic
acid were performed by treatment with 6 M HCl, followed by es-
terification with diazomethane to give optically enriched ꢂ-keto
ester 12. The absolute configuration of 12 was assigned to be R
by comparison of the value of specific rotation with the literature
data,4b,5 which indicates that the reaction might proceed by the
proposed transition state shown in Figure 1. The level of asym-
metric induction of this conjugate addition was determined using
1H NMR experiment by measuring diastereomeric ratio of one of
the two methylene protons located on ꢀ-position to ester carbon-
yl in 13 which was obtained by ketalization with optically pure
(2R,3R)-2,3-butanediol.
Chiral C2-symmetric malonamide Michael donors 7–9 were
prepared from malonic acid (5) and L-proline benzyl ester hydro-
chloride (6) as shown in Scheme 2. We first employed the ethyl
O
O
CO2R
H+
N
Michael
Addition
O
O
RO2C
CO2R
O
O
+
N
N
N
O
CO2R'
Table 1 summarizes the variation of diastereoselectivity of
the asymmetric Michael addition step (2 + 9 ! 11) with the
change of reaction temperature. A steady increase of the stereo-
selectivity was observed as the reaction temperature lowered to
ꢁ43 ꢂC. No further increase in diastereoselectivity was achieved
below ꢁ43 ꢂC. The other chiral Michael donors 7 and 10 also
gave the optically enriched Michael adducts under the same re-
action conditions (Entries 6 and 7), however, a slightly decreas-
ed enantioselectivity was obtained in each case.
1
2
CO2R
4
3
Scheme 1. Michael addition of chiral malonamide 1 to enone 2.
OR
O
O
H
N
N
Li
Li
O
H
O
Li
O
RO
Interestingly, we found that optical purity of the initially
formed Michael adduct 11 gradually decreased during acid cat-
alyzed hydrolysis–decarboxylation process. In order to confirm
Figure 1. Proposed transition state of Michael addition of C2-
symmetric chiral malonamide to (E)-3-penten-2-one.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.4 (2008)
433
Table 1. Stereoselectivity in asymmetric Michael addition
(2 + 9 ! 11)a
H
O
O
O
H+
O
H+
-CO2
O
OH
Temp/ꢂC
Time/h
Yield/%
de/%
OH
Entry
OH
H
O
O
OH
1
2
3
4
rt
0
0.5
2
4
10
18
18
20
95
95
94
92
90
90
90
58
64
75
87
87
82
85
A
B
C
H
ꢁ10
ꢁ43
ꢁ78
ꢁ78
ꢁ78
O
O
O
H+
-CO2
OH
5
O
O
O
H
O
HO
6b
7b
CO2H
O
E
F
D
H+
aThe reaction was carried out with 2.0 equiv of (E)-3-penten-
2-one (2), 1.0 equiv of C2-symmetric chiral malonamide 9,
1.0 equiv of triethylamine, and 5.0 equiv of lithium bromide
in dichloromethane under the given conditions. Benzyl- (7,
for Entry 6) and tert-butyl ester derivatives (10, for Entry 7)
were used as chiral Michael donors instead of 9, respectively.
H2O
O
O
H
b
OH
O
H
G
Figure 2. Plausible mechanism of racemization.
1) AcOH-HCl (1:1), reflux,1h
LiBr, Et3N, CH2Cl2
11
2
+
9
O
1) 6 M-HCl
2) CH2N2, Et2O, 0 °C, 10 min
0 °C, 2 h, 85%
O
O
O
O
HO
OH
reflux, 20 h
2) CH2N2, Et2O
0 °C, 10 min
p-TsOH, Toluene
reflux, 1 h
CO2Me
CO2Me
13 (87% ee)
CO2Me
13' (56% ee)
O
O
O
O
HO
OH , p-TsOH
+
CO2Me
12'
Toluene, reflux, 1 h, 95%
CO2Me
CO2Me
14 (45%)
CO2Me
CO2Me
Scheme 4. Partial racemization.
12 (40%)
15 (79% ee)
this racemization, we repeated the acidic hydrolysis of 87% ee
13, methyl esterification and ketalization to give 130 as shown
in Scheme 4. The enantiomeric excess of 130 has decreased
to 56% ee which strongly supports the partial racemization
occurred in acidic medium.
Scheme 5. New process for the exact evaluation of stereoselec-
tivity.
process was developed for the exact measurement of stereoselec-
tivity in the Michael addition step.
Based on our experiments, a plausible racemization
mechanism in acidic condition is described in Figure 2. 1,3-Di-
carboxylic acid A obtained from acid-catalyzed hydrolysis of
Michael adduct is converted to monoacid B through decarbox-
ylation. Then, B undergoes acid-catalyzed Dieckmann type
condensation where chirality disappears as B is transformed
to achiral 5-methylcyclohexane-1,3-dione (F). Finally, F goes
back to H, a racemic form of B, through retro-Dieckmann proc-
ess. Another possible way of racemization proceeds in sequence
of Dieckmann condensation (A ! E), decarboxylation
(E ! F), retro-Dieckmann process (F ! H).
This work was supported by the Yeungnam University
Research Grants in 2007 (Grant No. 207-A-235-196).
References and Notes
1
a) P. Permutter, Conjugate Addition Reaction in Organic
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2
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According to the racemization mechanism in Figure 2, 1,3-
dicarboxylic acid A is not influenced by racemization, which in-
dicates that diacid A can reflect the real stereoselectivity gener-
ated in the course of Michael addition. Based on this hypothesis,
we prepared diester 15 from the Michael adduct 11, obtained
from the asymmetric Michael reaction between 2 and 9
at 0 ꢂC, by a short-time acidic hydrolysis with AcOH–HCl
(1:1) followed by sequential esterification and ketalization
(Scheme 5). The enantioselectivity of the Michael addition
performed at 0 ꢂC was found to be 79% ee. Compared with the
previous result (64% ee) shown in Entry 2 in Table 1, this
revised process would be more suitable for exact evaluation of
this type of Michael addition.
In summary, an asymmetric conjugate addition of chiral
malonyl nucleophiles to enone was developed in which chiral
C2-symmetric malonamides were employed as chiral Michael
donors. Optically enriched ꢂ-keto ester was obtained with high
level of enantioselectivity up to 87% ee. We found that the
acid-catalyzed Dieckmann ring closure occurred during hydrol-
ysis–decarboxylation step causes partial racemization. A revised
3
4
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Published on the web (Advance View) March 8, 2008; doi:10.1246/cl.2008.432