Rate acceleration of triethylamine-mediated guanidine-catalyzed enantioselective Michael reaction

Article abstract of DOI:10.1002/adsc.200800423

A chiral bicyclic guanidine was found to be an excellent catalyst for enantioselective Michael reactions. It was observed that additives such as non-chiral amines could accelerate the rate of reaction. When triethylamine (Et₃N) was as used as the solvent, the reaction rate can be increased up to 1000 times without compromising the enantioselectivity. Michael acceptors such as 2-cyclopenten-1-one 2 and N-alkylmaleimides were investigated, with various commercially available Michael donors such as dialkyl malonates and benzoylactetates. Michael adducts were obtained in excellent enantiomeric excesses (up to 96%) and yields (up to 99%).

Full text of DOI:10.1002/adsc.200800423

FULL PAPERS
DOI: 10.1002/adsc.200800423
Rate Acceleration of Triethylamine-Mediated Guanidine-
Catalyzed Enantioselective Michael Reaction
Zhiyong Jiang,a,b Weiping Ye,a,b Yuanyong Yang,a and Choon-Hong Tana,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Republic of Singapore
Fax : (+65)-6779-1691; e-mail: chmtanch@nus.edu.sg
Z. J. and W. Y. made equal contributions to this work
b
Received: July 8, 2008; Published online: October 1, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800423.
Abstract: A chiral bicyclic guanidine was found to commercially available Michael donors such as di-
be an excellent catalyst for enantioselective Michael
ACHTREaUNG lkyl malonates and benzoylactetates. Michael ad-
reactions. It was observed that additives such as non- ducts were obtained in excellent enantiomeric ex-
chiral amines could accelerate the rate of reaction. cesses (up to 96%) and yields (up to 99%).
When triethylamine (Et3N) was as used as the sol-
vent, the reaction rate can be increased up to 1000
times without compromising the enantioselectivity. Keywords: asymmetric catalysis; chiral bicyclic gua-
Michael acceptors such as 2-cyclopenten-1-one 2 and nidines; Michael addition; organic catalysis; triethyl-
N-alkylmaleimides were investigated, with various amine (Et3N)
Introduction
another example, tertiary amines such as tributyl-
AHCTREaNUG mine and Et3N were utilized as co-solvents, and led
It is well known that the efficiency of asymmetric or- to improvement in the diastereoselectivities upon the
ganometallic catalysts can often be improved through addition of n-BuLi to chiral aldehydes.[6] It was also
the use of additives or co-catalysts.[1] As such, catalyst demonstrated that a higher rate of ketone enolization
loading, turnover number, yield and enantioselectivity was achieved with Et3N as solvent and LHMDS (lith-
can be tuned and optimized. They can be employed ium hexamethyldisilazide) as a strong base.[7] Et3N
to alter the reaction pathway leading to less side was suggested to have promoted the formation of
products or different products. Nitrogen bases are dimer-based transition states.
among the most common additives.[1] Although orga-
We have recently shown that chiral bicyclic guani-
nocatalysis has made tremendous progress in recent dines, such as 1 (Table 1), are efficient catalysts for
years,[2] the use of additives and co-catalysts in orga- Diels–Alder, Michael, phospha-Michael and protona-
nocatalysis has yet to be systematically investigated. tion reactions.[8] We have observed that Michael reac-
A good example is the use of Brønsted acids as addi- tions using commercially available dialkyl malonates
tives in amine-catalyzed aldol reactions to promote gave very low reactivities and the Michael adducts ob-
the formation of enamines and iminiums.[3] Another tained had moderate enantioselectivities. Therefore,
example would be the use of peptides with proline as dialkyl dithiomalonates were introduced in our previ-
co-catalyst in the Baylis–Hilman reaction of alkyl ous work to overcome the problem.[8b] These donors
vinyl ketones.[4]
have much lower pKa values and thus higher acidities
Brønsted bases are usually utilized to remove acids and higher activities. We are still very keen to develop
generated in situ, but sometimes their role is not as methodology for the commercially available dialkyl
well defined. It has been demonstrated that the addi- malonates and therefore we continue to optimize the
tion of 5 equivalents of Hunigꢀs base greatly acceler- reaction.
ated the reaction between allyltrichlorosilane and al-
A particularly useful but slow reaction was the ad-
dehydes catalyzed by axially chiral N,N’-dioxides. It dition of 1,3-dicarbonyl compounds to 2-cyclopenten-
was postulated that the base might have promoted 1-one 2. This reaction provides a direct approach to
dissociation of the catalyst from the silicon atom.[5] In chiral cyclopentanones, allowing access to a variety of
Adv. Synth. Catal. 2008, 350, 2345 – 2351
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Table 1. Michael addition of dimethyl malonate 3a to 2-cyclopenten-1-one 2 using different solvents and additives.
Entry
Solvent
Additive
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
toluene
THF
CH2Cl2
PhCF3
toluene
none
none
none
none
96
144
96
96
108
92
91
82
80
73
78
73
58
70
70
t-BuOH (1 equiv.)
6
toluene
72
99
49
7
8
toluene
toluene
12
72
95
88
67
24
9
toluene
toluene
toluene
toluene
Et3N
pyridine (1 equiv.)
ACHTRE(UNG i-Pr)2EtN (1 equiv.)
Et3N (1 equiv)
toluene:Et3N (9:1)
none
72
72
72
12
9
80
99
99
86
92
78
80
81
82
82
10
11
12
13
[a]
Isolated yield.
Chiral HPLC.
[b]
natural products.[9] Examples using organometallic ly (Table 1, entry 5). It was known that sulfonamides
catalysts such as Al-Li-BINOL,[10] Al-Li-amino- or thioureas could activate the Michael acceptor
diols,[11] La-linked-BINOL[12] and Ru-amido complexs through hydrogen bonding.[17] Hence, two sulfon-
had been reported.[13] Organocatalytic methods in-
ACHTREaUNG mides were examined as additive (Table 1, entries 6
clude the use of (2-pyrrolidyl)alkylammonium hy- and 7). The reaction rate was increased as expected
droxide derivatives[14] and Cinchona alkaloid deriva- but the ee decreased.
tives.[15] Herein, we report a highly enantioselective
As amidines and guanidines are known to absorb
version using chiral bicyclic guanidine 1 as catalyst carbon dioxide to form zwitterions,[18] the addition of
and mediated by Et3N.
non-chiral bases like amines may speed up the reac-
tion by assisting the regeneration of the guanidine
catalyst. One equivalent of a series of amines such as
Results and Discussion
N,N,N’,N’-tetramethyldiaminomethane, pyridine, Et
Pr)2N, and Et3N was used as additive (Table 1, en-
ACHTREUNG(i-
In the presence of 20 mol% of guanidine 1, the addi- tries 8–11). All the reactions were completed within
tion of dimethyl malonate 3a to 2-cyclopenten-1-one three days, much faster than without the additives.
2 was found to give a good yield using toluene as sol- The ees were maintained with the exception of
vent at room temperature (Table 1, entry 1). The N,N,N’,N’-tetramethyldiaminomethane (entry 8). Con-
adduct 4a was obtained with an ee of 78% but the re- sidering that Et3N has a low boiling point and subse-
action was slow (96 h). Solvents such as THF, CH2Cl2 quent removal from the reaction mixture may not be
and p-CF3Ph (Table 1, entries 2–4) were found to give much of a problem, the amount used was increased.
lower ees than toluene (Table 1, entry 1). Next, we The reaction rate improved tremendously when Et3N
screened several additives (Table 1, entries 5–8). Ad- was used as a 1:9 co-solvent with toluene (Table 1,
dition of t-BuOH[16] decreased the ee and yield slight- entry 12) and reaction rate was fastest when Et3N was
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Triethylamine-Mediated Guanidine-Catalyzed Enantioselective Michael Reaction
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Table 2. Chiral bicyclic guanidine 1-catalyzed Michael addition of malonates 3a–d to 2-cyclopenten-1-one 2.
Entry
3
Time [h]
Product
Yield [%][a]
ee [%][b]
1
2
3
4
3a [R=Me]
3b [R=Et]
3c [R=Bn]
3d [R=i-Pr]
120
120
120
192
4a
4b
4c
4d
94
93
99
84
91
92
92
96
[a]
Isolated yield.
Chiral HPLC.
[b]
used as solvent (Table 1, entry 13). More importantly,
The pKa values[19] of dialkyl malonates 3a–d fall
achieved without within the range 11.6–13.8 and the pKa of the conju-
gate acid of guanidine 1 should be in the range of
the increase in reaction rate was
compromising the enantioselectivity.
ACHTREUNG
We conducted further experiments at a lower tem- 13.3–14.4.[20] With lower pKa values ranging from 8.7
perature of À208C using Et3N as solvent and found to 10.0, benzoylacetates 3e–j should be more reactive
that ee was increased to 91% (Table 2, entry 1). Other due to their increased acidities. The possibility of side
commercially available dialkyl malonates 3b–d were reaction catalyzed by Et3N (pKa value of its conjugate
investigated and similar level of enantioselectivities acid is 10.6) should also be considered as it might
were observed. The reactions of diethyl malonate 3b compromise the enantioselectivity. Therefore, with
and dibenzyl malonate 3c were completed within ethyl benzoylacetates as donor, a comparison of enan-
120 h (Table 2, entries 2 and 3). The reaction of the tioselectivity in both toluene and Et3N was necessary.
more hindered substrate, diisopropyl malonate 3d As evident from Table 3, the reaction rate was about
gave the highest level of ee at 96% (Table 2, entry 4). 2–3 times faster in Et3N than in toluene, and for 3e–i
Table 3. Michael addition of various ethyl benzoylacetates 3e–j to 2-cyclopenten-1-one 2.
Entry
4
Solvent
Time [h]
Product
Yield [%][a]
ee [%][b,c]
1
2
3
4
5
6
7
8
3e [R=Ph]
3e [R=Ph]
Et3N
toluene
Et3N
toluene
Et3N
toluene
Et3N
toluene
Et3N
toluene
Et3N
72
120
60
192
72
144
48
144
48
144
72
4e
4e
4f
4f
4g
4g
4h
4h
4i
98
25[d]
89
85
91
90
99
99
99
99
99
91
90, 93
88, 92
86, 87
91, 90
91, 92
92, 96
94, 95
92, 93
93, 93
90, 90
78, 80
93, 94
3f [R=m-MeC6H4]
3f [R=m-MeC6H4]
3g [R=p-CF3C6H4]
3g [R=p-CF3C6H4]
3h [R=p-ClC6H4]
3h [R=p-ClC6H4]
3i [R=m-ClC6H4]
3i [R=m-ClC6H4]
3j [R=p-NO2C6H4]
3j [R=p-NO2C6H4]
9
10
11
12
4i
4j
4j
toluene
120
[a]
Isolated yield.
Chiral HPLC.
dr 1:1, determined by H NMR and chiral HPLC.
30 mol% of catalyst 1 was used.
[b]
[c]
[d]
1
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(Table 3, entries 1–10) the ees were similar in both
solvents. A slight decrease in ee was observed for the
reaction of ethyl p-nitrobenzoylacetates 3j (pKa: 8.7;
Table 3, entries 11 and 12) with Et3N as solvent. An
important and common donor, 1,3-diphenylpropane-
1,3-dione 3k (pKa: 8.95), was also investigated. The
reaction rate was increased using Et3N as solvent with
a slight decrease in ee was observed [Eq. (1)].
and the ee increased to 71% [Eq. (2)]. This promising
result prompted us to continue this investigation.
Ethyl benzoylacetate 3e, a more active donor, was
found to react with N-ethylmaleimide 5a using Et3N
as solvent at À508C and in the presence of 20 mol%
1 (Table 4, entry 1). The reaction was completed in
just 5 min with 99% yield and 93% ee. Different N-al-
kylmaleimides 5b–d were also tested under these re-
action conditions (Table 4, entries 2–4). All reactions
were completed within 5 min, providing the corre-
This strategy was expanded to include other classes sponding adducts in high yields and ees. Several sub-
of Michael acceptors. As important cyclic Michael ac- stituted ethyl benzoylacetates 3f, h, k and ethyl 2-fu-
ceptors, maleimides can provide a practical route to roylacetate 3l also gave excellent results (Table 4, en-
biologically important chiral a-substituted succinimi- tries 5–8).
des.[8b,21,22] Cinchona alkaloids were found to be suita-
The bulkier and more hindered substituted cyclic b-
ble catalysts for the conjugate addition of 1,3-dicar- keto esters 3m and n were examined. No Michael ad-
bonyl compounds to N-benzylmaleimide.[21a] We had ducts were found when chiral bicyclic guanidine 1 was
also previously reported the addition of dimethyl mal- used with toluene as solvent. However, the corre-
onate 3a to N-ethylmaleimide 5a using chiral bicyclic sponding 1,4-adducts were obtained with good yields
guanidine 1 as catalyst with toluene as solvent. Low and enantioselectivities were obtained when Et3N was
yield and poor enantioselectivity were obtained.[8b] used as the solvent [Eq. (3)]. b-Keto ester 3n with an
Employing the new reaction conditions, using Et3N as ethyl group gave adduct 6k with higher enantioselec-
solvent, the reaction could be completed at À508C tivity than adduct 6j.
Table 4. Michael additions of ethyl benzoylacetates 3e–f, h, k, l to N-alkylmaleimides 5a–d.
Entry
3
5
Product
Yield [%][a]
ee [%][b,c]
1
2
3
4
5
6
7
8
3e [R=Ph]
3e [R=Ph]
3e [R=Ph]
3e [R=Ph]
3f [R=m-MeC6H4]
3h [R=p-ClC6H4]
3k [R=p-MeOC6H4]
3l [R=2-furanyl]
5a [R=ethyl]
5b [R=methyl]
5c [R=cyclohexyl]
5d [R=n-hexyl]
5a [R=ethyl]
5a [R=ethyl]
5a [R=ethyl]
5a [R=ethyl]
6b
6c
6d
6e
6f
6g
6h
6i
99
93
99
90
88
99
91
99
93, 93
93, 93
93, 93
90, 91
92, 93
90, 91
89, 89
86, 86
[a]
Isolated yield.
Chiral HPLC.
dr 1:1, determined by H NMR and chiral HPLC.
[b]
[c]
1
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Triethylamine-Mediated Guanidine-Catalyzed Enantioselective Michael Reaction
FULL PAPERS
have absorbed atmospheric carbon dioxide and the
formation of a guanidinium carbonate may result in
the catalyst being quenched was ruled out.[19] Subse-
quent experiments were conducted under stringent
conditions such as under inert nitrogen atmosphere
but reactions with toluene as solvent still remained
slow and products still were obtained with poor yield
and ee. This is thus an unlikely reason for the rate en-
hancement. The catalyst was prepared as the guanidi-
nium iodide salt and in the final step of its prepara-
We studied the reaction between ethyl benzoylace- tion AcOH was used. The possibility of acid impuri-
tate 3e and N-ethylmaleimide 5a in more detail ties in the catalyst was also ruled out as the catalyst
(Figure 1). The reaction temperatures were varied was purified using flash chromatography and was
from ambient to À508C; the ee increased from 41% freshly basified using K2CO3 just before each experi-
to 93%. As the temperature was lowered to below ment.
À508C, the ee decreased dramatically. In the absence
of the catalyst 1, at À508C, the reaction was complet-
ed in 5 min with >80% yield. This shows that signifi- Conclusions
cant background reaction can be achieved by Et3N. It
is crucial for the catalyzed reaction to be much faster In summary, the guanidine-catalyzed reaction mediat-
than the non-catalyzed reaction for high enantioselec- ed by Et3N resulted in a huge acceleration in reaction
tivity to be obtained. The selectivity of the guanidine rate. Using this new methodology, high enantioselec-
improved as the temperature was lowered. As the tivities and yields can be obtained for Michael reac-
temperature decreased beyond À508C, however, the tions which were previously unattainable due to slow
catalyzed reaction became too slow as compared to reaction rates. This includes reactions between 2-cy-
the non-catalyzed reaction that was promoted by clopenten-1-one or N-alkylmaleimides with various
Et3N. The guanidine-catalyzed reaction mediated by commercially available Michael donors such as dialkyl
Et3N was about 1000 times faster than the guanidine- malonates and benzoylactetates. This approach ex-
catalyzed reaction in toluene (<5 min vs. 60 h). We pands the range of Michael donors and acceptors that
postulate that Et3N may be involved in the stabiliza- are compatible with the bicyclic guanidine catalyst.
tion of the enolate-guanidinium complex; allowing The role of Et3N in the guanidine-catalyzed Michael
the catalyzed reaction in Et3N to proceed at a much reaction will be investigated in more detail using both
faster rate. The initial speculation that guanidine may kinetic and computational studies.
Experimental Section
General Procedure for the Michael Addition of 1,3-
Dicarbonyl Compounds (3a–k) to 2-Cyclopenten-1-
one 2 Catalyzed by Bicyclic Guanidine 1
(a) Toluene as solvent: Toluene (0.2 mL) was added to 1,3-
dicarbonyl compounds (3a–k) (0.06 mmol) and catalyst 1
(2.24 mg, 0.01 mmol). After cooling the mixture at À208C
for about 30 min, 2-cyclopenten-1-one 2 (4.2 mL, 4.2 mg,
0.05 mmol) was added. The reaction mixture was monitored
by TLC and upon complete consumption of 2, the solvent
was removed under vacuum. The crude product was directly
loaded onto a short silica gel column, followed by gradient
elution with hexane:ethyl acetate=10/1 to 4/1 to provide
products 4a–k.
(b) Et3N as solvent: Et3N (0.2 mL) was added to 1,3-dicar-
bonyl compounds (3a–k) (0.06 mmol) and catalyst
1
(2.24 mg, 0.01 mmol). After cooling the mixture at À208C
for about 30 min, 2-cyclopenten-1-one 2 (4.2 mL, 4.2 mg,
0.05 mmol) was added. The reaction mixture was monitored
by TLC and upon complete consumption of 2, the solvent
was removed under vacuum. The crude product was directly
loaded onto a short silica gel column, followed by gradient
Figure 1. Michael addition of ethyl benzoylacetate 3e to N-
ethylmaleimide 5a at different reaction temperatures.
Adv. Synth. Catal. 2008, 350, 2345 – 2351
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Zhiyong Jiang et al.
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elution with hexane:ethyl acetate=10/1 to 4/1 to provide
products 4a–k.
Reactions were conveniently performed in capped round-
bottom flasks without special precautions. Catalyst can be
recovered from the column using MeOH:CH2Cl2 (1:4) and
reused without lost of ee.
3.37–3.22 (m, 1H), 2.49 (dd, J=18.5, 7.3 Hz, 1H), 2.37–2.12
(m, 3H), 1.96 (dd, J=18.5, 11.5 Hz, 1H), 1.73–1.63 (m, 1H);
13C NMR (75 MHz, CDCl3): d=217.1, 195.0, 194.8, 136.6,
136.5, 134.0 (two peaks), 129.2, 128.9, 63.2, 43.5, 38.4, 37.9,
28.3; IR (film): n=3019, 1740, 1697, 1217 cmÀ1; LR-MS
(ESI): m/z=305.1172 (MÀH); HR-MS (ESI): m/z=
305.3472 (MÀH), calcd. for C20H17O3: 305.3475. The ee was
determined by HPLC analyses of the Michael adduct.
CHIRALPAK AD-H (4.6 mm i.d.”250 mm); hexane/2-
propanol 90/10; flow rate: 1.0 mLminÀ1; 258C; 254 nm; re-
tention time: 22.0 min (minor), 24.5 min (major).
(R)-(+)-Dimethyl 2-(3-oxocyclopentyl)malonate (4a):
Colorless oil; yield: 94% (Et3N as solvent); 91% ee (Et3N as
1
solvent); [a]2D6: +132.8 (c 0.5, CHCl3); H NMR (300 MHz,
CDCl3): d=3.70 (s, 3H), 3.67 (s, 3H), 3.33 (d, J=9.2 Hz),
2.87–2.72 (m, 1H), 2.43 (dd, J=18.1, 8.0 Hz, 1H), 2.33–2.03
(m, 3H), 1.94 (dd, J=18.1, 10.8 Hz, 2H), 1.62–1.51 (m, 1H);
13C NMR (75 MHz, CDCl3): d=216.7, 168.4, 168.3, 55.9,
52.4, 42.7, 38.0, 36.2, 27.3; LRMS (ESI) m/z 231.9 (M+
General Procedure for the Michael Addition of 1,3-
Dicarbonyl Compounds (3a, e–f, h and k–n) to N-
Alkylmaleimides 5a–d Catalyzed by Bicyclic
Guanidine 1
+
NH4 ); HR-MS (ESI): m/z=213.0762 (MÀH), calcd. for
C10H13O5: 213.0763; The ee was determined by HPLC analy-
ses after conversion to the ethylene ketal.[23] CHIRALCEL
OD-H (4.6 mm i.d.”250 mm); hexane/2-propanol=97/3;
flow rate: 0.5 mLminÀ1; 258C; 210 nm; retention time:
24.6 min (major) and 25.9 min (minor).
Et3N (0.2 mL) was added to 1,3-dicarbonyl compounds (3a,
e–f, h and k–n) (0.06 mmol) and catalyst 1 (2.24 mg,
0.01 mmol). After cooling the mixture at À508C for about
30 min, the N-alkylmaleimide 5a–d (0.05 mmol) was added.
The reaction mixture was monitored by TLC and upon com-
plete consumption of 5a–d, the solvent was removed under
vacuum. The crude product was directly loaded onto a short
silica gel column, followed by gradient elution with hex-
(R)-Ethyl 3-oxo-2-(3-oxocyclopentyl)-3-phenylpropanoate
(4e): Colorless oil; yield: 98% (Et3N as solvent); 1:1 mixture
of diastereomers. 90% and 93% ee (Et3N as solvent);
1H NMR (300 MHz, CDCl3): d=8.04–7.99 (m, 4H), 7.62–
7.58 (m, 2H), 7.52–7.46 (m, 4H), 4.29 (d, J=6.3 Hz, 1H),
4.26 (d, J=6.6 Hz, 1H), 4.20–4.10 (m, 4H), 3.15–3.06 (m,
2H), 2.58–2.50 (m, 2H), 2.38–2.04 (m, 7H), 1.86–1.71 (m,
2H), 1.54–1.42 (m, 1H), 1.20–1.14 (m, 6H); 13C NMR
(75 MHz, CDCl3): d=217.3, 193.6, 193.4, 168.5, 168.4, 136.3,
136.1, 133.8, 128.8, 128.6, 61.7 (two peaks), 59.4, 59.1, 43.3,
42.8, 38.3, 38.1, 36.6, 36.4, 28.0, 27.4, 14.0; LR-MS (EI):
m/z=274.1 (M+); HR-MS (EI): m/z=274.1207 (M+), calcd.
for C16H18O4: 274.1205. The ee was determined by HPLC
analyses of the Michael adduct. Double columns, CHIRAL-
PAK (AD-H)-(AD-H) (4.6 mm i.d.”250 mm); hexane/2-
propanol 80/20; flow rate: 0.5 mLminÀ1; 258C; 254 nm; re-
tention time: 28.3 min (minor) and 45.3 min (major), 90%
ee; 32.7 min (minor) and 33.6 min (major), 93% ee.
AHCTREUNG
nylpropanoate (6c): Colorless oil; yield: 93%; 1:1 mixture of
diastereomers. 93% ee; 1H NMR (300 MHz, CDCl3): d=
7.97–7.88 (m, 2H), 7.63–7.41 (m, 3H), 5.11–4.86 (m, 1H),
4.20–4.08 (m, 2H), 3.49–3.28 (m, 1H), 2.99–2.81 (m, 5H),
1.16–1.09 (m, 3H); 13C NMR (75 MHz, CDCl3): d=193.8,
193.1, 177.8, 177.6, 176.1, 176.0, 167.9, 167.7, 135.6, 135.4,
134.0, 133.9, 128.8, 128.6 (two peaks), 128.4, 62.1, 61.9, 53.3,
51.9, 39.6, 39.4, 32.4, 32.1, 24.8, 13.7 (two peaks); IR (film):
n=2982, 2940, 1734, 1701, 1439, 1387, 1284, 1122 cmÀ1; LR-
MS (ESI): m/z=302.3 (MÀ); HR-MS (ESI): m/z=326.0999
(M+Na+), calcd. for C16H17NO5Na: 326.0999. The ee was
determined by HPLC analyses of the Michael adduct.
CHIRALPAK IA (4.6 mm i.d.”250 mm); hexane/2-propa-
nol 85/15; flow rate: 1.0 mLminÀ1; 258C; 254 nm; retention
time: 11.3 min (major), 18.9 min (minor); 13.9 min (minor),
43.5 min (major).
(R)-Ethyl 3-(4-nitrophenyl)-3-oxo-2-(3-oxocyclopentyl)-
propanoate (4j): Colorless oil; yield: 91% (toluene as sol-
vent); 1:1 mixture of diastereomers. 93% and 94% ee (tolu-
1
ene as solvent); H NMR (300 MHz, CDCl3): d=8.36–8.32
(m, 4H), 8.20–8.15 (m, 4H), 4.26 (dd, J=9.4, 7.7 Hz, 2H),
4.21–4.12 (m, 4H), 3.16–3.05 (m, 2H), 2.56 (dd, J=18.1,
7.7 Hz, 2H), 2.41–2.20 (m, 6H), 2.09 (dd, J=18.8, 11.2 Hz,
1H), 1.87–1.71 (m, 2H), 1.51 (m, 1H), 1.21–1.15 (m, 6H);
13C NMR (75 MHz, CDCl3): d =216.7, 216.6, 192.2, 192.0,
167.8, 167.7, 150.6, 140.5, 140.3, 129.6, 124.1, 62.2, 62.1, 60.1,
59.8, 43.3, 42.5, 38.2, 38.0, 36.3, 36.1, 28.0, 27.2, 14.0 (two
peaks); IR (film): n=1735, 1688, 1648, 1528, 1405, 1351,
1153, 999 cmÀ1; LR-MS (EI): m/z=318.9 (M+); HR-MS
(EI): m/z=319.1062 (M+), calcd. for C16H17NO6: 319.1056.
The ee was determined by HPLC analyses of the Michael
adduct. CHIRALPAK AD-H (4.6 mm i.d.”250 mm);
hexane/2-propanol 90/10; flow rate: 1.0 mLminÀ1; 258C;
254 nm; retention time: 21.6 min (minor), 23.6 min (major),
93% ee; 32.6 min (major), 36.5 min (minor), 94% ee.
Ethyl 1-[(S)-1-ethyl-2,5-dioxopyrrolidin-3-yl]-2-oxocyclo-
pentanecarboxylate (6k): Colorless oil; yield: 80%; 1:1 mix-
ture of diastereomers. 90% ee and 83% ee; 1H NMR
(300 MHz, CDCl3): d=4.24–4.04 (m, 2H), 3.55–3.32 (m,
3H), 2.91–1.96 (m, 8H), 1.28–1.07 (m, 6H); 13C NMR
(75 MHz, CDCl3): d=213.6, 212.6, 177.2, 176.9, 175.6, 175.3,
169.9, 169.7, 62.1, 62.0, 60.8, 60.67, 43.3, 42.0, 37.9, 37.8, 33.7,
32.7, 32.5, 31.9, 31.8, 19.6, 19.2, 14.0, 13.9, 12.7; IR (film):
n=2978, 1751, 1720, 1699, 1445, 1406, 1350, 1227 cmÀ1; LR-
MS (EI): m/z=281.1 (M+); HR-MS (FAB): m/z=281.1272
(M+), calcd. for C14H19NO5: 281.1263. The ee was deter-
mined by HPLC analyses of the Michael adduct. CHIRAL-
PAK IA (4.6 mm i.d.”250 mm); hexane/2-propanol 92/08;
flow rate: 0.8 mLminÀ1; 258C; 210 nm; retention time:
13.9 min (minor), 16.4 min (major), 90% ee; 18.5 min
(major), 22.2 min (minor), 83% ee.
(R)-(+)-3-(1,3-Dioxo-1,3-diphenylpropan-2-yl)cyclopenta-
none (4k): Colorless oil; yield: 99% (Et3N as solvent), 91%
ee (toluene as solvent); [a]2D6: +47.1 (c 0.24, CHCl3);
1H NMR (300 MHz, CDCl3): d = 8.03–7.95 (m, 4H), 7.61–
7.56 (m, 2H), 7.49–7.41 (m, 4H), 5.19 (d, J=9.4 Hz, 1H),
2350
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2345 – 2351

Triethylamine-Mediated Guanidine-Catalyzed Enantioselective Michael Reaction
FULL PAPERS
Scafato, M. Nardiello, D. Casarini, E. Giorgio, C.
Rosini, Tetrahedron 2004, 60, 4975–4981; d) H. C.
Hailes, B. Isaac, M. H. Javaid, Tetrahedron 2001, 57,
10329–10333.
Supporting Information
Experimental procedures, characterization and spectroscopic
data (PDF) are available as Supporting Information.
[10] T. Arai, H. Sasai, ; K.-i. Aoe, K. Okamura, T. Date, M.
Shibasaki, Angew. Chem. 1996, 108, 103–105; Angew.
Chem. Int. Ed. 1996, 35, 104–106.
Acknowledgements
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This work was supported by grants (R-143–000–337–112 and
R-143–000–342–112) from the National University of Singa-
pore. We thank the Medicinal Chemistry Program for their fi-
nancial support.
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Adv. Synth. Catal. 2008, 350, 2345 – 2351
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asc.wiley-vch.de
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