Organocatalytic enantioselective Michael additions of malonates to 2-cyclopentenone

Article abstract of DOI:10.1055/s-0030-1258533

The Michael reaction of a dialkyl malonate with a cyclic enone using a chiral diamine-acid combination catalyst gave the desired Michael adduct in high yield with excellent enantiomeric excess in a protic solvent such as methanol and ethanol. The methanol

Full text of DOI:10.1055/s-0030-1258533

2340
LETTER
Organocatalytic Enantioselective Michael Additions of Malonates to
2-Cyclopentenone
Organocatalytic
M
o
ichae
l
A
ddit
b
ions of
M
alo
u
nates to 2-Cy
y
clopentenon
u
e
ki Mase,* Maho Fukasawa, Norihiko Kitagawa, Fumiya Shibagaki, Naoyasu Noshiro, Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Fax +81(53)4781196; E-mail: tnmase@ipc.shizuoka.ac.jp
Received 21 June 2010
tional control of an iminium intermediate 2 derived from
2-cyclopentenone is more difficult than that from acyclic
enone 1. Calculations of the energy difference between
acyclic iminium intermediate 1A and 1B optimized at the
Abstract: The Michael reaction of a dialkyl malonate with a cyclic
enone using a chiral diamine–acid combination catalyst gave the de-
sired Michael adduct in high yield with excellent enantiomeric ex-
cess in a protic solvent such as methanol and ethanol. The methanol
molecule participates in a proton relay system in which the dialkyl HF/6-31G(d) level of theory using the GAMESS program
package8 showed that the intermediate 1A is relatively
malonate is activated through hydrogen bonding to afford the
Michael adduct with excellent enantioselectivity.
preferred over 1B due to steric repulsion (R1 = t-Bu, R2 =
H, DE = 2.6 kcal/mol).9 On the other hand, in a cyclic sys-
Key words: enone, malonate, Michael addition, organocatalysis,
proton relay
tem, no clear energy difference between 2A and 2B is ob-
served (R1 = t-Bu, DE = 0.8 kcal/mol, Scheme 1). The
second reason is that the activation of a less reactive mal-
The organocatalytic asymmetric Michael reaction via an onate is required for the Michael reaction with the imini-
iminium intermediate is a key transformation in organic um intermediate. Since an activating interaction between
synthesis. In recent years, many chiral organocatalysts the catalyst and the malonate donor through acid or base
have been developed that exhibit high reactivities and ste- functionality should be formed, the reactive site of the
reoselectivities for this fundamental transformation.1 b- acyclic iminium intermediate 3 is three-dimensionally
Chiral cyclic alkanones are common structures in natural different from that of the cyclic iminium intermediate 4.
products. One of the best ways to construct this skeleton Thus, it is difficult to achieve excellent stereoselectivity in
is through the asymmetric Michael addition of a nucleo- both acyclic trans acceptors and cyclic cis acceptors. As
phile to a,b-unsaturated cycloalkanones. In particular, detailed in this communication, we investigated the direct
iminium catalysis has been intensively studied due to its Michael reaction of malonate donors with 2-cyclopenten-
high versatility, adaptability, and stereoselectivity.2,3 Al- one acceptor using a chiral diamine–acid combination cat-
though malonate nucleophiles are valuable in modern or- alyst in a protic solvent in which the malonate was
ganic synthesis, the Michael addition of a malonate activated through hydrogen bonding to afford the Michael
nucleophile to cyclic enones via iminium catalysis is con- adduct with excellent enantioselectivity.
sidered a worthwhile subject in asymmetric synthesis4–6
First we examined amine catalysts 5–13 (Figure 1) for the
Michael reaction of dibenzyl malonate (15a) and 2-cyclo-
pentenone (14a) to afford the Michael product 16a. The
and its addition to 2-cyclopentenone is an especially chal-
lenging topic in organocatalysis.7 There are two likely
reasons for this difficulty. The first is that the conforma-
R2 = H
R1
R1
R1
R1
N
N
N
N
R2
R2
R2 = Ph
2A
2B
1A
1B
R1 = t-Bu
2 = H, Ph
R3
R
R
R3
N
3 = acid, base
N
Nu
R2
Nu
O
O
Nu:
4
R4O
OR4
3
Scheme 1 Michael addition of malonates to cyclic and acyclic enones
SYNLETT 2010, No. 15, pp 2340–2344
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258533; Art ID: U05810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Organocatalytic Michael Additions of Malonates to 2-Cyclopentenone
2341
results are shown in Table 1. When pyrrolidine (5) was
used as the catalyst, the desired product 16a was obtained
in 46% isolated yield (entry 1). The reaction with L-pro-
line (6) or (S)-a,a-diphenyl-2-pyrrolidinemethanol (7) did
not proceed (entries 2 and 3). Diarylprolinol silyl ether 8
and imidazolidinone 9 have been successfully used as imi-
nium catalysts,10 however, these catalysts did not yield the
Michael adduct 16a at all (entries 4 and 5). L-Prolinol (10)
was a good catalyst providing the desired product 16a in
quantitative yield but with no enantioselectivity (entry 6).
Similarly, (S)-1-(2-pyrrolidinylmethyl)pyrrolidine (11)
afforded the adduct 16a in 87% yield in racemic form (en-
try 7).11 In contrast, the diamine–TFA combination cata-
lyst 1212,13 improved the enantioselectivity up to 58% ee
(entry 7 vs. entry 8). The tetrazole catalyst 13 also gave
the adduct 16a with 49% ee, but the reaction was slow and
the yield was low (entry 9).
OH
Ph
Ph
OTMS
N
H
N
H
N
N
H
OH
H
O
Ph
Ph
5
7
6
8
O
Me
N
OH
N
Ph
N
N
H
N
H
H
9
10
11
CF3CO2
N
N
N
N
N
H
H
H
HN
N
12
13
Figure 1 Various amine catalysts
the chemical yield as well as the enantioselectivity (en-
tries 7–10); in particular, methanol gave the highest chem-
ical yield and enantiomeric excess of the solvents tested
(entry 10). Excellent enantioselectivity in the Michael
reaction of less reactive malonate to 2-cyclopentenone
(14a) was achieved by simple diamine catalyst 12.
Table 1 Michael Addition of 15a to 14aa
O
O
O
O
catalyst
(0.1 equiv)
+
CO2Bn
BnO
OBn
THF, 25 °C
48 h
CO2Bn
16a
14a
15a
Encouraged by these results, we further examined the
scope of this class of Michael reaction with a series of
Entry
Catalyst
Conv. (%)b Yield (%)c ee (%)d
Table 2 Screening of Various Solvents in Michael Addition of 15a
to 14aa
1
2
3
4
5
6
7
8
9
5
6
67
46
–
–
–
–
–
–
NRe
NRe
NRe
NRe
99
O
O
O
O
catalyst 12
7
–
(0.1 equiv)
+
CO2Bn
CO2Bn
BnO
OBn
solvent
25 °C, 48 h
8
–
14a
15a
9
–
16a
10
11
12
13
98
87
30
8
0
0
Entry
Solvent
THF
Conv. (%)b
Yield (%)c ee (%)d
95
1
2
39
30
19
66
75
NRe
29
70
75
99
30
30
18
56
70
–
58
64
64
67
46
–
39
58
49
toluene
CHCl3
DMSO
DMF
10
3
a Reactions were carried out using 14a (0.5 mmol), 15a (0.6 mmol,
1.2 equiv), and catalyst (0.05 mmol, 0.1 equiv) in THF (0.5 mL) at 25
°C for 48 h.
4
5
b Determined by GC analysis.
c Isolated yield.
6
AcOH
t-BuOH
2-PrOH
EtOH
d Determined by chiral-phase HPLC analysis.
e NR = no reaction.
7
27
69
74
98
76
81
85
94
8
Using catalyst 12, a series of different solvent systems
was evaluated as shown in Table 2. Nonpolar solvents,
such as toluene and CHCl3, were inferior in terms of their
product yield (entries 2 and 3). Aprotic polar solvents
such as DMSO and DMF showed better yield with mod-
erate enantioselectivities (entries 4 and 5). The Michael
addition was prevented in protic polar acetic acid (entry
6). Interestingly, protic polar alcoholic solvents improved
9
10
MeOH
a Reactions were carried out using 14a (0.5 mmol), 15a (0.6 mmol,
1.2 equiv), and catalyst (0.05 mmol, 0.1 equiv) in THF (0.5 mL) at 25
°C for 48 h.
b Determined by GC analysis.
c Isolated yield.
d Determined by chiral-phase HPLC analysis.
e NR = no reaction.
Synlett 2010, No. 15, 2340–2344 © Thieme Stuttgart · New York

2342
N. Mase et al.
LETTER
Table 3 Michael Addition of Various Donors 15 to Cyclic Enones
Table 4 Michael Addition of 15 to Acyclic Acceptors 17a
14a
O
O
O
R1
O
O
catalyst 12
O
R1
(0.3 equiv)
CO2R3
O
O
R3O
OR3
+
R2
catalyst 12
MeOH
25 °C, 96 h
R2
CO2R
CO2R
+
n
CO2R3
18
RO
OR
MeOH
25 °C, 48 h
17
15
n
14
15
16
Entry R1
R2
R3
Conv. Yield ee
Product
(%)b (%)c (%)d
Entry
n
R
Conv.
Yield
(%)c
ee
Product
(%)b
(%)d
1
2
3
Me
Ph
Ph
Me
Me
Bn
98
10
60
97
9
71
80
80
18a
18b
18c
1
1
1
1
1
1
2
3
Bn
Me
Et
99
98
75
46
36
23
95
35
94
>95g
>95g
>95g
>95g
87
16a
16b
16c
16d
16e
16f
Ph
2e
3e
4e
5e
6
80
Me
C5H11
40
51
a Reactions were carried out using 17 (0.5 mmol), 15 (1.0 mmol, 2.0
equiv), and catalyst 12 (0.15 mmol, 0.3 equiv) in MeOH (0.5 mL) at
25 °C for 96 h.
i-Pr
t-Bu
Bn
Bn
40
28
b Determined by GC and/or HPLC analysis.
c Isolated yield.
99
d Determined by chiral-phase HPLC analysis.
7e,f
40
69
16g
Michael product 18 has R-configuration by comparison
with the reported HPLC data,7 thus, re-facial attack is pre-
ferred with acyclic trans acceptors 17.
a Reactions were carried out using 14 (0.5 mmol), 15 (0.6 mmol, 1.2
equiv), and catalyst (0.05 mmol, 0.1 equiv) in THF (0.5 mL) at 25 °C
for 48 h.
b Determined by GC analysis.
For a better understanding of the mechanism of this
Michael addition, the transition state was computationally
calculated. The methanol molecule plays an important
role in reactivity as well as in enantioselectivity, as de-
scribed above. We proposed the following set of transition
states: (1) direct addition of the nucleophile (TS-1), (2) di-
rect activation of the nucleophile by the catalyst (TS-2),
and (3) proton relay activation system (TS-3).15 These
transition states were initially optimized at the PM3 level
of theory and further optimized at the HF/6-31G(d) level
of theory using the GAMESS program package. Results
are shown in Figure 2. The difference in the relative ener-
gies of the transition states shows that TS-3 is preferred to
TS-1 and TS-2. Two intermolecular bondings and one in-
tramolecular hydrogen bonding in TS-3 form a proton re-
lay system to activate the malonate nucleophile. It is noted
that catalyst 12 could not activate the nucleophile well in
a direct way, but, with the aid of the methanol molecule,
it could indirectly catalyze the Michael reaction. This
flexible catalysis system probably gives rise to good-to-
excellent enantioselectivities in the Michael addition to
both cyclic cis acceptors and acyclic trans acceptors.
c Isolated yield.
d Determined by chiral-phase HPLC analysis.
e Donor (2 equiv) and catalyst (0.3 equiv) were used.
f Reaction was carried out for 96 h.
g Determined by 13C NMR after transformation to chiral aminals.
malonate donors 15 and cycloalkenone acceptors 14 using
catalyst 12 under the same reaction conditions (Table 3).14
High enantioselectivities were observed in the Michael
addition to cyclopentenone acceptor 14a. Substituents on
malonate donor did not affect the enantioselectivity
(>95% ee), but decreasing reactivity was observed as a
bulkier substituent was used (entries 1–5). 2-Cyclohex-
enone (14b) was also a good acceptor: the reaction pro-
vided the Michael product 16f in excellent yield in 48
hours with 87% ee (entry 6), while the reaction of 2-cyclo-
heptanone (14c) afforded the adduct 16g in 35% yield
with 69% ee after 96 hours of stirring (entry 7).
Next, we probed the scope of the reaction with a variety
of acyclic trans acceptors 17 and malonates 15 (Table 4).
Benzalacetone (17a) was suitable as a Michael acceptor,
providing high yield and enantioselectivity (Table 4, en-
try 1). Chalcone (17b) was a poor acceptor to give the ad-
duct 18b in low yield with 80% ee (entry 2). Aliphatic 3-
nonen-2-one (17c) was a moderate acceptor, furnishing
the product 18c with good enantioselectivity (entry 3).
Finally, we examined the decarboxylation of the Michael
product 16b as shown in Scheme 2. The usual heating
condition16 was not effective, giving the decarboxylated
product 19b in low yield (method A). Currans’s procedure
using microwave irradiation was employed for the decar-
boxylation of our compound 16b.17 N-Methylpyrrolidone
was the most effective solvent, affording the ketone 19b
in good yield after 30 minutes with no loss of enantiose-
lectivity (method B).18 This b-chiral cyclopentanone de-
rivative 19b is a useful intermediate in methyl jasmonate
syntheses.19
The major cyclic Michael product 16a was determined to
have an S-configuration by comparison with the reported
26
optical rotation value of 16a {[a]D –49.4° (c = 1.00,
24
CHCl3); lit. [a]D –35.1° (c = 1.33, CHCl3, 92% ee)}.6a
This result shows a si-facial attack of a malonate nucleo-
phile on the iminium intermediate derived from the cyclic
enone 14a (Figure 2). On the other hand, the major acyclic
Synlett 2010, No. 15, 2340–2344 © Thieme Stuttgart · New York

LETTER
Organocatalytic Michael Additions of Malonates to 2-Cyclopentenone
2343
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Figure 2 Proposed transition state through a proton relay system
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O
O
CO2Me
CO2Me
CO2Me
19b
16b
(4) For iminium catalysis in Michael addition of malonate to
cyclic enones, see: (a) Yamaguchi, M.; Shiraishi, T.;
Hirama, M. Angew. Chem. Int. Ed. 1993, 32, 1176.
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method A: DMSO, H2O (1 equiv), 190 °C, 12 h, 24% yield
method B: NMP, H2O (1 equiv), microwave, 0.5 h, 80% yield.
Scheme 2 Decarboxylation of the Michael product 16b
In summary, we have developed a direct access to b-chiral
cyclopentanone possessing malonate functionality. The
diamine bifunctional catalyst 12 demonstrated excellent
reactivity and enantioselectivity in this class of Michael
reactions. Further studies focusing on the full scope of this
unique catalyst system are currently under investigation
and will be reported in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(6) For pioneering studies on metal-complex catalysis in
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(a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc.
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K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.
(7) Only one example of high enantioselectivity (>90% ee) in
iminium catalysis using a primary–secondary diamine
catalyst, reported by Zhao’s group, has been identified:
Yang, Y.-Q.; Zhao, G. Chem. Eur. J. 2008, 14, 10888.
(8) http://www.msg.ameslab.gov/GAMESS/. See also
Supporting Information.
Acknowledgment
This study was supported in part by a Grant-in-Aid from Scientific
Research from the Japan Society for the Promotion of Science.
References and Notes
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Synlett 2010, No. 15, 2340–2344 © Thieme Stuttgart · New York

2344
N. Mase et al.
LETTER
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(14) Typical Procedure for the Direct Michael Reaction of the
Malonate 15 with the Enone 14 Using Catalyst 12 (Table
3, entry 1): A catalyst stock solution (1.0 M in MeOH) was
prepared as a mixture of (S)-(+)-1-(2-pyrrolidinyl-
methyl)pyrrolidine (11, 0.5 mmol) and trifluoroacetic acid
(0.5 mmol) in anhyd MeOH (0.5 mL) before use. 2-
Cyclopentenone (14c, 0.5 mmol) was dissolved in MeOH
(0.45 mL) and dibenzyl malonate (15a, 0.6 mmol) was
added. To the mixture the catalyst stock solution (1.0 M in
MeOH, 50 mL, 0.05 mmol) was added at 25 °C. After stirring
for 48 h, the reaction mixture was directly purified by
column chromatography (silica gel 5 g, hexanes–EtOAc,
90:10) to afford the Michael product 16a (98% yield, 94%
ee). The enantiomeric excess (ee) of Michael products was
determined by chiral-phase HPLC analysis and/or 13C NMR
(see Supporting Information). The absolute configuration of
Michael products was determined by comparison of the
reported specific optical rotation and HPLC data.
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Synlett 2010, No. 15, 2340–2344 © Thieme Stuttgart · New York

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