Chiral pyrrolidine sulfonamide catalyzed enantioselective Michael addition of cyclohexanones to maleimides

Article abstract of DOI:10.1055/s-0030-1259517

An organocatalytic enantioselective conjugate addition of cyclohexanones to maleimides has been developed. The process catalyzed by a (S)-pyrrolidine sulfonamide affords synthetically and medicinally useful chiral succinimides under mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259517

CLUSTER
473
Chiral Pyrrolidine Sulfonamide Catalyzed Enantioselective Michael Addition
of Cyclohexanones to Maleimides
E
nantiosel
i
e
ctive
M
ichae
l
A
d
n
dition of Cyclohex
W
anones to Maleimides ang,a Man-Man Zhang,b Shieli Zhang,a Zi-An Xu,b Hao Li,c Xin-Hong Yu,*b Wei Wang*a,b,c
a
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA
Fax +1(505)2772609; E-mail: wwang@unm.edu
Department of Medicinal Chemistry, School of Pharmacy, East China University of Science & Technology,
b
Shanghai 200237, P. R. of China
E-mail: xhyu@ecust.edu.cn
c
Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences,
Graduate School of the Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Received 20 November 2010
imides, promoted by chiral pyrrolidine trifluoromethane-
sulfonamide. This approach affords succinimides with
good to high enantioselectivities (up to 94% ee), and mod-
erate to high diastereoselectivities (up to 12:1 dr) and in
good yields (61–86%).
Abstract: An organocatalytic enantioselective conjugate addition
of cyclohexanones to maleimides has been developed. The process
catalyzed by a (S)-pyrrolidine sulfonamide affords synthetically and
medicinally useful chiral succinimides under mild reaction condi-
tions.
Key words: cyclic ketones, maleimides, Michael reaction, pyrroli-
dine sulfonamide
In the exploratory study, we carried out a model reaction
between cyclohexanone (1a, 2.0 equiv) and N-phenylma-
leimide (2a) in the presences of (S)-pyrrolidine trifluo-
romethanesulfonamide (I, 10 mol%) at room temperature
(Table 1). Initially, the reaction was performed in protic
solvent (i-PrOH). Our successful experience showed that
the catalyst displayed higher catalytic activity and better
stereocontrolling capability in a protic solvent.11d,g It is be-
lieved that two H-bond forces may be involved in the tran-
sition state based on our mechanistic study (Figure 1).11d,g
One H-bond arises from the solvent i-PrOH, the catalyst
I, and the substrate maleimide 2a in addition to the direct
H-bond interaction between I and 2a. Such a unique dual
H-bond activation mode, which cannot be identified in
other organocatalysts, is important for achieving high re-
activity and stereoselectivity.11d,f,g Indeed, the conjugate
addition process promoted by I proceeded smoothly with
high enantioselectivity (84% ee for the major diastere-
omer) and high yield (83% yield) and relatively low dia-
stereoselectivity (2.1:1 dr) in a shorter reaction time (7 h,
Table 1, entry 1). In contrast, L-proline (II)12 and L-proli-
namide (III)13 could catalyze the process, but with poor
efficiency (entries 2 and 3). The other organocatalysts
chiral pyrrolidine diamine (IV),14 MacMillan’s imida-
zolindinone (V),15 and diphenylprolinol TMS ether (VI)16
were not effective for this process (entries 4–6).
The broad biological1 and synthetic2 utility of succinim-
ides renders them attractive targets in organic synthesis.
In the recent past, a great deal of effort has been dedicated
towards the development of asymmetric methods for the
synthesis of chiral succinimides.3 Notably, organocatalyt-
ic versions have also been actively pursued recently.4
Bartoli and coworkers have used cinchona alkaloids to
promote the direct conjugated addition of 1,3-dicarbonyl
compounds to maleimides.5 You and Alcaide have inde-
pendently reported N-heterocyclic carbene catalyzed ring
expansion of chiral b-lactam aldehydes to give rise to
enantiomerically pure succinimides.6
Organocatalytic enantioselective conjugate reactions
have been the subject of intense investigations in the past
decade. The general observation is that enals, enones, and
nitroolefins are often used as Michael acceptors.7 In con-
trast, the use of maleimides 2 for the C–C formation re-
mains underexplored.8,9 Furthermore, organocatalytic
Michael additions of ketones to maleimides have been
challenging.10
Recently, we have developed new chiral pyrrolidine sul-
fonamides as general catalysts for promoting a variety of
organic transformations.11 They display high catalytic ac-
tivity and stereoselectivity as a result of unique activation
modes of involving two H-bond interactions.11d,f,g Based
on this important insight, we envisioned that this class of
catalyst could be an effective promoter for direct conju-
gate addition of unmodified ketones to maleimides. As
demonstrated, in this communication, we described the
results of the study of carrying out asymmetric conjugate
addition reactions of unmodified ketones with male-
We further demonstrated experimentally that the reaction
media had a significant effect on this process (Table 2).
The reactions carried out in aprotic solvents generally
O
NHTf
N
H
S
N
N
O
CF3
I
H
H
O+
O
H
i-Pr
Ph
N
O
SYNLETT 2011, No. 4, pp 0473–0476
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
DOI: 10.1055/s-0030-1259517; Art ID: Y02010ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Proposed possible transition state of catalyst I catalyzed
conjugate addition of cyclohexanone to maleimide

474
J. Wang et al.
CLUSTER
Table 2 Solvent Effect on (S)-Pyrrolidine Trifluoromethane-
Table 1 Results of Exploratory Studies of Organocatalytic Asym-
metric Conjugate Addition of Cyclohexanone (1a) to N-Phenylmale-
imide (2a)a
sulfonamide (I) Catalyzed Catalytic Asymmetric Conjugate Addition
of Cyclohexanone to N-Phenylmaleimidea
O
O
O
O
NPh
O
O
O
O
NPh
NPh
catalyst I (10 mol%)
catalyst (10 mol%)
i-PrOH, r.t.
+
+
NPh
solvent, r.t.
O
O
2.0 equiv
O
O
2.0 equiv
1a
2a
3a
1a
2a
3a
Entry
Solvent
xylenes
CH2Cl2
Time (h) Yield (%)b ee (%)c drd
NHTf
nde
95
92
88
94
95
84
88
92
nde
CONH2
1
24
24
24
24
24
24
7
<5
32
26
23
63
67
83
83
85
COOH
N
N
H
N
H
H
I
III
II
2
2.0:1
2.0:1
1.6:1
2.1:1
2.3:1
2.1:1
2.5:1
2.5:1
Me
O
3
Cl(CH2)2Cl
anisole
Ph
N
N
Ph
OTMS
N
H
4
N
N
⋅TFA
IV
H
H
Ph
⋅HCl
5
THF
V
VI
6
Et2O
Entry
Catalyst
Time (h) Yield (%)b ee (%)c
drd
7
i-PrOH
1
2
3
4
5
6
I
7
24
24
24
24
24
83
77
15
<5
<5
<5
84e
10
2
2.1:1
1.5:1
1:1
8f
9f,g
i-PrOH–Et2O
i-PrOH–Et2O
12
24
II
III
IV
V
a Reaction conditions: unless specified, see footnote a in Table 1.
b Isolated yields for both diastereomers.
c Determined by chiral HPLC analysis (Chiralcel OD-H).
d Determined by 1H NMR.
ndf
ndf
ndf
ndf
ndf
e Not determined.
VI
ndf
f 1:1 v/v ratio.
g Reaction performed at 0 °C.
a Reaction conditions: unless specified, a mixture of 1a (60 mg, 0.6
mmol, 2.0 equiv), 2a (52 mg, 0.3 mmol), and catalyst (7 mg, 0.03
mmol) in a solvent was stirred for a specified period of time at r.t.
b Isolated total yield for both isomers.
enantioselectivities (72–94% ee), good to high yields (61–
86%), and moderate to high diastereoselectivities (2.0:1 to
12.0:1 dr) were achieved for maleimides containing both
aromatic (entries 1–3 and 5–7) and alkylic substituents
(entries 4, 8, and 9). It was found that the electronic effect
on the process was limited. The organocatalyst I promot-
ed processes were successful with aromatic systems pos-
sessing neutral (entries 1, 5, and 6), electron-withdrawing
(entries 2 and 7), or a combination of both electron-with-
drawing and electron-donating substituents (entry 3) and
alkyl ones (entries 8 and 9). Moreover, the reactions were
applicable for various six-membered-ring ketones includ-
ing cyclohexanone (entries 1–4) and heteratom-contain-
ing cyclic systems (entries 5–9). The mild reaction
conditions could tolerate an acid-labile ketal group (entry
6). Interestingly, cyclopentanone reacted under these con-
ditions to generate a conjugate addition adduct with a
good yield (80% yield, entry 10) but no enantioselectivity.
This indicates that the conformation of the rings (5 vs. 6)
has a significant influence on the stereoselectivity of the
process. Despite the fact that the reaction occurred for
electron-donating substituted aromatic maleimide in a
high yield (84%) and good dr (4.7:1, see Supporting Infor-
mation), the conjugate-addition product 4 could not be
separated by chiral HPLC. We were fortunate to obtain its
single-crystal structure by X-ray crystallography to deter-
mine the absolute configuration (Figure 2),17 and the ob-
c Determined by chiral HPLC analysis (Chiralcel OD-H).
d Determined by 1H NMR.
e Referred to major isomer.
f Not determined.
gave poor yields (entries 1–4). Although high enantiose-
lectivites for THF and Et2O were observed, relatively low
yields were obtained, and longer reaction times were re-
quired (entries 5 and 6). The observation indicates that the
reactivity and enantioselectivity of the process was also
significantly influenced by the polarity of solvents. Fur-
ther optimizing reaction media led to the use of a mixture
of i-PrOH–Et2O (1:1 v/v ratio) for this process (entry 8).
By lowering the temperature to 0 °C, an improved enantio-
selectivity (92% ee for major diastereomer, 91% ee for
minor diastereomer, entry 9) without any loss of yield and
diastereoselectivity was attained.
Under the optimized reaction conditions, the scope and
limitation of this asymmetric catalytic conjugate addition
process were explored by employing a wide range of un-
modified ketones and maleimides. As summarized in
Table 3, the reaction catalyzed by I has broad applicabili-
ty with respect to maleimides as Michael acceptors. Struc-
ture variation in the maleimides was found to be tolerated
in the conjugate addition reactions. Moderate to high
Synlett 2011, No. 4, 473–476 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Michael Addition of Cyclohexanones to Maleimides
475
served stereochemical outcome is in agreement with the In summary, we have developed an organocatalytic, direct
proposed transition state as well (Figure 1).
conjugate addition reaction of unmodified cyclohex-
anones with maleimides. This process, catalyzed by a
chiral pyrrolidine sulfonamide catalyst I, is carried out un-
der mild reaction conditions to afford synthetically and
medicinally useful chiral succinimides in good to high
yields and with good to excellent levels of enantioselec-
tivity.
Table 3 Catalyst I Catalyzed Asymmetric Conjugate Addition of
Ketones to Maleimidesa
O
O
O
O
catalyst I (10 mol%)
N
R
+
N R
i-PrOH–Et2O
(1:1 v/v)
0 °C
X
O
O
2.0 equiv
X
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1a: X = CH2
1b: X = O
2
3
1c: X = C[(OCH2)2O]
1d: X = S
1e: X = none
Acknowledgment
Entry X, R, 3
Time Yield ee
drd
(h)
24
24
(%)b (%)c
We are grateful for the National Science Foundation of China
(20972051, X.-H.Y.), the Science and Technology Commission of
Shanghai Municipality (08430703900 and 08431901800, X.-H.Y.),
the Thousand Talents Program (W.W.), the China 111 Project
(Grant No. B07023, W.W.), and the University of New Mexico
RAC program (W.W.) for the support of this research. The Bruker
X8 X-ray diffractometer was purchased via an NSF CRIF:MU
award to the University of New Mexico, CHE-0443580. We also
thank Dr. Eileen N. Duesler for her X-ray crystal structural analysis.
1
2
1a, Ph, 3a
1a, 4-BrC6H4, 3b
85
79
77
70
86
70
76
82
61
80
92
81
72
91
85
87
85
94
76
2.5:1
3.7:1
2.0:1
8.5:1
3.9:1
4.5:1
2.2:1
4.3:1
12.0:1
4.1:1
3
1a, 4-Br-3-MeOC6H3, 3c 36
4
1a, Bn, 3d
48
48
48
48
60
60
24
5
1b, Ph, 3e
6
1c, Ph, 3f
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