Enantioselective intermolecular crossed-conjugate additions between nitroalkenes andα,β-enals through a dual activation strategy

Article abstract of DOI:10.1002/anie.200805558

Double the fun: The title reaction was developed by using a Lewis base/iminium activation strategy (see scheme). The reaction proceeded with excellent yields and ee values, and the products were additionally transformed into a single enantiomer of a subst

Full text of DOI:10.1002/anie.200805558

Angewandte
Chemie
DOI: 10.1002/anie.200805558
Asymmetric Catalysis
Enantioselective Intermolecular Crossed-Conjugate Additions
between Nitroalkenes and a,b-Enals through a Dual Activation
Strategy**
Cheng Zhong, Yunfeng Chen, Jeffrey L. Petersen, Novruz G. Akhmedov, and Xiaodong Shi*
The electron withdrawing group (EWG) activated alkene is
considered one of the most important building blocks in
organic synthesis. Its primary reaction mode is the conjugate
1,4-addition (Michael addition).[1] Recent developments
within organocatalysis have led to the recognition of the
Our interest in developing Lewis base mediated stereo-
selective cascade reactions led to the investigation of an
intermolecular crossed-conjugate addition (Scheme1,
path b). This process will produce highly functionalized
products which can be additionally transformed into various
structurally attractive skeletons with high atom efficiency.[7]
However, there are significant challenges associated with this
transformation: a) the sequential addition of the LB catalyst
in the presence of two different Michael receptors (the
kinetically preferred homo-crossed addition versus the
desired hetero-crossed addition) and b) the stereochemical
control. For these reasons, to our best knowledge, no
enantioselective intermolecular crossed-conjugate addition
has been reported.[8]
To study this transformation, our group investigated the
double Michael addition of nitroalkenes and enones. With a
b-alkyl group on the nitroalkene, the crossed-conjugate
addition was successfully achieved through an irreversible
b-hydride elimination (Scheme 2A). Notably, mechanistic
studies revealed that the secondary amine served as the LB
catalyst and added in a 1,4 fashion to the nitroalkene,
activating it for addition to the carbonyl group; l-proline
did not activate the enone in this case.[7] As an attractive new
enantioselective conjugate addition as one of the most
[2]
À
important approaches to asymmetric C C bond formation.
The general strategy involves carbonyl activation via iminium
intermediates.[3] Moreover, such iminium catalysis has been
incorporated into cascade (or domino) reactions, successful
examples of which have been achieved by different research
groups.[4]
Another important reaction of EWG-activated alkenes is
the Lewis base (LB) promoted carbanionic nucleophilic
addition (Scheme1; path a), which produces cross-coupling
À
C C bond-formation method, the enantioselective trans-
formation is highly desired. Herein, we report a dual
activation approach, Lewis base/iminium, for the enantiose-
lective nitroalkene/enal cross-coupling and its application in
the synthesis of substituted pyrrolidines.
Scheme 1. Reaction pathways for electron withdrawing group activated
alkenes.
The crossed-conjugate addition shown in Scheme 2A
gave a low d.r. value because of the epimerization of the C4
stereogenic center. Thus, we rationalized that setting the C3
stereogenic center through an asymmetric Michael addition
was a reasonable approach to achieving enantioselectivity
(Scheme 2B). Nitroalkene 1a and enal 2a were used with
different chiral secondary amine catalysts to investigate the
enantioselectivity of the reaction, and the results are sum-
marized in Table 1.
products (such as the Baylis–Hillman reaction).[5] Although
excellent results regarding enantioselective LB-promoted
reactions have been reported by various research groups,
effective LB-promoted enantioselective transformations is
still considered a significant challenge.[6]
Conducting the reaction in DMSO gave 3a in modest
yield with poor stereoselectivity, as there was competing
polymerization of the starting materials (Table 1, entry 1). By
using MeOH as the solvent, 3a was obtained in 11% ee
(Table 1, entry 2), which strongly supported the proposed of a
dual activation mechanism (LB activation of the nitroalkene
and carbonyl activation via an iminium). The use of cat-2 at
lower temperatures gave an improved enantioselectivity
(Table 1, entries 3 and 6); however, the additional lowering
of the reaction temperature caused a significant decrease in
the reaction rate (Table 1, entry 7). This result may have been
[*] C. Zhong, Dr. Y. Chen, Prof. J. L. Petersen, Dr. N. G. Akhmedov,
Prof. X. Shi
C. Eugene Bennett Department of Chemistry
West Virginia University, Morgantown, WV 26506 (USA)
Fax: (+1)304-293-4904
E-mail: xiaodong.shi@mail.wvu.edu
[**] We thank the C. Eugene Bennett Department of Chemistry, the
Eberly College of Arts and Science, the WV Nano Initiative at West
Virginia University, and the ACS-PRF for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805558.
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tivity (Table 1, entry 9). The reaction sub-
strate scope was investigated as shown in
Table 2.
As shown in Table 2, the aldehydes 3
were reduced to alcohols 4 so that the two
diastereomers could be isolated. This
transformation tolerated a large range of
substrates, giving good yield and good to
excellent enantioselectivity.[9] Various b-
substituted enals, including aryl, alkyl, and
heterocyclic substituents, were all suitable
for this transformation. Although the a-
methyl enal gave good yields (> 90%), it
suffered from low stereoselectivity
(<20% ee), which was probably
caused by the poor spatial arrange-
ment of the groups on the iminium
intermediates. Both alkyl/aryl- and
Scheme 2. A) Intermolecular crossed-conjugate addition and b-hydride elimination. B) Pro-
posed dual activation method for the enantioselective crossed-Michael addition.
Table 1: Optimization of reaction conditions.[a]
dialkyl-substituted
nitroalkenes
could be promoted in this trans-
formation. Although monoalkyl-
substituted nitroalkenes are suita-
ble for the b-hydride elimination,
they gave low yields because of
significant polymerization.
To achieve high atom efficiency,
it would be ideal to convert both
diastereomers into one stereoiso-
mer. It was reported that the ste-
reogenic center to which the nitro
group is appended can be removed
by using transformations such as the
Entry
Solvent
Catalyst
Co-catalyst[a]
T
[8C]
t
[h]
Conv.
[%][b]
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
7
8
DMSO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
other solvents[f]
MeOH
MeOH
MeOH
MeOH
cat-1
cat-1
cat-1
cat-1
cat-2
cat-2
cat-2
cat-2
cat-2
cat-2
cat-1
cat-3
cat-4
cat-5
–
–
–
RT
RT
0
0
RT
0
À20
À20
À25
RT
0
3
3
12
8
95
86
69
83
57
54
14
69
>95
<55
<80
80
32
74
58
71
64
78
51
47
12
64
0
11
23 Nef reaction, allylic nitro arrange-
ment, and reduction.[7] To extend
(MeO)3P
–
–
–
28
35
79
n.d.
90
3
the scope of this new method, a
12
48
48
48
8
24
24
24
24
simple
reductive
cyclization
approach was developed, using the
NO2 group as the nitrogen source
(Scheme 3).
(MeO)3P
9
(MeO)3P, AcOH
–
90[e]
<50
<74
76
23
68
93
10
11
12
13
14
<30
<28
70
46
68
other LBs[f]
(MeO)3P, AcOH
(MeO)3P, AcOH
(MeO)3P, AcOH
The reduction of syn/anti-3a
gave pyrrolidines 5a, which can be
converted into carbamate- or
amide-protected compounds 6a
and 6b, respectiviely, through
amine protection and ozonolysis.
Mixtures of diastereomers were
obtained for both 6a and 6b with
a d.r. value less than 2:1. However,
upon treatment with K2CO3 in
MeOH, the cis isomer was success-
fully converted into the trans is-
0
0
0
[a] Reaction conditions: 1a/2a 1:2, concentration of 1 is 0.2m, catalyst was 20mol %, LB and AcOH co-
catalysts were 1 equiv. [b] Based on the consumption of 1 as determined by NMR spectroscopy. [c] Yield
determined by NMR analysis with 1,3,5-trimethoxybenzene as internal standard. [d] The diastereomers
were separated and the ee values were determined by using HPLC on a chiral stationary phase (anti
isomer only). The low d.r. (less than 2:1) in all cases favors the anti isomer. [e] Yield of isolated product.
[f] See details in the Supporting Information. n.d.=not determined.
caused by the slow release of the amine catalyst from the
nitroalkene addition, thereby resulting in the lack of iminium
formation at low temperature. To help the release of the
amine, other LBs were used as co-catalysts, and P(OMe)3 was
identified as the best. As expected, both the reaction rate and
the enantioselectivity increased (Table 1, entry 8), and the
addition of 1.0 equivalent of AcOH promoted the iminium
formation, leading to 3a in excellent yield and enantioselec-
omer, with a d.r. value greater than 10:1 for 6a, and only
the trans isomer was observed for 6b. The trans-6b was then
converted into 7b with excellent yield and retention of
configuration. Interestingly, treating the carbamate cis-6a
with PhMgBr gave the cis cyclocarbamate, which significantly
extends the scope of the application of this transformation;
with the different protecting groups, both cis- and trans-
substituted pyrrolidine can be achieved with excellent reten-
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Table 2: Substrate scope of crossed-Michael addition.[a]
tions converted the mixture of diastereoisomeric products
into a single pyrrolidine stereoisomer, thereby extending the
potential application of this highly enantioselective method.
The application of 7b and its derivatives as new amine
catalysts in asymmetric synthesis[10] is currently under inves-
tigation and will be reported in due course.
R1
R2
4[a]
Yield [%][b] d.r.[c]
(syn/anti)
ee [%][d]
Experimental Section
syn anti
4a: Cinnamaldehyde (396 mg, 3.0 mmol) was added to a-methyl-b-
nitrostyrene (163 mg, 1.0 mmol) in MeOH (5 mL). The mixture was
cooled down to À258C. (S)-(À)-2-(Diphenylhydroxymethyl)pyrroli-
dine (45 mg, 0.2 mmol), AcOH (60 mg, 1.0 mmol), and (MeO)3P
(124 mg, 1.0 mmol) were added and the reaction mixture was stirred
for 48–60 h. The resulting reaction mixture was diluted with CH2Cl2
(20 mL), and the aqueous phase was extracted with CH2Cl2 (3 ꢀ
20 mL). The combined organic layers were washed with NaHCO3
(aq) and brine, then dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give a residue. Flash column
chromatography was used to remove the excess aldehyde and other
impurities. The crude products obtained were then dissolved in
MeOH (20 mL), to which NaBH4 (45 mg, 1.2 mmol) was added at
08C and monitored by TLC analysis. After the solvent had been
removed, the residue was diluted with ethyl acetate (30 mL) and
washed with water. The aqueous phase was extracted with ethyl
acetate (3 ꢀ 30 mL). The combined organic phases were then washed
with brine and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and purification using flash silica gel
chromatography (hexane/EtOAc 7:1) gave two alcohol diastereomers
syn-4a and anti-4a each as colorless oils (270 mg, overall yield: 91%).
For explicit experimental data, including spectroscopic data, see
the Supporting Information.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-ClC6H4
p-ClC6H4
p-ClC6H4
furyl
p-MeC6H4
naphthyl
p-CNC6H4
Ph
nBu
furyl
4a
4b
4c
91
83
76
80
89
85
93
89
78
74
64
82
82
86
79
75
71
1:1.2
91 93
94 86
87 87
94 95
82 83
86 86
88 88
88 90
86 86
84 88
90 88
91 92
90 88
82 80
77 81
70 75
87 87
1:1.1
1:1.1
1:1.2
1:1
p-MeOC6H4 4d
p-NO2C6H4 4e
o-NO2C6H4 4 f
Me
Ph
furyl
p-MeOC6H4 4j
Me
Ph
1:1
4g
4h
4i
1:1.2
1:1.2
1:1.1
1:1.2
1:1
1:1.1
1:1.3
1:1
4k
4l
p-NO2C6H4 4m
[e]
[e]
Ph
Ph
Ph
4n
4o
4p
p-NO2C6H4
1:1
1:2
1:2.5
p-MeOC6H4 4q
[a] Reaction conditions: 1/2 1:3, concentration of 1 was 0.2m. [b] Yield of
isolated products. [c] The d.r. values were determined by 1H NMR
analysis of the crude reaction mixture. [d] The ee values were determined
by HPLC on a chiral stationary phase. [e] Yields of aldehydes, no further
reduction.
Received: November 14, 2008
Published online: January 2, 2009
Keywords: asymmetric catalysis · enantioselectivity ·
.
Lewis bases · pyrrolidines
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Scheme 3. Enantioselective synthesis of substituted pyrrolidines.
a) 1. Zn/HCl, iPrOH; 2. NaCNBH3, MeOH; b) 1. Boc2O, Et3N, DMAP;
2. O3, CH2Cl2, À788C; c) 1. Ac2O, Et3N, DMAP; 2. O3, CH2Cl2, À788C;
d) K2CO3, MeOH; e) 1. PhMgBr, THF, 08C; 2. NH4Cl. Boc=tert-butoxy-
carbonyl; DMAP=N,N-dimethylaminopyridine.
tion of configuration.[9] This transformation provided a
feasible approach for the preparation of substituted pyrroli-
dines, which are important building blocks with attractive
chemical and biological activities.
In conclusion, the enantioselective crossed-conjugate
addition of nitroalkene and enals was successfully developed.
The wide substrate scope, excellent yields, enantioselectivity,
and unique activation approach provides great potential for
À
this new C C bond-formation strategy. Simple transforma-
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O. Kwon, J. Am. Chem. Soc. 2007, 129, 12928 – 12929; b) L. C.
Wang, A. L. Luis, K. Agaplou, H. Y. Jang, M. J. Krische, J. Am.
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[9] The stereochemistry of the products was assigned based on the
X-ray crystal structures of 4e and 6a. CCDC 704977 (cis-4e),
704978 (trans-4e), 704979 (6a), and 704980 (trans-6a) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif..
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Elsner, R. G. Hazell, K. A. Jørgensen, Angew. Chem. 2007, 119,
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1282
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