Recyclable cinchona alkaloid catalyzed asymmetric Michael addition reaction

Article abstract of DOI:10.1016/j.tetlet.2013.08.094

A highly enantioselective and diastereoselective Michael addition reaction of α-fluoro-β-ketoesters with maleimides is catalyzed by fluorous cinchona alkaloid to afford two adjacent chiral centers. The catalyst attached with a perfluroalkyl tag can be rec

Full text of DOI:10.1016/j.tetlet.2013.08.094

Tetrahedron Letters 54 (2013) 6064–6066
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Recyclable cinchona alkaloid catalyzed asymmetric Michael addition
reaction
⇑
Xin Huang, Wen-Bin Yi, Danash Ahad, Wei Zhang
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective and diastereoselective Michael addition reaction of a-fluoro-b-ketoesters with
Received 13 August 2013
Revised 22 August 2013
Accepted 24 August 2013
Available online 2 September 2013
maleimides is catalyzed by fluorous cinchona alkaloid to afford two adjacent chiral centers. The catalyst
attached with a perfluroalkyl tag can be recovered by fluorous solid-phase extraction (F-SPE).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Asymmetric synthesis
Cinchona alkaloid
Fluorous
Michael addition
Introduction
The construction of chiral quaternary carbons is a challenging
task in organic synthesis.14 Creation of fluorinated chiral quater-
Organocatalysis is becoming an increasingly important tool for
asymmetric synthesis.1 Compared to metal catalysis, organocataly-
sis has advantages of being free from toxic heavy metal, mild reac-
tion condition, and easy structure modification. However, high
catalyst loading (up to 20 mol %) and difficulty for catalyst recovery
are the major drawbacks of organocatalysis,2 which make organo-
catalyst recycling highly desirable. A great deal of attention has
been focused on the development of supported organocatalysts
with polymers,3 ionic liquids,4 and fluorous tags.5 The perfluori-
nated alkyl chain-attached catalyst can be easily recovered by flu-
orous solid-phase extraction (F-SPE)6 or by precipitation with
fluorophobic solvents such as hexane and water. Since the first flu-
orous catalyst was reported in 2001,7 many new fluorous organo-
catalysts have been developed and successfully applied in a range
of asymmetric transformations.5,8
Because of strong carbon–fluorine bond, small covalent radius,
and high electronegativity, fluorinated organic molecules could
generate significant influence on reactivity, metabolic stability,
and bioavailability of the compounds.9,10 Organofluorine com-
pounds have been developed as pharmaceutical and agricultural
products such as fluoxetine (antidepressant),11 atorvastatin (cho-
lesterol-reducer),12 and ciprofloxacin (antibacterial).13 There is a
strong demand for the development of new fluorine-containing
building blocks.
nary carbon center is even more difficult and only a handful of
examples which mainly rely on metal catalysis can be found in
the literature.15 Introduced in this Letter is a cinchona alkaloid-
based recyclable organocatalyst for asymmetric Michael addition.
Reactions of a-fluoro-b-ketoesters with maleimides afford Michael
addition product with a fluorine-containing chiral quaternary car-
bon adjacent to another chiral carbon.16
The synthesis of fluorous hydroquinine (F-HQN) was accom-
plished by a radical addition of perfluoroalkyliodide to quinine fol-
lowed by the reduction of iodide by hydrogenation (Scheme 1).7a
The screening of organocatalysts was carried out using ethyl 2-flu-
oro-3-oxo-3-phenylpropanoate and N-ethyl maleimide as sub-
strates. In addition to F-HQN, other cinchona alkaloids, proline,
and related organocatalysts were also evaluated (Table 1). Com-
pared to free quinine, F-HQN has almost the same yield and enanti-
oselectivity which means the fluorous tag has a minimal impact on
C8F17
1) C8F17I, NaHCO3
OMe
OMe
N
NaS2O3
ACN, H2O
N
N
2) H2, Pd/C
Et3N
EtOH, AcOEt
OH
OH
N
F-HQN, 50%
⇑
Corresponding author. Tel.: +1 617 286 6147; fax: +1 617 287 6030.
E-mail address: wei2.zhang@umb.edu (W. Zhang).
Scheme 1. Synthesis of F-HQN.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.094

X. Huang et al. / Tetrahedron Letters 54 (2013) 6064–6066
6065
Table 1
Catalyst screening for the Michael addition reaction
O
O
N
O
O
Cat. (Scheme 2)
20 mol%
Ph
OEt
F
Ph
OEt
O
O
+
N
Et
DCM, 72 h
O
F
O
Et
Entry
Cat.
T (°C)
Yielda (%)
drb
eec (%)
1
2
3
4
5
F-HQN
Quinine
Hydroquinine
25
25
25
25
25
93
94
50
95
—
>20:1
>20:1
>20:1
>20:1
—
77
80
77
ꢀ85
—
Hydroquinidine
-Proline
-Prolinol
L
6
7
8
9
25
25
25
25
—
—
—
D
10
—
>20:1
—
19
—
L
L
L
-Prolinamide
-Leucine
—
—
—
-Histidine
10
11
12
F-HQN
F-HQN
F-HQN
0
92
88
85
>20:1
>20:1
>20:1
77
82
87
ꢀ10
ꢀ20
a
b
c
Yield of isolated product.
Determined by 1H NMR.
Determined by chiral HPLC.
C8F17
OMe
OMe
OMe
N
OMe
N
N
N
N
N
HO
OH
OH
OH
N
N
hydroquinine
quinine
hydroquinidine
O
F-HQN
O
O
O
H3C
OH
OH
NH2
N
OH
OH
NH2
NH
NH
NH
CH3 NH2
L-leucine
N
H
L-proline
D-prolinol
L-prolinamide
L-histidine
Scheme 2. Structures of screened catalysts.
Table 2
Scope of the Michael addition reaction
O
O
O
O
F-HQN, 20 mol%
DCM, -20 oC, 72 h
Ar
OEt
O
Ar
O
OEt
O
+
F
N
R
F
O
N
R
Entry
Ar
R
Yield (%)
drb
eec (%)
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Et
93
98
90
75
92
90
95
90
92
88
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
82
83
87
73
80
75
85
83
84
85
Me
Bn
Ph
Et
Ph
Bn
Me
Et
10
Bn
a
b
c
Yield of isolated product.
Determined by 1H NMR.
Determined by chiral HPLC.

6066
X. Huang et al. / Tetrahedron Letters 54 (2013) 6064–6066
O
In conclusion, we have developed a highly enantioselective and
diastereoselective Michael addition reaction of -fluoro-b-ketoest-
ers with maleimides to afford products with a fluorinated quater-
nary carbon adjacent to another chiral carbon. This process is
efficiently catalyzed by a recyclable fluorous cinchona alkaloid
which can be recovered through F-SPE with high yield and purity.
F
a
OEt
Ph
O
O
O
O
N
N
O
O
O
O
O
N
F-HQN, 20 mol%
DCM, -20 oC, 72 h
+
Ph
OEt
F
2 equiv
O
Supplementary data
N
O
O
Supplementary data (reaction procedures and spectra) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.08.094.
EtO
Ph
F
O
78% (83% ee)
References and notes
Scheme 3. Reaction of (1,4-phenylene)dimaleimide.
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Ph
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tolerated. Moreover, N,N0-(1,4-phenylene)dimaleimide was also
found to be a good substrate to give double Michael addition prod-
uct in 78% yield and 83% ee (Scheme 3). The substitute groups on
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ence on the outcome of the products. Electron-withdrawing (en-
tries 5–8), electron-donating (entries 9–10), and electron-neutral
substrates (entries 1–4) all gave excellent results.
The efficiency of catalyst recovery was tested (Scheme 4). Upon
the completion of reaction, a base was added to the reaction mix-
ture. The organic phase was loaded onto a fluorous silica gel car-
tridge for F-SPE. It was found F-HQN was recovered in high yield
(94%) and excellent purity (98%). The second-round reaction using
the recovered catalyst gave similar product yield and ee.
17. Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K. W.; Wong, M. W.;
Tang, C. H. Angew. Chem., Int. Ed. 2009, 48, 3627–3631.