Highly enantioselective synthesis of γ-nitro heteroaromatic ketones in a doubly stereocontrolled manner catalyzed by bifunctional thiourea catalysts based on dehydroabietic amine: A doubly stereocontrolled approach to pyrrolidine carboxylic acids

Article abstract of DOI:10.1021/ol8025268

A new class of dehydroabietic amine-substituted primary amine-thiourea bifunctional catalysts were designed and synthesized. The doubly stereocontrolled organocatalytic conjugate addition of a variety of heterocycles-bearing ketones to nitroalkenes was in

Full text of DOI:10.1021/ol8025268

ORGANIC
LETTERS
2009
Vol. 11, No. 1
153-156
Highly Enantioselective Synthesis of γ-Nitro
Heteroaromatic Ketones in a Doubly
Stereocontrolled Manner Catalyzed by
Bifunctional Thiourea Catalysts Based on
Dehydroabietic Amine: A Doubly
Stereocontrolled Approach to Pyrrolidine
Carboxylic Acids
Xianxing Jiang,† Yifu Zhang,† Albert S. C. Chan,‡ and Rui Wang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and
Molecular Biology, Lanzhou UniVersity, Lanzhou, 730000, China, and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity,
Kowloon, Hong Kong
wangrui@lzu.edu.cn
Received November 1, 2008
ABSTRACT
A new class of dehydroabietic amine-substituted primary amine-thiourea bifunctional catalysts were designed and synthesized. The doubly
stereocontrolled organocatalytic conjugate addition of a variety of heterocycles-bearing ketones to nitroalkenes was investigated for the first
time, affording (S)- or (R)-γ-nitro heteroaromatic ketones with excellent enantioselectivities (up to ee >99%). Furthermore, the nearly optically
pure γ-nitro heteroaromatic ketones can be readily transformed into chiral pyrrolidine carboxylic acids.
From a synthetic perspective, both enantiomers of a chiral
compound are often useful and versatile in organic synthesis
and in the pharmaceutical industry. However, the doubly
stereocontrolled synthesis of chiral organic molecules is a
challenging task,1,2 and to the best of our knowledge,
effective metal-free organocatalytic methods using a double
asymmetric induction have rarely been reported to date. Thus,
† Lanzhou University.
‡ The Hong Kong Polytechnic University.
10.1021/ol8025268 CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society

developing an effective organocatalytic method is a highly
desirable goal. In the past few years, a series of thiourea-
based catalysts have been designed, synthesized, and used
to effectively catalyze various types of asymmetric reac-
tions.3,4 Great progress has been achieved in this field as a
result of seminal contributions from the groups of Jacobsen,5
Takemoto,6 Connon,7 Wang,8 and Deng.9 Nevertheless, the
potential application of these thiourea catalysts in doubly
stereocontrolled asymmetric reactions remains a much less
developed field, and there is still great demand for novel
bifunctional thiourea catalysts for this purpose. We first report
herein a new class of dehydroabietic amine-substituted
primary amine-thiourea bifunctional catalysts and their
application in a highly enantioselective and doubly stereo-
controlled synthesis of (S)- or (R)-γ-nitro heteroaromatic
ketones with excellent enantioselectivities.10,11 Our attention
was especially drawn to γ-nitro heteroaromatic ketones
because they could be readily converted to chiral pyrrolidine
carboxylic acids. In particular, ꢀ2-pyrrolidine carboxylic acids
are important building blocks in the synthesis of ꢀ-peptides,
bioactive molecules, and pharmaceuticals or are of other
potential biomedical utilities.12
Inspired by the excellent structural backbone and well-
defined stereocenters of dehydroabietic amine, we designed
and synthesized a new class of primary amine-thiourea
bifunctional catalysts (1S,2S)-L3 and (1R,2R)-L3 (see Sup-
porting Information). With these novel catalysts in hand, the
effects of the thiourea catalysts were investigated in com-
parison with other thiourea catalysts. A model reaction of
acetophenone to trans-ꢀ-nitrostyrene was performed in
CH2Cl2 at room temperature in the presence of 15 mol % of
thiourea catalysts (Table 1).
These results indicate that the stereochemical control
of the reaction is mainly provided by the 1,2-diaminocy-
clohexane moiety of thiourea (switching the configuration
of 1,2- diaminocyclohexane moiety from (R,R) to (S,S)
exhibited an opposite sense of asymmetric induction) and
that the catalytic activity depends mainly on the remaining
chiral scaffold moiety of thiourea (the inherent property
of stereochemical structure of the remaining chiral scaffold
moiety of thiourea) and also on the suitable matching of
the configuration of the 1,2-diaminocyclohexane moiety
with the remaining chiral scaffold moiety. In addition, this
remaining chiral amine moiety of thiourea also has an
important effect on the stereoselectivity for the formation
of adduct. These results also reveal that the catalytic
activity increased in the order of L3 > L2 > L1, which
corresponds to thiourea catalysts bearing a dehydroabietic
amine scaffold, a saccharide scaffold, and a phenyletha-
namine scaffold. Although Ma’s catalyst L213 with an
(R,R)-1,2-diaminocyclohexane moiety can induce high
enantioselectivity (97% ee, entry 3) and afford the (S)-
adduct with a moderate yield of 60%, the catalytic activity
of L2 can be inhibited drastically when replacing the (R,R)
configuration with an (S,S) configuration (in other words,
the (S,S) configuration of the 1,2-diaminocyclohexane
moiety could not match the ꢀ-D-glucopyranose scaffold
of thiourea), resulting in relatively low enantioselectivity
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154
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Enantioselective Michael Addition of Acetophenone to
trans-ꢀ-Nitrostyrenea
Table 2. Enantioselective Michael Addition of Acetophenone to
trans-ꢀ-Nitrostyrene with Lower Loadinga
entry
catalyst
loading (%)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
(1R,2R)-L3
(1S,2S)-L3
(1R,2R)-L3
(1S,2S)-L3
(1R,2R)-L3
(1S,2S)-L3
(1R,2R)-L3
10
10
5
5
1
82
80
68
64
58
59
42
99 (S)
98 (R)
98 (S)
98 (R)
98 (S)
98 (R)
97 (S)
1
0.5
a The reaction was conducted with trans-ꢀ-nitrostyrene (0.2 mmol),
acetophenone (0.6 mmol), and PhCOOH (0.15 equiv) in CH2Cl2. b Isolated
yield. c The ee values were determined by HPLC.
the loading of thiourea to 0.5 mol % and 97% ee was still
obtained but with a low yield of 42% (entry 7).
Heterocycles are among the most common substructures
found in organic active compounds. Although the asymmetric
Michael reactions of simple ketones to nitroalkenes have
been investigated intensely,14 the reaction of heterocycles-
bearing ketones has not been developed so far. Results of
experiments under the optimized conditions that probe the
scope of the reaction are summarized in Table 3. First, the
doubly stereocontrolled catalytic conjugate addition of a
variety of heterocycles-bearing ketones to nitroalkenes was
examined considering their usefulness and versatility in
organic synthesis (entries 1-11). All reactions underwent
clean reactions affording the desired products of the (S) or
(R) configuration with excellent enantioselectivities ((S)-
adducts, 98-99% ee; (R)-adducts, 98-99% ee) and moderate
to high yields. In view of the utility of γ-nitro heteroaromatic
ketones in the synthesis of ꢀ2-pyrrolidine carboxylic acids,
the doubly stereocontrolled catalytic conjugate addition of
a variety of ketones to furyl- and thienyl-substituted nitroalk-
enes was probed next (Table 3). As expected, the reaction
proceeded not only with heterocycles-bearing and aromatic
ketones but also with aliphatic ketones to give nearly
optically pure (S)- or (R)-adducts with high to excellent yields
(entries 12-21). The excellent performance of our doubly
stereocontrolled catalytic system also encouraged us to check
entry
catalyst
yield (%)b
ee (%)c
1
2
(1R,2R)-L1
(1S,2S)-L1
(1R,2R)-L2
(1S,2S)-L2
(1R,2R)-L3
(1S,2S)-L3
(1R,2R)-L3
(1S,2S)-L3
10
6
76 (S)
72 (R)
97 (S)
87 (R)
99 (S)
98 (R)
>99 (S)
98 (R)
3d
4d
5
60
46
79
78
96
93
6
7e
8e
a The reaction was conducted with trans-ꢀ-nitrostyrene (0.2 mmol) and
acetophenone (0.6 mmol). b Isolated yield. c The ee values were determined
by HPLC, and the configuration was assigned by comparison of the retention
time and specific rotation with literature data. d See ref 13. e PhCOOH (0.15
equiv) was added to the reaction for 72 h.
(87% ee, entry 4) and the (R)-adduct with a poor yield of
46%. In contrast, the (R,R) configuration of 1,2-diami-
nocyclohexane moiety or the (S,S) configuration can well-
match the dehydroabietic amine scaffold of L3 due to its
excellent structural backbone and well-defined stereo-
centers, resulting in excellent enantioselectivities ((S)-
adducts, 99% ee; (R)-adducts, 98% ee) and good yields
((S)-adducts, 79%; (R)-adducts, 78%; entries 5 and 6). It
was realized that the two chiral moieties of thiourea are
mutually reinforcing for the high efficacy of catalyst, and
primary amine-thiourea L3 is found to be the best one
for the doubly stereocontrolled organocatalytic process.
Gratifyingly, the addition of catalytic amounts of benzoic
acid could lead to further improvement of the yield in
CH2Cl2 (entries 7 and 8).
(14) For selected organocatalytic Michael addition of ketones to
nitroalkenes, see: (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 4966. (b) Zu, L.-S.;
Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077. (c) Wang, J.; Li, H.;
Lou, B.; Zu, L.-S.; Guo, H.; Wang, W. Chem.-Eur. J. 2006, 12, 4321. (d)
Enders, D.; Chow, S. Eur. J. Org. Chem. 2006, 4578. (e) Cao, C.-L.; Ye,
M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901. (f) Luo, S.; Mi, X.;
Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45,
3093. (g) Xu, Y.-M.; Co´rdova, A. Chem.Commun. 2006, 460. (h) Xu, Y.-
M.; Zou, W.-B.; Sunde´n, H.; Ibrahem, I.; Co´rdova, A. AdV. Synth. Catal.
2006, 348, 418. (i) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006,
128, 9624. (j) Almas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron:
Asymmetry. 2006, 17, 2064. (k) Kotrusz, P.; Toma, S.; Schmalz, H.-G.;
Adler, A. Eur. J. Org. Chem. 2004, 1577. (l) Andrey, O.; Alexakis, A.;
Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147. (m)
Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004,
126, 9558. (n) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka,
F.; Barbas, C. F., III. Synthesis 2004, 1509. (o) Martin, H. J.; List, B. Synlett
2003, 1901. (p) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003,
5, 2559. (q) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (r) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260. (s) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
In addition, we attempted to decrease the loading of
thiourea ligands (Table 2). To our surprise, the decrease of
the loading of thiourea ligands did not affect the stereose-
lectivity of the doubly stereocontrolled catalytic conjugate
addition, but a decrease in yield was observed (entries 1-6).
To test the power of the thiourea ligands, we further lowered
Org. Lett., Vol. 11, No. 1, 2009
155

Table 3. Enantioselective and Double Sterecontrolled Synthesis
of (S)- or (R)-γ-Nitro Heteroaromatic Ketonesa
Scheme 1
.
Synthesis of Chiral Pyrrolidine Derivatives and
ꢀ2-Pyrrolidine Carboxylic Acids
yield (%)b ee (%)c
entry adduct
R1
R
(S/R)
(S/R)
1
3b
3c
3d
3e
3f
3g
3h
3i
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
Ph
83/82
85/82
81/84
85/83
71/73
75/70
72/71
61/59
56/54
68/66
57/55
83/81
80/80
66/70
71/68
83/81
87/85
89/89
92/90
85/89
93/85
98/98
2
4-FPh
98/98
3
2-ClPh
3-ClPh
4-MeOPh
4-MePh
2-MeOPh
Ph
>99/>99
>99/>99
>99/98
98/98
>99/98
98/99
>99/98
>99/98
>99/>99
98/98
98/98
98/98
>99/>99
98/98
>99/98
99/98
4
5
6
7
8
5-methylfuryl
9
3j
3k
3l
2,5-dimethylfuryl Ph
10
11
12
13
14
15
16d
17
18
19
20
21
2-thienyl
2-thiazoleyl
2-furyl
Ph
Ph
yield of 50% (Scheme 1). In the same way, we could attain
6a (60% yield) and 7a (56% yield), which correspond to
(R)-3b and (R)-3m (Scheme 1). This representative example
demonstrates the inherent synthetic potential of this meth-
odology, our route being shorter and more convenient, which
will be of immense benefit for biomedical utilities and
industrial applications.
3m
3n
3o
3p
3q
3r
3s
3t
2-furyl
2-thienyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
5-methylfuryl
2-thienyl
Ph
4-ClPh
4-FPh
3-BrPh
3-MePh
Me
>99/98
>99/98
96/95
In conclusion, we have developed a new class of bifunc-
tional primary amine-thiourea catalysts based on dehydroa-
bietic amine, which has been successfully applied to the
doubly stereocontrolled synthesis of γ-nitro heteroaromatic
ketones. Furthermore, the adducts can be readily transformed
into chiral pyrrolidine carboxylic acids, and the synthetic
route is more convenient for practical use. Further investiga-
tion of the efficacy of these organocatalysts in other doubly
stereocontrolled asymmetric reactions and mechanistic stud-
ies are ongoing in our laboratories.
3u
3v
a The reaction was conducted with nitroalkenes (0.2 mmol), ketones
(0.6 mmol), and PhCOOH (0.15 equiv). b Isolated yield. c The ee values
were determined by HPLC, and the configuration was assigned by
comparison of the retention time and specific rotation with literature data.
d The reaction was conducted with trans-2-(2-nitrovinyl)furan (5.0 mmol).
if it could suit multigramscale synthesis, and the catalytic
conjugate addition of acetophenone to trans-2-(2-nitrovinyl)-
furan (5 mmol) was conducted under the optimized condi-
tions. In general, we obtained a satisfactory result, although
the yield was slightly diminished (entry 16).
Conversion of the conjugate addition products to pyrro-
lidine carboxylic acids proved straightforward. As an il-
lustration, the adduct (R)-3q was transformed into ꢀ2-
pyrrolidine carboxylic acid 5a by means of a three-step
procedure (Scheme 1). Adduct 3q was caused to undergo
reduction and cyclization to pyrrolidine 4a with 64% yield,
followed by protection with benzyl chloroformate and
oxidation, which provided the Cbz-protected ꢀ2-pyrrolidine
carboxylic acid 5a (dr ) 98/2, 80% yield). In the same
manner, starting from (S)-3q, 5b was attained with an overall
Acknowledgment. We are grateful for the grants from
the National Natural Science Foundation of China (nos.
20525206, 20772052, 90813012, and 20621091) and the
Chang Jiang Program of the Ministry of Education of China
for financial support.
Supporting Information Available: Experimental details
on the syntheses and analyses of the presented compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8025268
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