Enantio- and diastereoselective asymmetric addition of 1,3-dicarbonyl compounds to nitroalkenes in a doubly stereocontrolled manner catalyzed by bifunctional rosin-derived amine thiourea catalysts

Article abstract of DOI:10.1021/jo9009276

(Chemical Equation Presented) Starting from commercially available natural rosin derivatives, a class of bifunctional rosin-derived amine thiourea catalysts were designed and synthesized. The doubly stereocontrolled asymmetric addition of a variety of 1,3

Full text of DOI:10.1021/jo9009276

pubs.acs.org/joc
Enantio- and Diastereoselective Asymmetric Addition of 1,3-Dicarbonyl
Compounds to Nitroalkenes in a Doubly Stereocontrolled Manner
Catalyzed by Bifunctional Rosin-Derived Amine Thiourea Catalysts
Xianxing Jiang,†,‡ Yifu Zhang,† Xing Liu,† Gen Zhang,† Luhao Lai,†,‡ Lipeng Wu,†
Jiannan Zhang,† 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; bcrwang@polyu.edu.hk
Received May 4, 2009
Starting from commercially available natural rosin derivatives, a class of bifunctional rosin-derived
amine thiourea catalysts were designed and synthesized. The doubly stereocontrolled asymmetric
addition of a variety of 1,3-dicarbonyl compounds to nitroalkenes was investigated. These rosin-
derived chiral thioureas have been shown to serve as effective catalysts for this double-sterecontrolled
organocatalytic process by the investigation of the efficacy of the thiourea catalysts in comparison
with other thiourea catalysts reported. In addition, these chiral thiourea ligands are easily available.
Furthermore, the rosin-derived tertiary amine-thiourea was also revealed to be highly efficient for
construction of contiguous stereogenetic centers containing an asymmetric quaternary carbon by the
Michael reaction of R-substituted β-ketoesters to nitroalkenes.
Introduction
applied to the highly enantioselective and doubly stereocon-
trolled synthesis of γ-nitro heteroaromatic ketones. While
previous studies on doubly stereocontrolled catalytic con-
jugate addition of ketones gained limited success, in view
of the doubly stereocontrolled synthesis of chiral organic
molecules remains as an elusive goal, the investigation of
potential application of thiourea catalysts based on rosin in
other doubly stereocontrolled asymmetric reactions is ur-
gently needed. Encouraged by the good results from previous
experiments, we consider if other Michael donors such as 1,3-
dicarbonyl compounds could also be suitable for this doubly
stereocontrolled catalytic process catalyzed by rosin-derived
chiral thiourea.
A key goal of the synthesis of chiral catalysts is to both
maximize the efficiency of using readily available materials
and minimize the generation of waste. Thus, the current
synthetic strategy often relies on the derivatization of the
available chiral pool of the natural organic products, which
limits the number of accessible derivatives, and the natural
compounds and their easily available derivatives as chiral
scaffolds for the design and synthesis of catalysts have
received great attention so far. Although the natural rosin
with excellent structural backbone and well-defined stereo-
centers is abundant in nature, its easily available derivatives
have rarely been developed in the synthesis of efficient
catalysts for asymmetric catalytic reactions to date.1 We
recently reported2 a class of primary amine-thiourea bifunc-
tional catalysts based on rosin, which have successfully been
In the past few years, a series of thiourea-based cata-
lysts were designed and synthesized because of their strong
hydrogen-bonding activity3 and effectively catalyzed various
(3) (a) Linton, B. R.; Goodman, M. S.; Hamilton, A. D. Chem.;Eur. J.
2000, 6, 2449. (b) Wilcox, C. S.; Kim, E.; Romano, D.; Kuo, L. H.; Burt, A.
L.; Curran, D. P. Tetrahedron 1995, 51, 621. (c) Kelly, T. R.; Kim, M. H. J.
~
Am. Chem. Soc. 1994, 116, 7072. (d) Etter, M. C.; Urbanczyk-Lipkowska, Z.;
Zia-Ebrahimi, M.; Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415.
(1) For the use of rosin derivatives as organocatalysts, see: Tayana, B.
K.; Nikalai, N. K.; Olga, V. T.; Alexander, G. T. Chirality 2004, 16, 40.
(2) Jiang, X. X.; Zhang, Y. F.; Chan, A. S. C.; Wang, R. Org. Lett. 2009,
11, 153.
5562 J. Org. Chem. 2009, 74, 5562–5567
Published on Web 06/24/2009
DOI: 10.1021/jo9009276
r
2009 American Chemical Society

Jiang et al.
JOCArticle
types of asymmetric reactions.4,5 The most remarkable
advances in this field were achieved by Jacobsen’s group.6
Takemoto and co-workers7,8 reported the first bifunctional
thiourea catalyst bearing a dimethyl amino group, which
was capable of the efficient promotion of the addition of
malonate esters and ketoesters to nitroalkenes. Herein, we
first report a class of bifunctional rosin-derived amine
thiourea catalysts and their application in the doubly
stereocontrolled catalytic conjugate addition of a variety
of 1,3-dicarbonyl compounds to nitroalkenes under mild
conditions.
Results and Discussion
Synthesis and Activity of Bifunctional Thiourea Catalysts.
Bifunctional rosin-derived tertiary amine-thiourea bifunc-
tional catalysts (1R,2R)-L1 and (1S,2S)-L1 were synthesized
as shown in Scheme 1. Using the same procedure, thiourea
catalysts L28f and L3 were also synthesized from 3,5-bis
(trifluoromethyl)aniline and R-phenylethanamine, respec-
tively (Figure 1). The efficacy of thiourea catalysts was
initially evaluated by the reaction of 2,4-pentanedione to
trans-β-nitrostyrene in the presence of 10 mol % of thiourea
ligands under different conditions (Table 1).
FIGURE 1. Structure of thiourea catalysts.
SCHEME 1. Preparation of Rosin-Derived Amine Thiourea Cata-
lystsa
In the initial experiment, a range of solvents were screened
for the process (entries 1-7, Table 1). An investigation
of different reaction media revealed that solvent had a
(4) For reviews concerning bifunctional thiourea organocatalysis, see:
(a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (b) Connon, S.
J. Chem.;Eur. J. 2006, 12, 5418. (c) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520. (d) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299.
(5) Selected for bifunctional chiral thiourea catalyzed reactions: (a)
Wang, Y.; Li, H. M.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J.
Am. Chem. Soc. 2007, 129, 6364. (b) Wang, B. M.; Wu, F. H.; Wang, Y.;
Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (c) Sibi, M. P.; Itoh,
K. J. Am. Chem. Soc. 2007, 129, 8064. (d) Pan, S. C.; Zhou, J.; List, B.
Angew. Chem., Int. Ed. 2007, 46, 612. (e) Zu, L. S.; Wang, J.; Li, H.; Xie, H.
X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (f) Zu, L. S.;
Xie, H. X.; Li, H.; Wang, H.; Jiang, W.; Wang, W. Adv. Synth. Catal. 2007,
349, 1882. (g) McCooey, S. H.; Conon, S. J. Org. Lett. 2007, 9, 599. (h) Liu,
K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9,
923. (i) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (j)
Wang, J.; Li, H.; Zu, L. S.; Jiang, W.; Xie, H. X.; Duan, W. H.; Wang, W. J.
Am. Chem. Soc. 2006, 128, 12652. (k) McCooey, S. H.; McCabe, T.;
Connon, S. J. J. Org. Chem. 2006, 71, 7494. (l) Tillman, A. L.; Ye, J. X.;
Dixon, D. J. Chem. Commun. 2006, 1191. (m) Dixon, D. J.; Richardson, R.
D. Synlett 2006, 81. (n) Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Adv.
Synth. Catal. 2006, 348, 826. (o) Herrera, R. P.; Sgarzani, V.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576. (p) Tsogoeva, S. B.;
Yalalov, D. A.; Hateley, M. J. Eur. J. Org. Chem. 2005, 4995.
(q) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. Catal. 2005,
347, 1643. (r) Wang, J.; Li, H.; Yu, X. H.; Zu, L. S.; Wang, W. Org. Lett.
2005, 7, 4293.
(6) For selected recent examples, see: (a) Zuend, S. J.; Jacobsen, E. N. J.
Am. Chem. Soc. 2007, 129, 15872. (b) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404.
(c) Tan, K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315.
(d) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 6366. (e) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
7170. (f) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964.
(g) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466.
(h) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 6700.
aReagents and conditions: (a) AcOH, 10% NaOH, Tol and Et2O, 45%;
(b) CS2, DCC, dry Et2O, 15 h, 92%; (c) CH2Cl2, 12 h, 83%.
significant effect on the efficiency of this process. Reactions
in solvents (THF, Et2O, and CHCl3) afforded the desired
Michael adduct (R)-3a with low yields (15-58%) and en-
antioselectivities (8-40%, entries 1-7, Table 1), whereas
those in dichloromethane proceeded in higher yields
and enantioselectivities (entries 4 and 5, Table 1). The best
results were attained when toluene was used as solvent
of the reactions (entries 6 and 7, Table 1). From the results
of recent studies,2 we have disclosed that the stereo-
chemical control of the reaction is mainly provided by the
1,2-diaminocyclohexane moiety of thiourea and the mutual
relationship between the catalytic activity and two chiral
moieties of thiourea. These results indicated that the replace-
ment of thiourea catalysts bearing a dehydroabietic amine
scaffold with a 3,5-bis(trifluoromethyl)aniline scaffold did
not impact the stereoselection, and bifunctional thiourea
catalysts L1 and L2 provided almost the same high enantios-
electivities ((R)-adducts, 82%; (S)-adducts, 80-84%; entries
6-9, Table 1). However, catalysts L2 showed relatively
low catalytic activity, resulting in lower yields ((R)-adducts,
(7) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
(8) For selected recent examples, see: (a) Yamaoka, Y.; Miyabe, H.;
Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686. (b) Inokuma, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413. (c) Hoashi, Y.; Okino,
T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032. (d) Xu, X. N.;
Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.;Eur. J. 2005,
12, 466. (e) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625. (f) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672.
J. Org. Chem. Vol. 74, No. 15, 2009 5563

Jiang et al.
JOCArticle
TABLE 1. Enantioselective Michael Addition Reactions of 2,4-Pentane-
TABLE 2. Enantioselective Michael Addition Reactions of 2,4-Pentane-
dione (1a) to trans-β-Nitrostyrenea
dione (1a) to Nitroalkenes by (R,R)-L1a
entry
catalyst
solvent
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
(1R,2R)-L1
(1R,2R)-L1
(1R,2R)-L1
(1R,2R)-L1
(1S,2S)-L1
(1R,2R)-L1
(1S,2S)-L1
(1R,2R)-L2
(1S,2S)-L2
(1R,2R)-L3
(1S,2S)-L3
(1R,2R)-L1
(1S,2S)-L1
THF
Et2O
CHCl3
CH2Cl2
CH2Cl2
Tol
Tol
Tol
Tol
Tol
15
50
58
78
75
95
93
73
70
52
48
91
89
8 (R)
35 (R)
40 (R)
66 (R)
62 (S)
82 (R)
80 (S)
82 (R)
84 (S)
63 (R)
50 (S)
90 (R)
91 (S)
9
10
11
12 d
13 d
Tol
Tol
Tol
aThe reaction was conducted with trans-β-nitrostyrene (0.1 mmol)
b
c
and 2,4-pentanedione (0.5 mmol). Isolated yield. The ee values were
determined by HPLC, and the configuration was assigned by compar-
ison of the retention time and specific rotation with literature data.9b,9c
dThe reaction was stirred at -30 °C.
73%; (S)-adducts, 70%; entries 8 and 9, Table 1). In con-
trast, thiourea catalysts L3 also gave the desired adduct,
but lower yields and enantioselectivities were observed
(entries 10 and 11, Table 1). It was realized that the ter-
tiary amine-thiourea L1 is found to be the best choice
for this doubly stereocontrolled organocatalytic process.
Gratifyingly, we further lowered the temperature to -30 °C,
and better enantioselectivities could be obtained ((R)-ad-
ducts, 90%; (S)-adducts, 91%; entries 12 and 13, Table 1)
without a significant decrease in yields ((R)-adducts, 91%;
(S)-adducts, 89%).
Enantioselective Asymmetric Addition of 2,4-Pentanedione
to Nitroalkenes in a Doubly Stereocontrolled Manner Cata-
lyzed by Bifunctional Thiourea Catalysts Based on Rosin
((1R,2R)-L1 and (1S,2S)-L1). Results of experiments under
the optimized conditions that probe the scope of the reaction
are summarized in Tables 2 and 3. The doubly stereocon-
trolled asymmetric addition of 2,4-pentanedione to a variety
of nitroalkenes was examined considering the usefulness
and versatility of adducts in organic synthesis9 (entries 1-
11, Table 2, and entries 1-11, Table 3). It is seen that all
reactions of aromatic nitroalkenes proceed smoothly afford-
ing the desired products of the (S) or (R) configuration with
high to excellent enantioselectivities ((R)-adducts, 82-99%,
entries 1-10, Table 2, and (S)-adducts, 82-99%, entries 1-
10, Table 3) and yields. As expected, the reaction proceeded
with aliphatic nitroalkenes also to give (S)- or (R)-adducts
aThe reaction was conducted with nitroalkenes (0.1 mmol) and
2,4-pentanedione (0.5 mmol). bIsolated yield. cThe ee values were
determined by HPLC, and the configuration was assigned by
comparison of the retention time and specific rotation with litera-
ture data.9 dValues in parentheses are those after a single recrystal-
lization.
(9) For organocatalytic asymmetric Michael addition of 2,4-pentane-
dione to nitroalkenes, see: (a) Wang, C. J.; Zhang, Z. H.; Dong, X. Q.;
Wu, X. J. Chem. Commun. 2008, 1431. (b) Peng, F. Z.; Shao, Z. H.; Fan, B.
M.; Song, H.; Li, G. P.; Zhang, H. B. J. Org. Chem. 2008, 73, 5202.
(c) Wang, J.; Li, H.; Duan, W.-H.; Zu, L. S.; Wang, W. Org. Lett. 2005, 7,
4713.
5564 J. Org. Chem. Vol. 74, No. 15, 2009

Jiang et al.
JOCArticle
TABLE 3. Enantioselective Michael Addition Reactions of 2,4-Pentane-
TABLE 4. Enantio- and Diastereoselective Michael Addition Reactions
dione (1a) to Nitroalkenes by (S, S)-L1a
of 1,3-Dicarbonyl Compounds to Nitroalkenes by (R,R)-L1a
entry
R1
R2
R3 time (h) yieldb (%)
drc
eed (%)
1
2
3
2-ClPh MeO Me
2-ClPh EtO Et
2-ClPh BnO Bn
48
48
48
12
12
12
5a: 80
5b: 83
5c: 85
5d: 86
5e: 90
5f: 83
57
64
59
4 e,f
5 e,f
6 e,f
Ph
Ph
Et
Et
Et
7:3 (99:1) 71 (99)
7:3 (99:1) 82 (99)
6:4 (99:1) 87 (99)
4-ClPh Ph
4-MePh Ph
aThe reaction was conducted with nitroalkenes (0.2 mmol) and 1,3-
dicarbonyl compounds (0.6 mmol). bIsolated yield. cDetermined by 1H
NMR spectroscopy. dThe ee values were determined by HPLC, and
the configuration was assigned by comparison of the retention time
and specific rotation with literatures data (see the Supporting Infor-
mation).10e,10h, 11 eValues in parentheses are those after a single recrys-
tallization. fThe reaction was stirred at -60 °C.
TABLE 5. Enantio- and Diastereoselective Michael Addition Reactions
of 1,3-Dicarbonyl Compounds to Nitroalkenes by (S,S)-L1a
entry
R1
R2 R3 time (h) yieldb (%)
drc
eed (%)
1
2
3
2-ClPh MeO Me
2-ClPh EtO Et
2-ClPh BnO Bn
48
48
48
12
12
12
5a: 81
5b: 81
5c: 80
5d: 82
5e: 99
5f: 86
75
62
67
4 e,f Ph
Ph
Et
Et
Et
7.8:2.2 (99:1) 90 (99)
5.4:4.6 (99:1) 70 (99)
6.4:3.6 (99:1) 79 (99)
5 e,f 4-ClPh Ph
6 e,f 4-MePh Ph
aThe reaction was conducted with nitroalkenes (0.2 mmol) and 1,3-
dicarbonyl compounds (0.6 mmol). bIsolated yield. cDetermined by 1H
NMR spectroscopy. dThe ee values were determined by HPLC, and
the configuration was assigned by comparison of the retention time
and specific rotation with literatures data (see the Supporting Infor-
mation).10e,10h,11 eValues in parentheses are those after a single recrys-
tallization. fThe reaction was stirred at -60 °C.
Enantio- and Diastereoselective Asymmetric Addition of
1,3-Dicarbonyl Compounds to Nitroalkenes10,11 in a Doubly
Stereocontrolled Manner Catalyzed by Bifunctional Thiourea
Catalysts Based on Rosin ((1R,2R)-L1 and (1S,2S)-L1).
Bifunctional thioureas (1R,2R)-L1 and (1S,2S)-L1 have
been proven to be very efficient catalysts for the doubly
stereocontrolled asymmetric addition of 2,4-pentanedione.
Following that encouraging result, subsequent studies were
(10) Selected for asymmetric conjugate addition of 1,3-dicarbonyl com-
pounds, see: (a) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007,
129, 11583. (b) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006,
128, 1454. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(d) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (e)
Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958. (f) Li, H.; Wang,
Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (g) Watanabe, M.;
Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126,
11148. (h) Barnes, D. M.; Ji, J. G.; Fickes, M. G.; Fitzgerald, M. A.; King, S.
A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger,
S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097. (i) Ji, J.; Barnes, D. M.;
Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc.
1999, 121, 10215.
aThe reaction was conducted with nitroalkenes (0.1 mmol) and 2,4-
pentanedione (0.5 mmol). bIsolated yield. cThe ee values were deter-
mined by HPLC, and the configuration was assigned by comparison of
the retention time and specific rotation with literature data.9 dValues in
parentheses are those after a single recrystallization.
with high yields ((R)-adducts, 85%, entry 11, Table 2, and
(S)-adducts, 81%, entry 11, Table 3) and moderate to good
enantioselectivities.
(11) Chen, F.-X.; Shao, C.; Wang, Q.; Gong, P.; Zhang, D.-Y.; Zhang,
B.-Z.; Wang, R. Tetrahedron Lett. 2007, 48, 8456.
J. Org. Chem. Vol. 74, No. 15, 2009 5565

Jiang et al.
JOCArticle
TABLE 6. Enantio- and Diastereoselective Michael Addition Reactions
further lowered to -60 °C for the adducts with a high level of
stereoselectivity. Studies revealed that the reaction pro-
ceeded not only in the presence of (1R,2R)-L1 but also in
the presence of (1S,2S)-L1 to give the desired adducts with
high to excellent yields (83-90%, entries 4-6, Table 4, and
82-99%, entries 4-6, Table 5). Although the diastereos-
electivies of products were low (up to 7.8/2.2), the enantios-
electivities were still satisfactory (71-87%, entries 4-6,
Table 4, and 70-90%, entries 4-6, Table 5). Gratifyingly,
the nearly optically pure products could be obtained after a
simple single recrystallization for all adducts in diethyl ether.
Application to the Construction of Quaternary Carbon
Centers. Conjugate addition of carbon nucleophiles to acti-
vated C-C double bonds is one of the most important and
versatile reactions for the construction of quaternary or
tertiary carbon centers. Several catalytic systems for the
enantioselective construction of quaternary carbon centers
through Michael addition have been developed in recent
years.12 Nevertheless, to the best of our knowledge, the
construction of quaternary carbon centers is still a difficult
task in organic synthesis, and there are only two reports of
organocatalytic Michael addition of R-substituted β-ketoe-
sters to nitroalkenes constructing a stereogenic quaternary
carbon center with high enantio- and diastereoselectivity.7,13
Having succeeded in the Michael reaction of nitroalkenes
with 1,3-dicarbonyl compounds such as 2,4-pentanedione,
malonates and R-unsubstituted β-ketoesters catalyzed by
our tertiary amine-thiourea L1, the Michael reaction of a
variety of nitroalkenes with R-substituted β-ketoesters 6a,b,
which generates a configurationally stable quaternary
stereocenter, was performed in the presence of 10 mol % of
(1R,2R)-L1 at -60 °C (Table 6). To our delight, all reactions
underwent clean reactions affording the desired adducts that
contain quaternary carbon centers with quantitive chemical
yields (98-99%, entries 1-9), excellent diastereoselectivies
(96/4-99/1, entries 1-9), and high to excellent enantioselec-
tivities (81-99%, entries 1-9). These observations suggest
that tertiary amine-thiourea L1 can serve as a very efficient
promoter for this process.
of Ketoesters to Nitroalkenes by (R,R)-L1a
Conclusion
In conclusion, we have developed a class of bifunctional
rosin-derived amine-thiourea catalysts that have been suc-
cessfully applied to the doubly stereocontrolled asymmetric
addition of 1,3-dicarbonyl compounds to nitroalkenes.
Furthermore, this tertiary amine-thiourea under mild
conditions could be used for construction of contiguous
stereogenetic centers containing an asymmetric quaternary
aThe reaction was conducted with nitroalkenes (0.2 mmol) and
ketoesters (0.6 mmol). bIsolated yield. cDetermined by 1H NMR spec-
troscopy. dThe ee values were determined by HPLC, and the configura-
tion was assigned by comparison of the retention time and specific
rotation with literature data.11
focused on other 1,3-dicarbonyl compounds such as various
malonates and R-unsubstituted β-ketoesters (Tables 4 and 5).
We first investigated the addition of three malonates to
nitroalkenes. When malonates (3 equiv) and nitroalkenes
were conducted in toluene in the presence of 10 mol % of
bifunctional thiourea catalysts L1 at -15 °C, in general, the
reactions were completed within 48 h, giving the desired
products of (S) or (R) configuration in high yields ((R)-
adducts, 80-85%, entries 1-3, Table 4, and and (S)-ad-
ducts, 80-81%, entries 1-3, Table 5) and moderate to good
enantioselectivities. β-Ketoester 4d was next employed as a
substrate for this process. Unexpectedly, this substrate re-
acted much more rapidly than the malonates, which may
result in low stereoselectivity. The reaction temperature was
(12) (a) Forbeck, E. M.; Evans, C. D.; Gilleran, J. A.; Li, P.; Joullie, M.
M. J. Am. Chem. Soc. 2007, 129, 14463. (b) Denmark, S. E.; Wilson, T. W.;
Burk, M. T.; Heemstra, J. R. Jr. J. Am. Chem. Soc. 2007, 129, 14864. (c) Liu,
T. Y.; Long, J.; Li, B. J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L. S.; Chen, Y. C.
Org. Biomol. Chem. 2006, 4, 2097. (d) Zu, L.; Wang, J.; Li, H.; Wang, W. Org.
Lett. 2006, 8, 307. (e) Christoffers, J.; Baro, A. Quaternary stereocenters:
challenges and solutions for organic synthesis. Wiley-VCH: Weinheim, 2005.
(f) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127,
4584. (g) Christoffers, J.; Baro, A. Angew Chem Int Ed. 2003, 42, 1688. (h) Mase,
N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F. III. Org. Lett. 2004, 6, 2527.
(i) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240.
€
(j) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. (k) Sibi, M. P.; Manyem,
S. Tetrahedron 2000, 56, 8033. (l) Leonard, J.; DMez-Barra, E.; Merino, S. Eur.
J. Org. Chem. 1998, 2051. (m) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M.
Tetrahedron Lett. 1996, 37, 5561.
(13) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B.
M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105.
5566 J. Org. Chem. Vol. 74, No. 15, 2009

Jiang et al.
JOCArticle
HPLC analysis (Chiralcel AS-H, i-PrOH/hexane = 15/85,
carbon by the Michael reaction of R-substituted β-ketoesters
to nitroalkenes. In this process, the adducts that con-
tain quaternary carbon centers were obtained with quanti-
tive chemical yields, excellent diastereoselectivies, and high
to excellent enantioselectivities.
1.0 mL/min, 210 nm): retention time tmajor =14.46 min,
t
minor =21.28 min, ee=91%.
Representative Procedure for the Asymmetric Addition of
Malonates and r-Unsubstituted β-Ketoesters to Nitroalkenes.
To a stirred solution of (1R,2R)-L1 or (1S,2S)-L1 (0.02 mmol,
10 mol %) and nitroalkene (0.2 mmol) in dry toluene (1.0 mL)
under Ar was added 1,3-dicarbonyl compound (0.6 mmol) over
a period of 15 min. After the reaction was completed (monitored
by TLC), the resulting mixture was concentrated under reduced
pressure and the residue was purified through column chroma-
tography on silica gel (eluent, ethyl acetate/hexane 1:6) to give
the optical pure product. The enantiomeric purity of the product
was determined by using HPLC and the dr values determined by
400 MHz 1H NMR (see the Supporting Information).
Experimental Section
Synthesis of Rosin-Derived Amine-Thiourea Catalysts. Using
the reported procedures,14 the pure dehydroabietic amine as
a white solid was obtained in 45% yield. Carbon bisulfide
(4.0 mL) and N,N0-dicyclohexylcarbodiimide (10 mmol) were
added to a solution of dehydroabietic amine (10 mmol) in dry
ether (35 mL) at 0 °C. The reaction mixture was allowed to warm
slowly to room temperature over a period of 3 h and then was
stirred for a further 12 h at room temperature. After separation
of the precipitated thiourea by filtration, the solvent was
removed under reduced pressure. After column chromatogra-
phy on silica gel eluted with 25% ethyl acetate in hexanes, the
corresponding isothiocyanate as a white solid was isolated in
92% yield. Under argon atmosphere, to a solution of the above
isothiocyanate (9.17 mmol) in dry dichloromethane (80 mL) was
added N,N-dimethyl-trans-diaminocyclohexane (10 mmol). The
reaction mixture was stirred for 12 h at room temperature and
was concentrated in vacuo. After column chromatography on
silica gel (ethyl acetate/hexane=2/1 as eluent), the thiourea L1
as a white solid was isolated in 83% yield.
(R)-Dimethyl
2-(1-(2-chlorophenyl)-2-nitroethyl)malonate
1
(5a):. colorless oil; [R]20D=-10.0 (c=1.0, CHCl3); H NMR
(300 MHz, CDCl3) δ 7.42 (m, 1H), 7.23 (m, 3H), 5.11 (dd, J=
8.7 Hz, 13.5 Hz, 1H), 4.96 (dd, J=4.5 Hz, 13.5 Hz 1H), 4.73 (dt,
J=4.5 Hz, 8.4 Hz 1H), 4.11 (d, J=8.4 Hz, 1H), 3.74 (s, 3H), 3.64
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.7, 167.2, 134.0, 133.6,
130.5 129.5, 128.5, 127.3, 75.4, 52.9, 52.8, 52.9, 39.3; IR 3008,
2955, 1734, 1594, 1554, 1435, 1379, 1255, 1074 cm-1; MS (CI)
m/z 315 [M]þ. ee was determined by HPLC analysis (Chiralcel
AD-H, i-PrOH/hexane=15/85, 1.0 mL/min, 215 nm): retention
time tminor =11.32 min, tmajor =34.87 min, ee=57%. Config-
uration assignment: The absolute stereochemistry was assigned
as R by comparison of the optical rotation with the following
literature value: Lit.11 (S)-5a: colorless oil; [R]20D= þ7.0 (c=
1.0, CHCl3). ee was determined by HPLC analysis (Chiralcel
AD-H, i-PrOH/hexane=15/85, 1.0 mL/min, 215 nm): retention
time tmajor =10.44 min, tminor =34.19 min, ee=75%.
1-((1R,2R)-2-(Dimethylamino)cyclohexyl)-3-(((1R,4aS,10aR)-
7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanth-
ren-1-yl)methyl)thiourea ((1R,2R)-L1):. [R]20D = þ2 (c = 2.0,
1
CHCl3); mp 82 °C; H NMR (300 MHz, CDCl3) δ 7.14-7.17
(d, J=8.1 Hz, 1 H), 6.97-6.99 (m, 1 H), 6.88 (s, 1H), 6.45 (br,
1 H), 3.68-3.70 (m, 1 H), 3.35 (m, 1 H), 2.79-2.91 (m, 3 H),
2.39-2.45 (m, 1 H), 2.20-2.34 (m, 7 H), 1.67-1.88 (m, 8 H),
1.43-1.50 (m, 2 H), 1.21-1.38 (m, 16 H), 0.85-1.64 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 147.1, 145.7, 134.7, 126.8, 124.1,
123.8, 67.1, 56.3, 55.4, 45.6, 40.3, 38.3, 37.8, 37.4, 36.6, 33.4,
33.1, 30.0, 25.2, 25.1, 24.5, 24.0, 23.9, 22.1, 19.1, 18.6, 18.5; IR
3437, 3259, 3066, 2928, 2248, 2122, 1550, 1452, 1380, 1058, 1029,
913, 822, 759, 624 cm-1; ESI-MS m/z 470 [Mþ]; HRMS-ESI
(m/z) calcd for C29H47N3S [M þ H]þ 470.3563, found 470.3573,
2.1 ppm.
Representative Procedure for the Asymmetric Addition of
r-Substituted β-Ketoesters to Nitroalkenes. To a stirred solution
of (1R,2R)-L1 or (1S,2S)-L1 (0.02 mmol, 10 mol %) and nitro-
alkene (0.2 mmol) in dry toluene (1.0 mL) under Ar was added
R-substituted β-ketoester (0.6 mmol). The solution was stirred
at -60 °C for 12 h. After the reaction was completed (monitored
by TLC), the resulting mixture was concentrated under reduced
pressure and the residue purified through column chromato-
graphy on silica gel (eluent, ethyl acetate/hexane 1:6) to give the
optical pure product. The enantiomeric purity of the product was
determined by using HPLC, and the dr values were determined by
400 MHz 1H NMR (see the Supporting Information).
Methyl 1-(2-nitro-1-phenylethyl)-2-oxocyclopentanecarboxy-
late (7a):. colorless oil; [R]20D = -33.0 (c = 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.23-7.33 (m, 5 H), 5.14-5.20 (dd,
J=4.2 Hz, 13.8 Hz, 1 H), 4.98-5.09 (dd, J=10.8 Hz, 13.5 Hz, 1
H), 4.06-4.11 (dd, J=3.9 Hz, 10.8 Hz, 1 H), 3.76 (m, 3 H), 2.34-
2.41 (m, 2 H), 1.79-2.09 (m, 4 H); 13C NMR (75 MHz, CDCl3)
δ 212.3, 169.8, 135.2, 129.3, 128.8, 128.3, 76.4, 62.4, 53.1, 46.1,
37.9, 31.1, 19.3; IR 3020, 2959, 2872, 2400, 1729, 1556, 1435,
1377, 1215, 1161, 1045, 758, 669 cm-1;ESI-MSm/z314 [M þ Na ]þ.
Major diastereomer: ee was determined by HPLC analysis (Chir-
alcel OD-H, i-PrOH/hexane = 10/90, 1.0 mL/min, 213 nm):
retention time tminor =18.49 min, tmajor=29.65 min, ee=92%.
Representative Procedure for the Asymmetric Addition of 2,4-
Pentanedione to Nitroalkenes. To a stirred solution of (1R,2R)-L
or (1S,2S)-L (0.01 mmol, 10 mol %) and nitroalkene (0.1 mmol)
in dry toluene (1.0 mL) under Ar was added 2,4-pentanedione
(0.5 mmol) over a period of 30 min. The solution was stirred at -
30 °C for 12 h. After the reaction was completed (monitored by
TLC), the resulting mixture was concentrated under reduced
pressure, and the residue was purified through column chroma-
tography on silica gel (eluent, ethyl acetate/hexane 1:8) to give the
optical pure product. The enantiomeric purity of the product was
determined by using HPLC (see the Supporting Information).
(R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (3a):. color-
less needles; [R]20D= -13.3 (c = 0.5, CHCl3); H NMR (300
1
MHz, CDCl3) δ 7.29-7.37 (m, 3 H), 7.18-7.20 (t, J=1.5 Hz,
2 H), 4.58-4.67 (m, 2 H), 4.36-4.40 (d, J=10.8 Hz, 1 H), 4.21-
4.28 (m, 1 H), 2.30 (s, 3 H), 1.94 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 201.8, 201.0, 136.0, 129.3, 128.6, 128.0, 78.2, 70.7,
42.8, 30.4, 29.5; IR 3155, 2924, 2254, 1794, 1702, 1558, 1469,
1381, 1095, 908, 734, 651 cm-1; ESI-MS m/z 272 [M þ Na ]þ.
ee was determined by HPLC analysis (Chiralcel AS-H, i-PrOH/
hexane = 15/85, 1.0 mL/min, 210 nm): retention time tminor
=14.78 min, tmajor =21.63 min, ee = 90%. (S)-3a: colorless
needles; [R]20D=þ5.4 (c=0.5, CHCl3). ee was determined by
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
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Gottstein, W. J.; Cheney, L. C. J. Org. Chem. 1965, 30, 2072.
J. Org. Chem. Vol. 74, No. 15, 2009 5567