Highly enantioselective Michael addition of aromatic ketones to nitroolefins promoted by chiral bifunctional primary amine-thiourea catalysts based on saccharides

Article abstract of DOI:10.1021/ol0701666

(Chemical Equation Presented) A new class of thiourea catalysts have been developed which integrate saccharide and primary amine moieties into one small organic molecule. These simple catalysts are shown to be highly enantioselective for direct Michael ad

Full text of DOI:10.1021/ol0701666

ORGANIC
LETTERS
2007
Vol. 9, No. 5
923-925
Highly Enantioselective Michael Addition
of Aromatic Ketones to Nitroolefins
Promoted by Chiral Bifunctional Primary
Amine-thiourea Catalysts Based on
Saccharides
Kun Liu, Han-Feng Cui, Jing Nie, Ke-Yan Dong, Xiao-Juan Li, and Jun-An Ma*
Department of Chemistry, Tianjin UniVersity, Tianjin 300072, China
majun_an68@tju.edu.cn
Received January 22, 2007
ABSTRACT
A new class of thiourea catalysts have been developed which integrate saccharide and primary amine moieties into one small organic molecule.
These simple catalysts are shown to be highly enantioselective for direct Michael addition of aromatic ketones to a range of nitroolefins (up
to 98% ee).
Aspiring to imitate enzymatic synergistic cooperation of
multicenters, chemists have succeeded in developing many
kinds of multifunctional catalysts for asymmetric synthesis.1
In the context, the design of bifunctional thiourea catalysts
is currently receiving considerable attention. Impressive
progress has been made in the development of the secondary
and tertiary amine-thiourea catalysts for a diverse range of
reactions with high enantioselectivities.2 Nevertheless, the
design of chiral primary amine-thiourea catalysts has proven
to be a formidable challenge.3 To the best of our knowledge,
only two types of chiral primary amine-thiourea molecules
were employed in catalytic asymmetric reactions for a limited
substrate scope.4 Therefore, the development of new bifunc-
tional catalysts is still in great demand. Here, we will describe
a new class of saccharide-substituted primary amine-thiourea
bifunctional catalysts and their application for asymmetric
Michael additions of aromatic ketones to nitroolefins.
Starting from commercially available â-D-glucopyranose,
glycosyl isothiocyanate 1 was readily prepared via acetyla-
tion, bromination, and substitution reactions.5 Consequently,
addition of chiral 1,2-cyclohexyldiamines to isothiocyanate
(1) For reviews of metallic bifunctional catalysts, see: (a) Gro¨ger, H.
Chem.-Eur. J. 2001, 7, 5246. (b) Shibasaki, M.; Yoshikawa, N. Chem.
ReV. 2002, 102, 2187. (c) Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed.
2004, 43, 4566. For reviews of bifunctional organic catalysts, see: (d)
Special issue on organocatalysis: Houk, K. N., List, B., Eds. Acc. Chem.
Res. 2004, 37, 487. (e) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719. (f) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem.,
Int. Ed. 2006, 45, 7496.
(2) For reviews concerning bifunctional thiourea-based organo catalysis,
see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Connon, S.
J. Chem.-Eur. J. 2006, 12, 5418. (c) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520.
(3) For examples of asymmetric catalysis based on the primary amine
functionality, see: (a) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151.
(b) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C. C. F., III
Tetrahedron Lett. 2004, 45, 325. (c) Amedjkouh, M. Tetrahedron: Asym-
metry 2005, 16, 1411. (d) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.;
Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 7028. (e) Xu, Y.; Co´rdova,
A. Chem. Commun. 2006, 460.
(4) (a) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (b) Huang,
H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (c) Lalonde, M.
P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366.
10.1021/ol0701666 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/09/2007

1 afforded desired bifunctional thiourea catalysts 2a,b with
the glycosyl scaffold and the primary amine group in good
yields (60% for 2a and 61% for 2b) (Scheme 1). Using the
esters, ketonesters, 1,3-diketones, and 1,3-dinitriles.9 In
contrast, little progress has been made in the development
of aromatic ketones as Michael donors, and only one report
by Jacobsen and co-workers has addressed two acetophe-
nones as nucleophilic species.4b We are delighted to find that
the saccharide-substituted primary amine-thiourea 2 serves
as an efficient organocatalyst for direct asymmetric conjugate
addition of aromatic ketones to a broad spectrum of nitroole-
fins with excellent enantioselectivities up to 98% ee.
In the presence of 15 mol % of 2a-d, the addition reaction
of acetophenone with nitrostyrene was examined under
different conditions. Table 1 summarizes the results. Bi-
Scheme 1. Synthesis of Saccharide-Substituted Bifunctional
Primary Amine-thiourea Catalysts
Table 1. Enantioselective Addition of Acetophenone to
Nitrostyrenea
entry
catalyst
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2b
2b
2b
2b
2b
2b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
CHCl3
n-hexane
ether
46
60
<10
17
16
42
62
27
23
72
87 (R)
97 (S)
93 (S)
96 (S)
91 (S)
95 (S)
96 (S)
93 (S)
95 (S)
97 (S)
10d
CH2Cl2
a
The reaction was conducted with 2 (0.15 equiv), acetophenone (10
b
c
equiv), and several solvents.
Isolated yield. The ee values were
determined by HPLC, and the configuration was assigned by comparison
d
of retention time and specific rotation with that of the literature data.
Reaction time was 96 h.
same procedure, thiourea catalysts 2c and 2d were also
synthesized from maltose and lactose, respectively (in a yield
of 60% for 2c and 73% for 2d).
functional amine-thiourea 2a promoted the addition with a
high enantioselectivity of 87% ee but a moderate yield of
46% (entry 1). Gratifyingly, chiral catalyst 2b exhibited a
superior level of stereoselectivity with an opposite sense of
asymmetric induction and up to 97% ee can be obtained
(entry 2). This indicates that the (R,R)-configuration of 1,2-
diaminocyclohexane matched the â-D-glucopyranose to
enhance the stereochemical control. Bifunctional catalysts
The conjugate addition of nucleophiles to electron-deficient
olefins (the Michael addition reaction) is an important tool
for the construction of highly functionalized carbon skeletons.
Among the variants of this strategy, direct catalytic Michael
addition of carbonyl compounds to nitroolefins appears to
be the most facile route to produce the useful building blocks
in an atom-economical manner.6 In recent years, numbers
of small organic molecules have been developed as efficient
catalysts for the asymmetric conjugate addition to nitroolefins
with simple aldehydes,7 aliphatic acyclo and cycloketones,8
as well as more reactive nucleophiles, such as malonate
(8) For selected examples of asymmetric conjugate additions of aliphatic
(cyclo)ketones to nitroolefins, see: (a) Andrey, O.; Alexakis, A.; Tomassini,
A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147. (b) Ishii, T.;
Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558.
(c) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem.,
Int. Ed. 2006, 45, 3093. (d) Enders, D.; Chow, S. Eur. J. Org. Chem. 2006,
20, 4578. (e) Dixon, D. J.; Richardson, R. D. Synlett 2006, 81. (f) Mase,
N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J.
Am. Chem. Soc. 2006, 128, 4966. (g) Pansare, S. V.; Pandya, K. J. Am.
Chem. Soc. 2006, 128, 9624. (h) Zhu, M.-K.; Cun, L.-F.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2006, 17, 491. (i) Li, Y.; Liu,
X.-Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2034. (j) Almasi, D.;
Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2006, 17, 2064. For
other examples, see: ref 2 and refs therein.
(9) For selected examples of asymmetric conjugate additions of relatively
acidic carbon pronucleophiles to nitroolefins, see: (a) Li, H.; Wang, Y.;
Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105. (c) Terada, M.; Ube, H.; Yaguchi, Y. J. Am.
Chem. Soc. 2006, 128, 1454. For other examples, see: ref 2 and refs therein.
(5) (a) Lindhorst, T.; Kieburg, C. Synthesis 1995, 10, 1228. (b) Selkti,
M.; Kassab, R.; Lopez, H. P.; Villain, F.; de Rango, C. J. Carbohydr. Chem.
1999, 18, 1019.
(6) For a review of asymmetric Michael addition to nitroolefins, see:
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(7) For selected examples of asymmetric conjugate additions of aldehydes
to nitroolefins, see: (a) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas,
C. F., III Org. Lett. 2004, 6, 2527. (b) Wang, W.; Wang, J.; Li, H. Angew.
Chem., Int. Ed. 2005, 44, 1369. (c) Hayashi, Y.; Gotoh, H.; Hayashi, T.;
Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (d) Palomo, C.; Mielgo,
S.; Vera, A.; Go´mez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984.
(e) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861. (f) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.-Eur.
J. 2006, 12, 4321. (g) Mosse´, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis,
A. Org. Lett. 2006, 8, 2559. For other examples, see ref 2 and refs therein.
924
Org. Lett., Vol. 9, No. 5, 2007

2c and 2d with an (R,R)-configuration of the 1,2-diaminocy-
clohexane moiety can also induce high enantioselectivities
(entries 3 and 4). A substantial change of the solvent did
not have a significant effect on the stereoselection; however,
the catalytic activity of the bifunctional amine-thiourea
appeared to be different for these solvents (entries 2 and
5-9). The good results were attained when dichloromethane
and chloroform were used as solvents of the reaction. In
addition, the addition was carried out in higher yield with
prolonged reaction time (entry 10).
-neutral (entry 1) groups on aromatic rings were used, the
reactions proceeded to give highly enantioselective adducts.
Interestingly, the performance of the catalyst system was
explored by using the mixture of substrates of ortho- and
para-bromoacetophenones in one pot. The ee value remained
approximately constant (entry 12). This experiment implies
that the one-pot multisubstrate screening of small organic
catalysts could be realized.10
Notably, no desired product was obtained when the
primary amine group of catalyst 2b was replaced by the
tertiary amine, thus the prerequisite for good reactivity and
enantioselectivity is that the thiourea catalysts possess the
neighboring primary amine functionality. A bifunctional
catalytic mechanism was suggested in which a thiourea
moiety interacts through hydrogen bonding with a nitro group
of the nitroolefins and enhances their electrophilicity while
the neighboring primary amine activates ketones involving
an enamine intermediate. The observed absolute configura-
tion (S) of the conjugate adduct was explained by the
transition state assembly A (Figure 1) in which the si-face
Under the optimized experimental conditions, the scope
of the reaction was explored (Table 2). First, the conjugate
Table 2. Enantioselective Addition of Aromatic Ketones to
Nitroolefins
yield
(%)a
ee
entry adduct
Ar
R
(%)b
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
4-MePh
72
89
97
Ph
97
96
95
97
98
94
98
94
96
97
3
Ph
4-MeOPh 78
4
Ph
4-ClPh
2-BrPh
2-ClPh
2-naphthyl 74
2-furyl
Et
65
83
99
5
Ph
6
Ph
7
Ph
8
Ph
99
20
84
64
9
Ph
10
11
12
13
14
3j
3k
3l
4-MePh
4-MeOPh
Ph
Ph
4-BrPh/2-BrPh (44:56) Ph
42 (58:42) 96 (96)
92
46
3m 4-ClPh
3n 2-naphthyl
Ph
Ph
96
95
a
b
Figure 1. Transition state model.
Isolated yield. The ee values were determined by HPLC.
of the nitroolefin was predominantly approached by the
enamine intermediate generated from ketone and the primary
amine group of the bifunctional catalyst. The attack of the
enamine to the re-face of the nitroolefin was restricted by
the cyclohexyl scaffold of the catalyst.
In conclusion, we have developed a new class of bifunc-
tional primary amine-thiourea catalysts based on saccharides.
These simple organic molecules are shown to be excellently
enantioselective for direct Michael addition of aromatic
ketones to a series of aromatic-, heteroaromatic-, and alkyl-
substituted nitroolefins. Further investigation of the efficacy
of these organocatalysts in other catalytic asymmetric reac-
tions and the design of new bifunctional catalyst systems
are ongoing in our laboratories and will be reported in due
course.
addition of acetophenone to a variety of nitroolefins was
examined. The results showed that the reactions took place
in good to excellent yields (65-99%) and with high
enantioselectivity (94-98% ee) for aromatic- and heteroaro-
matic-substituted nitroolefins (entries 1-8). High stereose-
lection was also observed with alkyl-substituted nitroolefin,
and the moderate product yield appears to reflect formation
of small amounts of insoluble polymeric material (entry 9).
A variation of ketone substrates were probed next. It was
found that the 2b-catalyzed conjugate addition processes
were also applicable to various aromatic methyl ketones in
moderate to high yields (42-92%) and excellent enantiose-
lectivities (95-97% ee) (entries 10-14). It appears that the
position and the electronic property of the substituents for
aromatic rings of either nucleophiles or electrophiles have a
very limited effect on the stereoselection of conjugate
additions. No matter whether electron-withdrawing (entries
4-6, 12, and 13), -donating (entries 2, 3, 10, and 11), or
Acknowledgment. This work was supported financially
by NSFC (20542008) and the Ministry of Education of
China.
(10) For reviews, see: (a) Satyanarayana, T.; Kagan, H. B. AdV. Synth.
Catal. 2005, 347, 737. For selected examples, see: (b) Gao, X.; Kagan, H.
B. Chirality 1998, 10, 120. (c) Gennari, C.; Ceccarelli, S.; Piarulli, U.;
Montalbetti, C. A. G. N.; Jackson, R. F. W. J. Org. Chem. 1998, 63, 5312.
(d) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2002, 58,
5773. The utility of organocatalysts for the multisubstrate screening is under
investigation in our laboratories.
Supporting Information Available: Experimental details
and spectral data of all the new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0701666
Org. Lett., Vol. 9, No. 5, 2007
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