Rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water

Article abstract of DOI:10.1016/j.tetlet.2007.04.037

A rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water has been developed. High yield (up to 99%), diastereoselectivity (up to 99:1) and enantioselectivity (up to 97%) were obtained under optimal conditions.

Full text of DOI:10.1016/j.tetlet.2007.04.037

Tetrahedron Letters 48 (2007) 4281–4285
Rationally designed organocatalyst for direct asymmetric
aldol reaction in the presence of water
a
a
Chao Wang,a,c Yi Jiang,a,b,c, Xiao-xia Zhang, Yi Huang,
*
Bo-gang Lib and Guo-lin Zhangb,*
aChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
bChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
cGraduate School of the Chinese Academy of Sciences, Beijing 100039, China
Received 27 January 2007; revised 5 April 2007; accepted 6 April 2007
Available online 14 April 2007
Abstract—A rationally designed organocatalyst for direct asymmetric aldol reaction in the presence of water has been developed.
High yield (up to 99%), diastereoselectivity (up to 99:1) and enantioselectivity (up to 97%) were obtained under optimal conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
The use of water as reaction media has attracted much
attention because water is cheap, safe and environmen-
tally benign.1 Moreover, certain reactions can even be
accelerated in dilute aqueous solutions.2 Although it is
generally assumed that solubility is essential for efficient
reaction, Sharpless and co-workers found that substan-
tial rate acceleration could be obtained when insoluble
reactants were stirred in aqueous suspension, which they
termed as ‘on water’ phenomena.3 The organocatalytic
direct asymmetric aldol reaction ‘in the presence of’
water was developed by Takabe, Barbas and Hayashi
etc., which also proceeded in a heterogeneous way.4
Though the origins of such ‘on water’ reactions are pres-
ently unclear, it is believed that hydrophobic effect is one
of the key factors.5
rings of NOBIN are hydrophobic. We envisioned that
an appropriate combination of NOBIN moiety and
pyrrolindine in a chiral scaffold might result in a poten-
tial bifunctional hydrophobic organocatalyst. There-
fore, we designed two NOBIN–pyrrolindine based
organocatalyst 3a and 3b as shown in Scheme 1 and
found that both of them can catalyze the direct asym-
metric aldol reaction of cyclohexanone and aldehydes
in water efficiently. Here, we report the preliminary
results.
The reaction of cyclohexanone and p-nitrobenzaldehyde
was selected as a model. Initially, various conditions
were examined at room temperature using 3a as a cata-
lyst. Without any additives, the reaction afforded moder-
ate yield, enantioselectivity and good diastereoselectivity
(entry 1) in the presence of water. The addition of a cat-
alytic amount of TFA could increase dramatically both
the yield and enantioselectivity (entry 2). Acetic acid
can accelerate the reaction and slightly increase the dia-
and enantioselectivity (entry 3). The reaction can pro-
ceed in brine affording moderate yield and good dia-
and enantioselectivity (entry 4). The reaction can also
proceed in THF using 3a/TFA as catalyst, affording
good results (entry 5). Interestingly, Catalyst 3b/TFA
gave slightly better diastereoselectivity and similar
enantioselectivity and yield (entry 6).
The design of organocatalyst is of great current inter-
est.6 The enamine based organocatalysts such as proline
and its derivates are proven to be very efficient in vari-
ous reactions.7 NOBIN 2 is an excellent ligand8 with
axis chirality and a scaffold similar to amino alcohol,
which can provide double hydrogen bonding.9 Since
stronger acidity could provide stronger hydrogen bond-
ing,9 the very acidic hydrogens of NOBIN’s –NH2 and –
OH groups may be better hydrogen bond donors than
common amino alcohols’. Furthermore, the aromatic
The generality of the reaction was examined in detail
using catalyst 3a/TFA. The results were summarized
in Table 2. In most cases, reactions afforded anti-aldol
Keywords: Asymmetric catalysis; Organocatalysis; Direct aldol
reaction; NOBIN; Water.
*
Corresponding authors. E-mail: yjiang@cioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.037

4282
C. Wang et al. / Tetrahedron Letters 48 (2007) 4281–4285
O
N
N
H
H
a, b, c
HO
NH2
COOH
N
OH
3a
Cbz
O
N
H
HO
1
N
(rac)-2
H
3b
Scheme 1. The synthesis of the catalysts. Reagents: (a) ClCOOEt, NEt3; (b) flash chromatography separation; (c) Pd/C, H2.
Table 1. The effects of catalyst and additives on the reaction of cyclohexanone and p-nitrobenzaldehydea
O
O
OH
O
Catalyst
H2O, 25 οC
H
NO2
NO2
4
5
6
Entry
Catalyst
Additives
Time (h)
Yieldb (%)
anti:sync
eed (%)
1
2
3
4e
5f
6
3a
3a
3a
3a
3a
3b
None
TFA
CH3COOH
TFA
TFA
24
24
24
24
24
24
41
99
95
56
83
85
81:19
93:7
83:17
94:6
93:7
96:4
63
96
73
91
92
90
TFA
a The reactions were conducted with p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (1 mmol) catalyst (0.05 mmol), TFA (0.05 mmol) and water
(1 mL).
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by chiral-phase HPLC analysis for anti-products.
e The reaction was carried out in brine.
f The reaction was carried out in THF.
products in high yield with high enantioselectivity and
excellent diastereoselectivity. For electron-poor aro-
matic aldehydes, the reaction could complete within
24 h (entries 1–4). Longer reaction time was required
for less reactive aromatic aldehydes (entries 5–12). The
ring size of the cyclic ketones was also examined-both
cyclopentanone and cycloheptanone could be used as
donors but giving poorer results than cyclohexanone
(entries 13–14). The hydrophobic nature of the substrate
seems to be crucial for this reaction system. All the water
insoluble aldehydes and ketones formed an emulsion
during the reaction. The limitation of this catalytic sys-
tem is that it cannot extend to the simple acyclic ketones
and aliphatic aldehyde. The reaction of acetone and p-
nirobenzaldhyde in the presence of 3a/TFA in THF
could afford moderate yield and ee (entry 15), but no
reaction was detected in water.
formed in the transition state. Our hypothesis was fur-
ther proved by our experiments. We prepared catalyst
21 in which the hydroxyl group of the NOBIN scaffold
was protected by –CH3 (Fig. 2). The reaction of cyclo-
hexanone and p-nitrobenzaldehyde catalyzed by
10 mol % of 21/TFA afforded 98% yield, 97:3 anti:syn
selectivity and 91% enantioselectivity in the presence
of water in 24 h, which indicated that the hydroxyl
group had little influence to the transition state.
The 3a/TFA system was only applicable to aromatic
aldehydes. And the reaction carried out in THF also
afforded good results (Table 1, entry 5), which indicated
that the hydrophobic effect might not serve as a key fac-
tor to the selectivity. We supposed that the pi–pi interac-
tion between the aldehyde and the catalyst’s aromatic
rings in the transition state may play an important role
in the selectivity. Based on the above analysis, we pro-
posed a plausible transition state for the 3a/TFA cata-
lyzed aldol reaction as depicted in Scheme 2. The
enamine attacks the aldehyde from the Re face, resulting
in the formation of the major stereoisomer.
Catalyst 3a/TFA gave similar results as 3b/TFA (Table
1, entries 2 and 6). According to the X-ray crystal struc-
ture of 3a (Fig. 1), it is difficult to form double hydrogen
bond due to the distance between the hydroxyl group
and amino group and the rigid structure of NOBIN
scaffold. Hence, we reasoned that only one hydrogen
bond between the amino group and the aldehyde was
In summary, we have designed a new kind of organocat-
alysts that can catalyze the direct asymmetric aldol reac-

C. Wang et al. / Tetrahedron Letters 48 (2007) 4281–4285
Table 2. 3a/TFA catalyzed direct aldol reactions in watera
4283
O
O
OH
O
3a/TFA
(0.1 equiv)
H
R1
R1
H2O, 25 ο
C
R
R
R2
R2
Entry
1
Product
Time (h)
Yieldb (%)
anti:sync
eed (%)
O
OH
24
99
93:7
96
NO2
6
O
O
OH NO2
2
3
24
24
99
92
94:6
96:4
97
93
7
OH
NO2
8
O
OH NO2
4
6
99
94:6
88
NO2
9
O
O
OH
5
6
48
72
90
95
93:7
92:8
94
93
CN
Br
10
OH
11
O
O
O
OH
7
8
9
72
72
72
92
90
95
95:5
99:1
94:6
91
86
91
Cl
12
OH Cl
13
OH
Cl
14
O
OH
10
72
55
92:8
84
F
(continued on next page)
15

4284
C. Wang et al. / Tetrahedron Letters 48 (2007) 4281–4285
Table 2 (continued)
Entry
Product
Time (h)
72
Yieldb (%)
anti:sync
eed (%)
O
OH
11
50
90:10
81
16
O
OH
12
13
72
24
48
24
85
90
53
60
94:6
70:30
72:28
—
80
83
62
67
17
OH
O
NO2
18
O
OH
14
NO2
19
O
OH
15e
NO2
20
a The reactions were conducted with aldehyde (0.5 mmol), cyclohexanone (1 mmol) catalyst (0.05 mmol), TFA(0.05 mmol) and water (1 mL).
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by chiral-phase HPLC analysis for anti-products.
e THF was used as solvent.
O
N
N
H
H
H3CO
21
Figure 2. The structure of protected catalyst 21.
O
N
H
Figure 1. The X-ray crystal structure of 3a.
HO
O
N
H
tion in the presence of water efficiently. The 3a/TFA cat-
alyst system demonstrated excellent reactivity, diastere-
oselectivity and enantioselectivity in the presence of
water. The mechanism of the catalytic system was also
studied. The hydrogen bonding and the pi–pi interaction
might serve as key factors for the high selectivity.
pi-pi interaction
Scheme 2. Proposed transition state for the 3a/TFA catalyzed direct
asymmetric aldol reaction.

C. Wang et al. / Tetrahedron Letters 48 (2007) 4281–4285
4285
4966; (d) Jiang, Z.-J.; Liang, Z.; Wu, X.-Y.; Lu, Y.-X.
Chem. Commun. 2006, 2801; (e) Hayashi, Y. Angew. Chem.,
Int. Ed. 2006, 45, 8103.
Acknowledgement
We thank Prof. Kaibei Yu at Chengdu Institute of
Organic Chemistry for X-ray measurement.
5. (a) Lindstrom, U. M.; Andersson, F. Angew. Chem., Int.
Ed. 2006, 45, 548; (b) Otto, S.; Engberts, J. B. F. N. Org.
Biomol. Chem. 2003, 1, 2809; (c) Breslow, R. Acc. Chem.
Res. 2004, 37, 471.
Supplementary data
6. (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488; (b) Ooi, T.;
Maruoka, K. Acc. Chem. Res. 2004, 37, 526; (c) Tian, S.-K.;
Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc.
Chem. Res. 2004, 37, 621; (d) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138; (e) Seayad, J.; List,
B. Org. Biomol. Chem. 2005, 3, 719; (f) Wang, W.; Wang, J.;
Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369; (g) Cao,
L.-H.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8,
2901; (h) Cao, Y.-J.; Lu, H.-H.; Lai, Y.-Y.; Lu, L.-Q.; Xiao,
W.-J. Synthesis 2006, 3795; (i) Cao, Y.-J.; Lai, Y.-Y.;
Wang, X.; Li, Y.-J.; Xiao, W. J. Tetrahedron Lett. 2007, 48,
21.
7. (a) List, B. Acc. Chem. Res. 2004, 37, 548; (b) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580.
8. (a) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev.
2003, 103, 3213; (b) Ding, K.-L.; Guo, H.-C.; Li, X.; Yuan,
Y.; Wang, Y. Top. Catal. 2005, 35, 105.
Supplementary data associated with this article can be
found at doi:10.1016/j.tetlet.2007.04.037. The crystal
data are available at http://www.ccdc.cam.ac.uk. The
CCDC number is 620413.
References and notes
1. (a)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie A
& P: London, 1998; (b) Lindstrom, U. M. Chem. Rev. 2002,
102, 2751; (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res.
2002, 35, 209; (d) Li, C.-J. Chem. Rev. 2005, 105, 2751.
2. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b)
Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219.
3. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb,
H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44,
3275.
4. (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128,
734; (b) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958; (c) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
9. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 5262; (b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5755; (c) Tang, Z.; Yang, Z.-H.;
Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. J. Am. Chem. Soc. 2005, 127, 9285.