Highly efficient prolinamide-based organocatalysts for the direct asymmetric aldol reaction in brine

Article abstract of DOI:10.1016/j.tetlet.2009.04.013

Four prolinamide-based organocatalysts were readily synthesized and applied to the direct asymmetric aldol reactions of ketones and aromatic aldehydes in brine. When 2,4-dinitrophenol (DNP) was used as an acidic additive, 1 mol % low loading of 2b afforded aldol products with excellent diastereoselectivity of up to 98/2 dr and high enantioselectivity of up to 97% ee.

Full text of DOI:10.1016/j.tetlet.2009.04.013

Tetrahedron Letters 50 (2009) 3059–3062
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient prolinamide-based organocatalysts for the direct
asymmetric aldol reaction in brine
Ya-Ning Jia a, Feng-Chun Wu a, Xiao Ma a, Gong-Jian Zhu a, Chao-Shan Da a,b,
*
a Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Four prolinamide-based organocatalysts were readily synthesized and applied to the direct asymmetric
aldol reactions of ketones and aromatic aldehydes in brine. When 2,4-dinitrophenol (DNP) was used as
an acidic additive, 1 mol % low loading of 2b afforded aldol products with excellent diastereoselectivity of
up to 98/2 dr and high enantioselectivity of up to 97% ee.
Received 1 December 2008
Revised 1 April 2009
Accepted 3 April 2009
Available online 9 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Organocatalysis
Direct aldol reaction
Low loading of catalyst
Brine
Asymmetric aldol reaction is one sort of the most important
carbon–carbon formation reactions, which can generate many
valuable biologically optically active b-hydroxy carbonyl com-
pounds and it has tremendous utility in organic synthesis.1 Up to
now, three direct procedures can be performed to achieve chiral al-
dol products. They are biocatalysis methods,2 procedures catalyzed
by chiral metal especially zinc-involved complexes,3 and the asym-
metric organocatalytic protocols.4 Among these methods, the third
one is currently the most important and interesting procedure.
Many highly efficient small molecular organocatalysts have been
developed5 and the asymmetric organocatalytic aldol reactions
have rapidly grown to their adolescence from infancy6 since List
respectively. Therefore, development of chiral organocatalysts that
not only can be used in the aqueous medium but also can achieve
high enantioselectivity and yield with their low loading is still
extensively interesting and urgently desired. Herein we report
our results on this topic that a prolinamide-based secondary–ter-
tiary diamine could effectively catalyze the highly enantioselective
aldol reaction in brine with only 1 mol % of catalyst.
Ph
Ph
O
O
Ph
Ph
NH2
DCC,
H2N
NH2
OH
Cbz
N
H
Cbz
N
N
et al. successfully demonstrated that L-proline can highly catalyze
CH2Cl2, 0 °C-rt
76%
the simple aldol reaction of acetone and aldehydes.7 Although
the water in which the aldol reaction is performed is more fasci-
nating and challenging today, most of these disclosed results used
organic solvents as reaction media to date.8 Use of water as reac-
tion medium is quite important and urgent for the sustainable
development and protection of the environment in today’s society
because it is cheap, safe, easy to operate, and environmentally ben-
eficial.9 Moreover, only few reports10 described the use of less than
5 mol % catalyst loading to perform the aldol reactions in aqueous
media although groups of Singh,10c Gong,10a and Hayashi10d suc-
cessfully disclosed a 0.5% and 1% loading catalyst in the aldol reac-
tion with high enantioselective outcome in aqueous medium,
1
Ph
Ph
N
O
2a, R=H
NH
1. RCHO, NaBH3CN, AcOH
2b, R=n-C4H9
2c, R=n-C9H19
R
2. H2, 10% Pd/C
100%
NH
R
2a−c
Ph
Ph
N
O
NH
n-C4H9
n-C4H9
NH
2d
* Corresponding author. Tel./fax: +86 931 8915208.
E-mail address: dachaoshan@lzu.edu.cn (C.-S. Da).
Scheme 1. Synthesis of chiral organocatalysts 2a–d.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.013

3060
Y.-N. Jia et al. / Tetrahedron Letters 50 (2009) 3059–3062
Table 2
Four organocatalysts were readily prepared according to the
routine methods (Scheme 1). The Cbz-protected -proline was con-
Direct asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde catalyzed by 2
L
in brinea
densed with (R,R)-diphenylethyl diamine by DCC method to yield
compound 1. The routine N-alkylation of 1 with aliphatic alde-
hydes and NaBH3CN quantitatively furnished the tertiary amines.11
Then direct deprotection of Cbz group by hydrogenation with Pd/C
quantitatively gave the catalysts 2a–c.12a–c Catalyst 2d12d was
prepared according to the same procedure as 2b starting with
Entry
Catalyst (mol %)
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a (5)
2a (5)
2a (1)
2b (5)
2b (1)
2b (1)
2b (0.5)
2c (1)
2d (1)
rt
0
rt
rt
rt
0
rt
rt
rt
18
23
68
4
20
40
43
29
21
99
97
85
98
96
30
47
94
84
82
83
92
83
94
90
90
D-proline.
Initially, 10 mol % of 2a was tested in the model reaction of 4-
93
nitrobenzaldehyde with acetone in the presence of water at room
temperature. To our disappointment, it gave very poor enantiose-
lectivity (Table 1, entry 1). Considering the effects of acid additives
on increasing the enantioselectivity and yield,13 a series of acidic
additives with a gradient pKa were tested in succession. Indeed,
the acidic additives increased the enantioselectivity and yield (Ta-
ble 1, entry 2). When water was replaced with the saturated brine,
the enantioselectivity was sharply increased to 80% ee from 53% ee
(Table 1, entries 2 and 3). However, strong acidic additives such as
trifluoroacetic acid (TFA) and 2,4,6-trinitrophenol (TNP) nearly did
not allow the reaction to proceed and only trace product was ob-
served even after 36 h (Table 1, entries 6 and 7). Using phenol as
an additive provided very low enantioselectivity (Table 1, entry
8). Acetic acid gave low yield in spite of higher enantioselectivity
(Table 1, entry 10). The stearic acid with a hydrophobic long alkyl
chain contributed a lot to yield with only moderate ee (Table 1, en-
try 9). But with 2,4-dinitrophenol (DNP) as an additive,14 both the
high yield (96%) and enantioselectivity (80%) were obtained.
Therefore, DNP was identified as the optimal additive.
Next, the catalysts 2a–d and influence of the loading on the
reaction were investigated (Table 2). Interestingly, reducing the
amount of catalyst 2a from 10 mol % to 5 mol % led to higher ee
without sacrifice of the yield (Table 1, entry 3 vs Table 2, entry
1). When the loading was reduced to only 1 mol %, the enantiose-
lectivity was greatly increased to 92% ee at the cost that the reac-
tion time was largely prolonged (Table 2, entries 1 and 3). The
same trend was found when 2b was used (Table 2, entries 4 and
5). Although 5 mol % 2b exhibited the same enantioselectivity
(83% ee) as 5 mol % 2a, 1 mol % 2b provided the highly increased
ee of 94%. Further lowering the loading to 0.5 mol % 2b resulted
in slightly decreased ee with sharply decreased yield. Low temper-
ature did not contribute to high enantioselectivity but made the
reaction quite sluggish (Table 2, entries 2 and 6). For 2c, longer
reaction time than that needed for 2b was needed though it
achieved high yield and enantioslectivity as well (Table 2, entry
8). The catalyst 2d gave a greatly decreased ee with the inversed
configuration (Table 2, entry 9). So the configuration of the aldol
product was controlled by the chiral pyrrolidine moiety.15,16 In
summary, among catalysts 2a–d, 1 mol % 2b afforded the adduct
ꢀ72d
a
Conditions: 4-nitrobenzaldehyde (0.2 mmol), acetone (2 mmol), 2, and DNP in
brine (1.2 mL). An equimolar amount of DNP was used as to the catalyst 2.
b
Isolated yield.
Determined by HPLC.
(S)-Isomer was the major product.
c
d
Table 3
Direct asymmetric aldol reaction in brine
O
O
OH
O
2b (1 mol%), DNP (1 mol%)
+
Ar
H
Ar
brine, rt
Entry
Ar
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
4-NO2-Ph
3-NO2-Ph
2-NO2-Ph
4-Br-Ph
4-Cl-Ph
4-F-Ph
20
12
12
120
120
120
20
96
97
85
64
26
17
93
85
94
91
89
90
77
89
92
82
5
6
7c
8d
4-NO2-Ph
4-NO2-Ph
20
a
Isolated yield.
Determined by HPLC.
The first recycled catalyst 2b was employed.
The second recycled catalyst 2b was employed.
b
c
d
not only with good yield but also with the highest enantioselectiv-
ity in the shortest reaction time.
A set of arylaldehydes were examined under the optimized con-
ditions: 1 mol % 2b and 1 mol % DNP in brine at room temperature
(Table 3). The results showed that the aldehydes with strong elec-
tron-withdrawing substituent participated in a fast reaction and
afforded high enantioselectivities. When the substituents of the
phenyl ring reduced their strength of withdrawing the electrons
such as halogen, the reaction was very sluggish and gave sharply
decreased yields and slightly decreased enantioselectivities. While
Table 1
Direct asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde catalyzed by 2a at room temperaturea
Entry
Catalyst (mol %)
Solvent
Additive
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
2a (10)
Water
Water
Brine
Water
Brine
Brine
Brine
Brine
Brine
Brine
None
DNP
DNP
PhCOOH
PhCOOH
TFA
16.5
36
14
24
17
36
36
14.5
28
24
82
92
96
87
11
53
80
46
49
—
89
Trace
Trace
45
90
25
TNP
—
Phenol
Stearic acid
AcOH
19
41
79
10
a
Conditions: 4-nitrobenzaldehyde (0.2 mmol), acetone (2 mmol), 2a (0.02 mmol), and additive (0.02 mmol) in water/brine (1.2 mL).
Isolated yield.
Determined by HPLC.
b
c

Y.-N. Jia et al. / Tetrahedron Letters 50 (2009) 3059–3062
3061
Table 4
vate the aldehyde. The enamine formed from the pyrrolidine and
acetone would chiefly attack the aldehyde from its Re-face. Thus,
the predominant R secondary alcohols were generated.
In conclusion, four prolinamide-based organocatalysts were
readily developed and employed to the highly asymmetric aldol
reactions of ketones and aromatic aldehydes in brine. The low
amount of 1 mol % 2b/DNP catalyst system showed excellent cata-
lytic activity, diastereoselectivity and enantioselectivity at room
temperature in brine.
Direct asymmetric aldol reaction of cyclohexanone in brine
O
O
OH
O
2b (1 mol%), DNP (1 mol%)
Ar
Ar
H
+
brine, rt
Entry
Ar
Time (h)
Yielda (%)
drb
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
4-NO2-Ph
3-NO2-Ph
2-NO2-Ph
4-Br-Ph
4-Cl-Ph
3-Cl-Ph
22
13
12
60
60
60
60
19
20
84
95
99
73
76
75
84
90
92
69
38
10
97
79:21
67:33
92:8
85:15
89:11
74:26
94:6
81:19
58:42
98:2
89:11
92:8
93
95
95
93
88
91
93
89
94
97
82
79
77
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 20672051).
2-Cl-Ph
2,4-Di-Cl–C6H4
4-CF3-Ph
2-CF3-Ph
4-CH3-Ph
4-OCH3-Ph
4-NO2-Ph
68
References and notes
125
125
11
1. (a) Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis;
Mahrwald, R., Ed. Modern Aldol reactions; Wiley-VCH: Weinheim, 2004; Vol.
1, (b) Metal Catalysis; Mahrwald, R., Ed. Modern Aldol reactions; Wiley-VCH:
Weinheim, 2004; Vol. 2, (c) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929.
2. For direct asymmetric aldol reactions with biocatalysis, see: (a) Machajewski,
T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352; (b) Gijsen, H. J. M.;
Qiao, L.; Fitz, W.; Wong, C.-H. Chem. Rev. 1996, 96, 443; (c) Wagner, J.; Lerner, R.
A., ; Barbas, C. F., III Science 1995, 270, 1797; (d) Dean, S. M.; Greenberg, W. A.;
Wong, C.-H. Adv. Synth. Catal. 2007, 349, 1308; (e) Li, C.; Feng, X.-W.; Wang, N.;
Zhou, Y.-J.; Yu, X.-Q. Green Chem. 2008, 10, 616.
3. For direct asymmetric aldol reactions catalyzed by chiral metal complexes, see:
(a) Li, H.; Da, C.-S.; Xiao, Y.-H.; Li, X.; Su, Y.-N. J. Org. Chem. 2008, 73, 7398; (b)
Kantam, M. L.; Ramani, T.; Chakrapani, L.; Kumar, K. V. Tetrahedron Lett. 2008,
49, 1498; (c) Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth. Catal. 2007,
349, 1041; (d) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706; (e) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497; (f)
Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett.
2001, 3, 1539.
4. For reviews on asymmetric organocatalytic aldol reactions, see: (a) Guillena,
G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (b) Tanaka,
F., ; Barbas, C. F., III In Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, 2007; p 19; (c) Pellissier, H. Tetrahedron 2007, 63, 9267; (d)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
5. For some recent reports on asymmetric organocatalytic aldol reactions, see: (a)
Chen, F.; Huang, S.; Liu, F.; Peng, Y. Tetrahedron 2008, 64, 9585; (b) D’Elia, V.;
Zwicknagl, H.; Reiser, O. Org. Lett. 2008, 73, 3262; (c) Xiong, Y.; Wang, F.; Dong,
S.; Liu, X.; Feng, X. Synlett 2008, 73; (d) Luo, S.; Xu, H.; Zhang, L.; Li, J.; Cheng, J.-
P. Org. Lett. 2008, 10, 653; (e) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H.
Angew. Chem., Int. Ed. 2008, 47, 2082; (f) Xu, Z.-X.; Li, G.-K.; Chen, C.-F.; Huang,
Z.-T. Tetrahedron 2008, 64, 8668; (g) Xu, X.-Y.; Wang, Y.-Z.; Gong, L.-Z. Org. Lett.
2007, 9, 4247; (h) Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc.
2007, 129, 3074; (i) Wang, F.; Xiong, Y.; Liu, X.; Feng, X. Adv. Synth. Catal. 2007,
349, 2665; (j) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am.
Chem. Soc. 2007, 129, 288; (k) Ma, G.-N.; Zhang, Y.-P.; Shi, M. Synthesis 2007,
197; (l) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S.
Tetrahedron: Asymmetry 2006, 17, 3351; (m) Rodriguez, B.; Rantanen, T.; Bolm,
C. Angew. Chem., Int. Ed. 2006, 45, 6924; (n) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.;
Yang, S.-T.; Wang, X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron Lett. 2006,
47, 7793; (o) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int. Ed.
2005, 44, 3055.
63:37
a
Isolated yield for aldol product (anti + syn).
Determined by HPLC. The value of dr is anti/syn.
Cyclopentanone was used instead of cyclohexanone.
b
c
aliphatic aldehydes were used as electrophiles of acetone, no aldol
adducts could be achieved. Notably, the catalyst could be recycled
once without reducing its catalytic activity.17
Hydrophobic cyclohexanone was further observed as a nucleo-
philic ketone. The same optimized reaction conditions were ap-
plied and the results are summarized in Table 4.17 The electron-
deficient arylaldehydes gave faster reaction rates, higher yields,
and higher enantioselectivities than the electron-rich ones. When
aliphatic aldehydes such as phenylpropionaldehyde and isobutyr-
aldehyde were used to replace the aromatic aldehydes, the reac-
tion failed to give aldols even with the increased loading of 2b.
Clearly, the predominant products were anti-isomers. It could be
easily found that the substituted position of the phenyl ring largely
effected the diastereoselectivity (dr) and the order was ortho > par-
a > meta, such as that of the three nitro-substituted benzalde-
hydes: 2-nitrobenzaldehyde gave the highest 92/8 dr,
4-nitrobenzaldehyde afforded 79/21 dr whereas 3-nitrobenzalde-
hyde gave only 67/33 dr. Similar results could be found among
the three chloro-substituted benzaldehydes. The highest enanti-
oselectivity (97% ee) and diastereoselectivity (98/2 dr) were
achieved when 2-trifluoromethylbenzaldehyde was used as a sub-
strate. But when cyclopentanone was employed as the nucleophilic
reagent, lower diastereoselectivity and enantioselectivity than
those achieved using cyclohexanone were afforded (Table 4, entry
13).
6. Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
Based on that the configuration of the aldol product was deter-
mined by the chiral pyrroline moiety and the previously reported
speculations on the stereochemical outcome,10c,13g,15 the transition
state shown in Figure 1 was proposed, in which the two hydroxyl
bonds from the aldehyde with the tertiary ammonium salt and the
amide group of the diamine framework should be favored to acti-
7. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am Chem. Soc. 2000, 122, 2395.
8. For reports on organocatalytic asymmetric aldol reactions in water, see: (a)
Chimni, S. S.; Singh, S.; Mahajan, D. Tetrahedron: Asymmetry 2008, 19, 2276; (b)
Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z. Adv. Synth. Catal. 2008, 350, 1390; (c) Tzeng,
Z.-H.; Chen, H.-Y.; Huang, C.-T.; Chen, K. Tetrahedron Lett. 2008, 49, 4134; (d)
Wang, C.; Jiang, Y.; Zhang, X.-x.; Huang, Y.; Li, B.-g.; Zhang, G.-l. Tetrahedron
Lett. 2007, 48, 4281; (e) Guizzeeti, S.; Benaglia, M.; Raimondi, M.; Celentano, G.
Org. Lett. 2007, 9, 1247; (f) Wu, X.; Jiang, Z.; Shen, H.; Lu, Y. Adv. Synth. Catal.
2007, 349, 812; (g) Lei, M.; Shi, L.; Li, G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li,
R. Tetrahedron 2007, 63, 7892; (h) Teo, Y.-C. Tetrahedron: Asymmetry 2007, 18,
1155; (i) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas, C. F., III Org.
Lett. 2006, 10, 1621; (j) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2006,
10, 1211; (k) Font, D.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2006, 8, 4653; (l) Wu,
Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417; (m) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem.
Soc. 2006, 128, 734.
Ph
O
Ph
N+
N
H
N
H
O
9. Comprehensive Organic Reactions in Aqueous Media; Li, C.-J., Chan, T.-H., Eds.,
2nd ed.; John Wiley & Sons: Hoboken, New Jersey, 2007.
10. (a) Zhao, J.-F.; He, L.; Jiang, J.; Tang, Z.; Cun, L.-F.; Gong, L.-Z. Tetrahedron Lett.
2008, 49, 3372; (b) Puleo, G. L.; Iuliano, A. Tetrahedron: Asymmetry 2007, 18,
2894; (c) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593; (d) Hayashi, Y.;
Ar
H
Figure 1. Proposed transition state model.

3062
Y.-N. Jia et al. / Tetrahedron Letters 50 (2009) 3059–3062
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 958.
13. Some references on additives, see: (a) Yuan, Y.; Long, J.; Sun, J.; Ding, K. Chem.
Eur. J. 2002, 8, 5033; (b) Sibi, M. P.; Manyem, S.; Palencia, H. J. Am Chem. Soc.
2006, 128, 13660; (c) Gryko, D.; Zimnicka, M.; Lipin´ ski, R. J. Org. Chem. 2007, 72,
964; (d) Pihko, P. A.; Laurikainen, K. M.; Usano, A.; Nuberg, A. I.; Kaavi, J. A.
Tetrahedron 2006, 62, 317; (e) Zhou, Y.; Shan, Z. J. Org. Chem. 2006, 71, 9510; (f)
Luo, S.; Hu, H.; Li, J.; Zhang, L.; Mi, X.; Zheng, X.; Cheng, J.-P. Tetrahedron 2007,
63, 11307; (g) Chen, F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008,
64, 9585; (h) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887; (i) Córdova, A.;
Notz, W.; Barbas, C. F., III Chem. Commun. 2002, 3024; (j) Wu, Y.-S.; Chen, Y.;
Deng, D.-S.; Cai, J. Synlett 2005, 16279.
14. Da, C.-S.; Che, L.-P.; Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N. J. Org. Chem. 2009, 74,
2541.
15. (a) Tang, Z.; Jiang, F.; Cui, F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5755; (b) 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.
11. Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
12. (a) Compound 2a: White solid; mp 146–148 °C; ½a D20
ꢁ
+31 (c 2.13, CHCl3); 1H
NMR (400 MHz CDCl3) d 8.50 (br, 1H), 7.19–7.25 (m, 3H), 7.04–7.12 (m, 7H),
5.22–5.27 (dd, 1H, J = 10.8 Hz, J = 5.6 Hz), 3.75–3.78 (dd, 1H, J = 8.8 Hz,
J = 4.8 Hz), 3.72–3.75 (d, 1H, J = 10.4 Hz), 2.98–3.06 (m, 2H), 2.41 (br, 1H),
2.17 (s, 6H), 2.01–2.13 (m, 2H), 1.72–1.79 (m, 2H); 13C NMR (100 MHz CDCl3) d
174.5, 140.9, 133.6, 129.6, 127.9, 127.6, 127.4, 126.7, 73.6, 60.9, 53.7, 47.2,
41.1, 30.7, 26.0; HRMS exact mass calcd for C21H27N3O ([M+H]+) 338.2227,
found 338.2222; IR (KBr) 3323, 3030, 2920, 2852, 2780, 1637, 1500, 1453,
1105, 1014, 870, 749, 700, 615 cmꢀ1. (b) Compound 2b: White solid; mp 51–
52 °C; ½a 2D0
ꢁ
+13 (c 2.00, CHCl3); 1H NMR (400 MHz CDCl3) d 8.82 (br, 1H), 7.17–
7.23 (m, 3H), 7.01–7.09 (m, 7H), 5.09–5.12 (d, 1H, J = 10 Hz), 3.81–3.84 (d, 1H,
J = 10.8 Hz), 3.74–3.78 (dd, 1H, J = 9.2 Hz, J = 4.8 Hz), 3.01–3.09 (m, 2H), 2.53–
2.60 (m, 2H), 2.03–2.11 (m, 4H), 1.70–1.85 (m, 3H), 1.24–1.53 (m, 12H), 0.93 (t,
6H, J = 7.4 Hz); 13C NMR (100 MHz CDCl3) d 174.5, 141.7, 134.8, 129.6, 127.8,
127.6, 127.3, 127.2, 126.6, 126.5, 69.1, 60.9, 54.1, 49.7, 47.3, 30.5, 29.7, 28.3,
26.3, 22.7, 14.1; HRMS exact mass calcd for C29H43N3O ([M+H]+) 450.3479,
found 450.3482; IR (KBr) 3342, 3062, 3083, 3027, 2956, 2928, 2860, 2818,
16. Similar to 2b, we also synthesized another catalyst 2e starting from L-proline
and racemic diphenylethyl diamine. However, the diastereoselectivity of 2e
was not 1:1 but 2:1 with the ratio of (S,R,R)- to (S,S,S)-isomer, which was
determined by 1H NMR, because of the stereoselectivity of the chiral building
blocks in synthetic course. With 1% 2e in brine at room temperature, the
reaction of acetone with 4-nitrobenzaldehyde afforded aldol with 92% yield
and slightly lowered enantioselectivity (85%) within 20 h. It could be
concluded in combination of the asymmetric outcome of 2d that the catalyst
1661, 1490, 1457, 1378, 1296, 1158, 1103, 1074, 756, 701, 612 cmꢀ1
.
(c) Compound 2c: White ceraceous solid; mp 42–45 °C; ½a D20
ꢁ
+10 (c 1.81,
CHCl3); 1H NMR (400 MHz CDCl3) d 8.63–8.64 (d, 1H, J = 4.4 Hz), 7.15–7.25 (m,
3H), 7.00–7.08 (m, 7H), 5.11–5.15 (dd, 1H, J = 10.8 Hz, J = 4.8 Hz), 3.86–3.89 (d,
1H, J = 11.2 Hz), 3.68–3.72 (dd, 1H, J = 8.8 Hz, J = 6.0 Hz), 2.99–3.04 (m, 2H),
2.52–2.59 (m, 2H), 2.04–2.16 (m, 3H), 1.93–1.99 (m, 2H), 1.73–1.79 (m, 2H),
1.19–1.49 (m, 32H), 0.89 (t, 6H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) d 174.6,
141.7, 134.8, 129.6, 127.8, 127.6, 127.3, 127.2, 126.5, 69.0, 60.9, 54.1, 49.7,
47.4, 31.9, 30.5, 29.8, 29.7, 29.6, 29.3, 28.7, 27.5, 26.3, 22.7, 14.1; HRMS exact
mass calcd for C39H63N3O ([M+H]+) 590.5044, found 590.5048; IR (KBr) 3332,
3062, 3027, 2924, 2854, 1660, 1488, 1378, 1300, 1186, 1148, 1106, 1073, 1026,
from L-Pro and (R,R)-diphenylethyl diamine should be superior to that from L-
Pro and (S,S)-diphenylethyl diamine in consideration of the enantioselectivity
of the reaction. Compound 2e: (S,R,R): 1H NMR (400 MHz CDCl3) d 8.86 (br, 1H),
6.99–7.77 (m, 10H), 5.10–5.18 (m, 1H), 3.81–3.84 (m, 1H), 3.73–3.75 (m, 1H),
2.92–3.07 (m, 2H), 2.51–2.60 (m, 2H), 2.04–2.18 (m, 4H), 1.61–1.86 (m, 3H),
1.17–1.50 (m, 12H), 0.92 (t, 6H, J = 7.0 Hz); (S,S,S): 1H NMR (400 MHz CDCl3) d
8.67 (br, 1H), 6.99–7.77 (m, 10H), 5.26–5.33 (m, 1H), 3.87–3.93 (m, 1H), 3.65–
3.69 (m, 1H), 3.11–3.19 (m, 2H), 2.73–2.76 (m, 2H), 2.22–2.27 (m, 4H), 1.91–
2.05 (m, 3H), 1.17–1.50 (m, 12H), 0.92 (t, 6H, J = 7.0 Hz).
909, 880, 757, 700, 614 cmꢀ1. (d) Compound 2d: Colorless colloid solid; ½a 2D0
ꢁ
+87 (c 2.06, CHCl3); 1H NMR (400 MHz, CDCl3) d 8.82 (br, 1H), 7.16–7.22 (m,
3H), 6.99–7.08 (m, 7H), 5.09–5.13 (dd, 1H, J = 11 Hz, J = 3 Hz), 3.81–3.84 (d, 1H,
J = 11.2 Hz), 3.74–3.77 (dd, 1H, J = 8.8 Hz, J = 5.2 Hz), 3.01–3.08 (m, 2H), 2.53–
2.60 (m, 2H), 2.02–2.11 (m, 4H), 1.68–1.85 (m, 3H), 1.24–1.53 (m, 12H), 0.93 (t,
6H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d 174.6, 142.0, 134.9, 129.6, 127.8,
127.6, 127.2, 127.1, 126.5, 69.2, 61.0, 54.1, 49.4, 47.4, 30.9, 29.6, 28.1, 26.2,
22.7, 14.1; HRMS exact mass calcd for C29H43N3O ([M+H]+) 450.3479, found
450.3469; IR (KBr) 3326, 3084, 3062, 3030, 2955, 2928, 2861, 1670, 1496,
17. General procedure for 2b-catalyzed aldol reaction in brine. A mixture of
ketone (2.0 mmol), DNP (0.37 mg), and the catalyst 2b (0.9 mg) in brine
(1.2 mL) was introduced with aldehyde (0.2 mmol). Then the reaction
mixture was stirred at room temperature until the reaction was complete
(determined by TLC). After addition of saturated aqueous NH4Cl (5 mL), the
mixture was extracted with ethyl acetate thrice. Then the combined organic
layers were dried over anhydrous Na2SO4, concentrated to dryness in vacuo,
and purified by preparative TLC to achieve the aldol products and the
recycled catalyst 2b.
1456, 1379, 1299, 1247, 1157, 1098, 757, 700, 625 cmꢀ1
.