Asymmetric direct aldol reactions catalyzed by a simple chiral primary diamine-Bronsted acid catalyst in/on water

Article abstract of DOI:10.1080/00397910802431131

The direct asymmetric aldol reaction catalyzed by the simple and commercially available chiral primary diamines, (1S,2S)-1,2-diphenylethane-1,2- diamine and (1R,2R)-1,2-diphenylethane-1,2-diamine, is presented. The catalyst system is a primary amine with Bronsted acid-catalyzed direct aldol reaction of p-nitrobenzaldehyde and cyclohexanone with high chemo- and stereoselectivity on water, which furnishes the corresponding β-hydroxyketone with up to 94% ee. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802431131

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Asymmetric Direct Aldol
Reactions Catalyzed by
a Simple Chiral Primary
Diamine–Br⊘nsted Acid
Catalyst in/on Water
Li Li a , Li-Wen Xu a b , Ya-Dong Ju a & Guo-Qiao Lai a
a Key Laboratory of Organosilicon Chemistry and
Material Technology of Ministry of Educations,
College of Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou, China
b State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Lanzhou,
China
Published online: 29 Jan 2009.
To cite this article: Li Li , Li-Wen Xu , Ya-Dong Ju & Guo-Qiao Lai (2009) Asymmetric
Direct Aldol Reactions Catalyzed by a Simple Chiral Primary Diamine–Br⊘nsted
Acid Catalyst in/on Water, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:5, 764-774, DOI:
10.1080/00397910802431131
To link to this article: http://dx.doi.org/10.1080/00397910802431131
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Synthetic Communications1, 39: 764–774, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802431131
Asymmetric Direct Aldol Reactions Catalyzed by
a Simple Chiral Primary Diamine–Brønsted Acid
Catalyst in/on Water
Li Li,1 Li-Wen Xu,1,2 Ya-Dong Ju,1 and Guo-Qiao Lai1
1Key Laboratory of Organosilicon Chemistry and Material Technology of
Ministry of Educations, College of Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou, China
2State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, China
Abstract: The direct asymmetric aldol reaction catalyzed by the simple and
commercially available chiral primary diamines, (1S,2S)-1,2-diphenylethane-1,2-
diamine and (1R,2R)-1,2-diphenylethane-1,2-diamine, is presented. The catalyst
system is a primary amine with Brønsted acid–catalyzed direct aldol reaction of
p-nitrobenzaldehyde and cyclohexanone with high chemo- and stereoselectivity
on water, which furnishes the corresponding b-hydroxyketone with up to 94% ee.
Keywords: Aldol, asymmetric catalysis, organocatalysis, primary amine, water
INTRODUCTION
The asymmetric aldol reaction is plausibly an ancient transformation and
one of the most powerful methods for the constructing carbon–carbon
bonds in organic synthesis.[1] Organometallic complexes and Lewis
base–based catalysts have been highly successful for the asymmetric aldol
Received May 4, 2008.
Address correspondence to Guo-Qiao Lai, Key Laboratory of Organosilicon
Chemistry and Material Technology of Ministry of Educations, College of Chem-
istry and Chemical Engineering, Hangzhou Normal University, Hangzhou
310012, China. E-mail: licpxulw@yahoo.com
764

Asymmetric Direct Aldol Reactions
765
reaction of unmodified ketone and Mukaiyama-type silyl enol ethers in
the past decades.[2] Recently, the development of organocatalytic stereo-
selective methods for asymmetric direct aldol reactions has been a subject
of intense research. Since the pioneering work of List and coworkers in
2000,[3] the proline and its derivatives are arguably that the most efficient
and versatile small organic ‘‘enzymes’’ that catalyze a wide range of
organic transformations. There have been numerous reports on direct
aldol reactions catalyzed by proline and its structural analogs that utilize
the enamine mechanism,[4] which showes organocatalysis has experienced
a renaissance in homogeneous catalysis and green chemistry.[5]
Currently, the use of water as solvent for asymmetric reactions is of
great interest because of the low cost, safety, and environmentally benign
nature of water.[6] However, the proline-catalyzed aldol reactions can
only afford moderate to high enantioselectivity in organic solvents, and
the presence of a large amount of water resulted in the formation of pro-
ducts with low or no enantioselectivity.[3] Recently, Hayashi et al. showed
that direct asymmetric aldol reaction could be carried out with excellent
enantioselectivity in water by employing proline-derivated organocata-
lysts.[7] Then the groups of Codrova and Lu demonstrated that primary
ꢀ
amino acids such as alkaline and tryptophan could catalyze the aldol
reaction with good enantioselectivity in the presence of water.[8] The
recent progress with aqueous primary amino acid[8h] and diamine–
Brønsted acid–catalyzed asymmetric aldol reactions[9], created great
demand to study and develop novel, cheap, and simple amine catalysts
in organic reactions. In our continuing interest in the development
of organocatalytic protocols for carbon–carbon bond-forming transfor-
mation,[10] we report herein a simple chiral primary diamine–catalyzed
direct aldol reaction with excellent stereoselectivity in=on water.
RESULTS AND DISCUSSION
Although the simple and commercially available chiral primary diamine
(1S,2S)-1,2-diphenylethane-1,2-diamine (2)–catalyzed aldol reaction in
ꢀ
the absence of any Brønsted acids has been explored by Cordova et al.,
only low conversion (23% yield) with poor enantioselectivity (12% ee)
was achieved after 3 days in the aldol reaction of p-nitrobenzaldehyde with
cyclohexanone in wet dimethyl sulfoxide (DMSO). We reasoned that the
by-product Shiff base was produced, which resulted in very low catalytic
activity. It is hypothesized that primary diamine (Scheme 1, 1 or 2) might
be an efficient aldol catalyst in the presence of Brønsted acid in water.
In our initial study, we investigated the catalytic effects of chiral
primary diamine (1) with various Brønsted acids in the direct aldol

766
L. Li et al.
Scheme 1. The structure of (1S,2S)-1,2-diphenylethane-1,2-diamine and (1R,2R)-
1,2-diphenylethane-1,2-diamine.
reactions between cyclohexanone and p-nitrobenzaldehyde in water. As
shown in Table 1, among the Brønsted acids tested, D-camphorsulfonic
acid, p-toluenesulfonic acid (TsOH), and trifluoromethanesulfonic acid
(TfOH) were suitable Brønsted acids in this reaction (entries 1–4), and
TfOH was best additive for the aldol reaction. 20 mol% of TfOH enabling
Table 1. Screening results of aldol reaction with diamine–Brønsted acid catalyst
Entrya
Solvent
Brønsted acid Time (h) Yield (%)b Anti=sync Ee (%)d
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
H2O
D-CSA
TsOH
48
24
24
12
12
48
48
48
48
12
12
12
90
95
37
92
3:1
6:1
6:1
9:1
9:1
—
0.6:1
0.6:1
5:1
91
80
81
94
93
—
37
78
TsOHe
TfOH
H2O
TfOHe
D-CSA
D-CSA
D-CSA
45
CH2Cl2
Solvent free
PEG-600
PEG-600=H2Of D-CSA
H2O
H2O
H2O
Trace
30
55
68
92
92
10
11
12
TfOH
TfOH
TfOH
9:1
1:1
3:1
ꢀ94g
90h
93i
40
85
aThe reactions were performed with 1.0 mmol of p-nitrobenzaldehyde, 10 equiv.
of cyclohexanone, 10 mol% of (R,R)-diamine catalyst (1), 20 mol% Brønsted acid,
2 mL of H2O, at room temperature.
bIsolated yield.
cDetermined by H NMR analysis of the products.
dThe ee % of anti-products.
e10 mol% of TsOH was used.
fPEG-600=H2O ¼ 1:1 (1mL=1mL).
gUsing 10 mol% of (S,S)-diamine catalyst (2).
hUsing 1 mol% of catalyst.
iUsing 5 mol% of catalyst.

Asymmetric Direct Aldol Reactions
767
the completion of reaction in 12h (entry 4, 92% yield, 94% ee). With
10mol% of Brønsted acid, the desired product was obtained in lower yield
(entries 3 and 5), which confirmed the importance of Brønsted acid for pri-
mary amine-catalyzed aldol reaction. The role of Brønsted acid is probably
related to its possible function in facilitating the enamine catalytic cycle.[11]
The enantioselectivity of primary diamine (1) catalyzed aldol reaction was
dramatically affected by solvent, low conversions with poor enantioselec-
tivities were exhibited under solvent free conditions and in CH2Cl2 (entries
6 and 7), and notably, the aldol reaction performed under solvent-free con-
ditions favored the syn -isomer. More interestingly, PEG-600 mediated the
priamine-catalyzed aldol reaction with moderate yield (55%), and syn-iso-
mer is the major aldol product with good enantioselectivity (entry 8, anti-
=syn ¼ 0.6:1, 67% ee for syn- and 78% ee for anti-product respectively). The
addition of water (PEG=H2O ¼ 1=1) increased the conversion and stereo-
selectivity of aldol reaction obviously (entry 9), which clearly showed the
importance of water in primary diamine (1)–TfOH catalyzed aldol reac-
tion. Under the best-screened conditions, the loading of catalyst could
be reduced to 5 mol% while still maintaining excellent enantioselectivity
and quite significant activity (entry 12).
We also investigated the relationship between the enantiomeric
excess of the aldol product, derived from the aldol reaction shown in
Scheme 2, and the optical purity of the chiral diamine (1). Plotting the
enantiomeric excess of diamine versus that of b-hydroxy ketone 3 showed
a linear correction (Figure 1). Our results supported the supposition that
only one molecular primary diamine and two TfOH molecules catalyzed
Scheme 2. Primary amine-catalyzed direct aldol reaction of cyclohexanone and
p-nitrobenzaldehyde.

768
L. Li et al.
Figure 1. Relation between the enantiomeric excess of (1R,2R)-1,2-diphenyl-
ethane-1,2-diamine and that of the aldol product 3 in the catalytic direct aldol
reaction.
asymmetric aldol reaction. This correlation together with previous
theoretical findings by Allemann et al.[12] for amino acid–catalyzed aldol
reactions suggested that enamine mechanism is more favorable (Figure 2).
Figure 2. Proposed transition state for the aldol reaction of cyclohexanone.

Asymmetric Direct Aldol Reactions
769
Scheme 3. Primary amine-catalyzed direct aldol reactions.
Encouraged by these results, we also investigated the primary diamine–
TfOH–catalyzed aqueous asymmetric aldol reaction for a set of different
aldehydes and cyclic ketones on water (Scheme 3 and Table 2). We found
that the primary diamine–TfOH mediated the enantioselective aldol
reactions of cyclohexanone and various aromatic aldehydes with excellent
enantioselectivities, giving the corresponding aldol products with 89–93%
ee (entries 2–5). Unfortunately, the yields of aldol reactions of cyclohexa-
none and aromatic aldehydes without electron-deficient substituents is
low; moreover, acyclic ketones, such as acetone and acetophenone, were
bad donors and the aldol reaction did not occur. Hence, the primary
diamine–TfOH exhibited substrate specificity in the aldol reaction.
In summary, we have shown that simple primary diamines, (1S,2S)-
1,2-diphenylethane-1,2-diamine and (1R,2R)-1,2-diphenylethane-1,2-
diamine, can catalyze the asymmetric aldol reaction in the presence of
Brønsted acid on water. Excellent enantioselectivities were achieved in
Table 2. (R,R)-Diamine (1)-catalyzed direct aldol reactions of several substrates
on watera
Entry
R
R1, R2
Yield (%)b
Anti=sync
Ee(%)d
Ref.
1
2
3
4
5
6
7
8
p-NO2
o-Cl
p-Br
P-Me
p-MeO
p-NO2
o-NO2
o-NO2
CH3,H
NRe
22
28
20
15
58
39
48
—
20:1
3:1
—
93
90
89
90
64
72
45
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)4-
-(CH2)3-
13b
13c
13d
13e
13f
3:1
19:1
1=1.3
3:1
13g
13h
1.4=1
aThe reactions were performed with 1.0 mmol of aldehyde, 10 equiv. of ketone,
10 mol% of (R,R)-diamine catalyst (1), 20 mol% TfOH, 2 mL of H2O, at room
temperature, for 4 days (entries 1–5) or 1 day (entries 6–8).
bIsolated yield.
cDetermined by H-NMR analysis of the products.
dThe ee% of anti-products.
eNR: no reaction.

770
L. Li et al.
the aldol reaction of cyclohexanone and p-nitrobenzaldehyde with up to
94% ee and 92% yield. Notably, the presence of water both accelerated
the reaction and improved the enantioselectivity, which suggests hydrogen
bonding is of significant importance in the transition state. The mechanism
and the transition-state model have been discussed on the basis of stereo-
chemistry of the aldol products and enantiomeric excess relationships.
EXPERIMENTAL
All reagents and solvents were used directly without purification. Flash-col-
umn chromatography was performed over silica (200–300 mesh). 1H NMR
and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, and
were referenced to the internal solvent signals. Infrared (IR) spectra
were recorded using a Fourier transform infrared (FTIR) apparatus.
Thin-layer chromatography (TLC) was performed using silica-gel F254
TLC plates and visualized with ultraviolet light. High pressure liquid chro-
matography (HPLC) was carried out with a Waters 2695 Millennium
with photodiode array detector. All the aldol products were known[13]
and confirmed by gas chromatography-mass spectrometry (GC-MS) and
usual spectral methods (NMR and IR).
General Procedure for Aldol Reactions
A catalytic amount of (1R,2R)-1,2-diphenylethane-1,2-diamine (10 mol%)
was added to a vial containing 4-benzaldehyde (0.5 mmol), cyclohexa-
none (2.5 mmol), TfOH (20 mol%), and 2 mL of water. After vigorous
stirring at room temperature for the times shown in the tables, the reac-
tion mixtures was poured into an extraction funnel containing brine and
then diluted with distilled water and EtOAc. The aqueous phase was
extracted with EtOAc. The combined organic phases were dried with
Na2SO4, and the solvent was removed under reduced pressure. The crude
product was purified by silica-gel column chromatography to furnish the
desired aldol products. The ees of the aldol products were determined by
chiral-phase HPLC analysis.
Data
(2 R,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)methyl]cyclohexan-1-one
(Table 1)[8,13a]
1H NMR (400 MHz, CDCl3) (ppm): d ¼ 1.32–1.72 (m, 4H), 1.80–1.88 (m,
1H), 2.08–2.15 (m, 1H), 2.32–2.41 (m, 1H), 2.47–2.51 (m, 1H), 2.56–2.61

Asymmetric Direct Aldol Reactions
771
(m, 1H), 4.08 (br s, 1H), 4.89–4.91 (d, J ¼ 8.4 Hz,1H), 7.49–7.52 (m, 2H),
8.19–8.23 (m, 2H). ee was determined by HPLC analysis (Chiralpak
OJ-H, hexane–2-PrOH ¼ 70:30, 0.8 mL=min, 254 nm, 25 ꢀC. Anti-
diastereomer: tr (minor) ¼ 12.91 min, tr (major) ¼ 14.94 min.
(2 R,10S)-2-[10-Hydroxy-10-(4-nitrophenyl)methyl]cyclopentan-1-one
(Table 2, Entry 6)[13f]
1H NMR (400 MHz, CDCl3) (ppm): 1.46–1.59 (m, 1H), 1.70–1.77 (m,
2H), 2.01–2.04 (m, 1H), 2.24–2.30 (m, 1H), 2.38–2.40 (m, 1H), 2.44–
2.49 (m, 1H), 4.72 (brs, 1H), 4.84–4.86 (d, J ¼ 9.2 Hz, 1H), 7.51–7.55
(d, J ¼ 8.6 Hz, 2H) 8.21–8.22 (d, J ¼ 8.8 Hz, 2H). Ee was determined by
HPLC analysis (Chiralpak AS-H, hexane–2-PrOH ¼ 85:15, 1 mL=min,
254 nm, 25 ꢀC Anti-diastereomer: tr (major) ¼ 23.86 min, tr (minor) ¼
30.98 min).
(2 R,10S)-2-[10-Hydroxy-10-(2-nitrophenyl)methyl]cyclohexan-1-one
(Table 2, Entry 7)[13g]
1H NMR (400 MHz, CDCl3) (ppm): 1.53–1.73 (m, 4H) 1.73–1.78 (m, 1H)
1.82–1.86 (m, 1H), 2.33–2.34 (m, 1H), 2.42–2.43 (m, 1H), 2.76–2.77 (m,
1H), 4.17 (brs, 1H), 5.43–5.45 (d, J ¼ 7.2 Hz,1H), 7.40–7.44 t,J ¼ 8.0 Hz,
1H), 7.61–7.65 (t, J ¼ 7.6 Hz, 1H), 7.75–7.77 (d, J ¼ 7.6 Hz, 1H)
7.84–7.85 (d, J ¼ 8.4 Hz,1H). Ee was determined by HPLC analysis
(Chiralpak AD-H, hexane–2-PrOH ¼ 95:5, 1–mL=min, 254 nm, 25 ꢀC.
Anti-diastereomer: tr (minor) ¼ 36.28 min, tr (major) ¼ 38.06 min).
(2 R,10S)-2-[10-Hydroxy-10-(2-nitrophenyl)methyl] cyclopentan-1-one
(Table 2, Entry 8)[13h]
1 H NMR (400 MHz, CDCl3) (ppm): 1.72–1.78 (m, 3H), 2.01–2.05 (m, 1H),
2.34–2.79 (m, 3H), 5.42–5.44 (d, J ¼ 8.4 Hz, 1H), 7.44–7.53 (m, 1H), 7.66
(m, 1H), 7.79–7.85 (m, 2H). Ee was determined by HPLC analysis
(Chiralpak OD-H, hexane–2-PrOH ¼ 95:5, 1 mL=min, 254 nm, 25ꢀC Anti-
diastereomer: tr (minor) ¼ 26.90 min, tr (major) ¼ 30.38 min, 82% ee. 25ꢀC.
ACKNOWLEDGMENTS
This study was partially supported by the Natural Science Foundation
of China (NSFC No. 20572114) and Hangzhou Normal University.

772
L. Li et al.
Xu L. W. is greatly indebted to Prof. Dr. Yixin Lu, Department of
Chmestry, National University of Singapore, for his help.
REFERENCES
1. (a) Takayama, S.; McGarvey, G. J.; Wong, C. H. Enzymes in organic synth-
esis: recent developments in aldol reactions and glycosylations. Chem. Soc.
Rev. 1997, 26, 407 (b) Palomo, C.; Oiarbide, M.; Garcia, J. M. Current pro-
gress in the asymmetric aldol addition reaction. Chem. Soc. Rev. 2004 , 33, 65;
(c) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. Application of com-
plex aldol reactions to the total synthesis of phorboxazole B. J. Am. Chem.
Soc. 2000, 122, 10033.
2. (a) Mahrwald, R. Diastereoselection in Lewis acid–mediated aldol additions.
Chem. Rev. 1999, 99, 1095; (b) Machajewski, T. D.; Wong, C. H. The cataly-
tic asymmetric aldol reaction. Angew. Chem., Int. Ed. 2000, 39, 1352; (c)
Denmark, S. E.; Stavenger, R. A. Asymmetric catalysis of aldol reactions
with chiral lewis bases. Acc. Chem. Res. 2000, 33, 432; (d) Abiko, A. Boron-
Mediated Aldol Reaction of Carboxylic Esters. Acc. Chem. Res. 2004, 37,
387; (e) Hamada, T.; Manabe, K.; Ishikawa, S.; Nagayama, S.; Shiro, M.;
Kobayashi, S. Catalytic asymmetric aldol reactions in aqueous media using
chiral bis-pyridino-18-crown-6-rare earth metal triflate complexes. J. Am.
Chem. Soc. 2003, 125, 2989 (f) Saito, S.; Yamamoto, H. Design of acid-base
catalysis for the asymmetric direct aldol reaction. Acc. Chem. Res. 2004, 37,
570; (g) Luo, S. Z.; Zhu, L. H.; Talukdar, A.; Zhang, G. H.; Mi, X. L.;
Cheng, J. P.; Wang, P. G. Recent advances in rare earth-metal triflate cata-
lyzed organic synthesis in green media. Mini-Rev. Org. Chem. 2005, 2, 177.
3. List, B.; Lerner, R. A.; Barbas III, C. F. Proline-catalyzed direct asymmetric
aldol reactions. J. Am. Chem. Soc. 2000, 122, 2395.
4. (a) Gro¨ger, H.; Wilken, J. The application of L-proline as an enzyme mimic
and further new asymmetric syntheses using small organic molecules as chiral
catalysts. Angew. Chem.Int. Ed. 2001, 40, 529; (b) Northrup, A. B.;
MacMillan, D. W. C. The first direct and enantioselective cross-aldol reac-
tion of aldehydes. J. Am. Chem. Soc. 2002, 124, 6798 (c) Jarvo, E. J.; Miller,
S. J. Amino acids and peptides as asymmetric organocatalysts. Tetrahedron
2002, 58, 2481; (d) List, B. Proline-catalyzed asymmetric reactions. Tetrahe-
dron 2002, 58, 5573; (e) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas III, C. F. Organocatalytic direct asymmetric aldol
reactions in water. J. Am. Chem. Soc. 2006, 128, 734.
5. (a) Benaglia, M.; Puglisi, A.; Cozzi, F. Polymer-supported organic catalysts.
Chem. Rev. 2003, 103, 3401; (b) Dalko, P. I.; Moisan, L. In the golden age of
organocatalysis. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Berkssel, A.;
Gro¨ger, H. Metal-Free Organic Catalysts in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2004; (d) Special issue: Asymmetric organocatalysis. Acc.
Chem. Res. 2004, 37, 487; (e) Berkessel, A.; Gro¨ger, H. Asymmetric Organo-
catalysis; Wiley-VCH: Weinheim, 2005; (f) Xu, L. W.; Li, L.; Lai, G. Q.

Asymmetric Direct Aldol Reactions
773
Recent examples of divergent catalysis in organic reactions: Unexpected find-
ings or rational design? Mini-Rev. Org. Chem., 2007, 4, 217.
6. Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. Amino acid catalyzed
direct asymmetric aldol reactions: A bioorganic approach to catalytic asym-
metric carbon-carbon bond-forming reactions. J. Am. Chem. Soc. 2001, 123,
5260.
7. Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Highly diastereo- and enantioselective direct aldol reactions in water. Angew.
Chem., Int. Ed. 2006, 45, 958.
8. (a) Pizzarello, S.; Weber, A. L. Prebiotic amino acids as asymmetric catalysts.
ꢀ
Science, 2004, 303, 1151; (b) Cordova, A.; Zou, W.; Ibrahem, I.; Reyes, E.;
Engqvist, M.; Liao, W. W. Acyclic amino acid-catalyzed direct asymmetric
aldol reactions: Alanine, the simplest stereoselective organocatalyst. Chem.
ꢀ
´
Commun. 2005, 3586; (c) Cordova, A.; Ibrahem, I.; Casas, J.; Sunden, H.;
Engqvist, M.; Reyes, E. Amino acid–catalyzed neogenesis of carbohydrates:
A plausible ancient transformation. Chem. Eur. J. 2005, 11, 4772; (d)
ꢀ
Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Direct
asymmetric intermolecular aldol reactions catalyzed by amino acids and
small peptides. Chem. Eur. J. 2006, 12, 5383; (e) Jiang, Z.; Liang, Z.; Wu,
X.; Lu, Y. Asymmetric aldol reactions catalyzed by tryptophan in water.
Chem. Commun. 2006, 2801; (f) Wu, X.; Jiang, Z.; Shen, H. M.; Lu, Y. Highly
efficient threonine-derived organocatalysts for the direct asymmetric aldol
reactions in water. Adv. Synth. Catal. 2007, 349, 812; (g) Deng, D. S.; Cai,
J. W. Stereoselective aldol reactions catalyzed by acyclic amino acids in aqu-
eous micelles. Helv. Chim. Acta 2007, 90, 114; (h) Xu, L. W.; Lu, Y. Primary
amino acids: Privileged catalysts in enantioselective organocatalysis. Org.
Biomol. Chem. 2008, 6, 2047; (i) Peng F.; Shao, Z. H. Advances in asymmetric
organocatalytic reactions catalyzed by chiral primary amines. J. Mol. Catal.
A: Chem. 2008, 285, 1.
9. Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J. P. A simple primary-tertiary dia-
mine-brønsted acid catalyst for asymmetric direct aldol reactions of linear ali-
phatic ketones. J. Am. Chem. Soc. 2007, 129, 3074.
10. (a) Xu, L. W.; Xia, C. G. Highly efficient phosphine-catalyzed aza-Michael
reactions of alpha,beta-unsaturated compounds with carbamates in the pre-
sence of TMSCl. Tetrahedron Lett. 2004, 45, 4507; (b) Xu, L. W.; Gao, Y.;
Yin, J. J.; Li, L.; Xia, C. G. Efficient and mild benzoin condensation reaction
catalyzed by simple 1-N-alkyl-3-methylimidazolium salts. Tetrahedron Lett.
2005, 46, 5317; (c) Zhou, W.; Xu, L. W.; Yang, L.; Zhao, P. Q.; Xia, C. G.
Novel Brønsted acid-catalyzed Michael-type Friedel-Crafts reactions of
indoles and acetalization of aldehydes. J. Mol. Catal. A: Chem. 2006, 249,
129; (d) Zhou, W.; Xu, L. W.; Li, L.; Yang, L.; Xia, C. G. Enantioselective
Michael-type Friedel-Crafts reactions of indoles to enones catalyzed by a
chiral camphor-based Brønsted acid. Eur. J. Org. Chem. 2006, 5225; (e) Yang,
L. Xu, L. W.; Zhou, W.; Li, L.; Xia, C. G. Highly efficient aza-Michael reac-
tions of aromatic amines and N-heterocycles catalyzed by a basic ionic liquid
under solvent-free conditions. Tetrahedron Lett. 2006, 47, 7723; (f) Xu, L. W.;

774
L. Li et al.
Zhou, W.; Yang, L.; Xia, C. G. Chlorotrimethylsilane: A powerful Lewis
acidic catalyst in Michael-type Friedel-Crafts reactions of indoles and enones.
Synth. Commun. 2007, 37, 3095; (g) Zhou, W.; Xu, L. W.; Qiu, H. Y.; Lai, G.
Q.; Xia, C. G.; Jiang, J. X. Synthesis of a novel chiral ionic liquid and its
application in enantioselective aldol reactions. Helv. Chim. Acta 2008, 91, 53.
ꢀ
11. (a) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Cordova, A. The origin of
stereoselectivity in primary amino acid catalyzed intermolecular aldol reac-
tions. Angew. Chem., Int. Ed. 2005, 44, 7028; (b) Huang, H.; Jacobsen, E.
N. Highly enantioselective direct conjugate addition of ketones to nitroalk-
enes promoted by a chiral primary amine-thiourea catalyst. J. Am. Chem.
Soc. 2006, 128, 7170; (c) Lalonde, M. P.; Chen, Y. G.; Jacobsen, E. N. A
chiral primary amine thiourea catalyst for the highly enantioselective direct
conjugate addition of alpha,alpha-disubstituted aldehydes to nitroalkenes.
Angew. Chem., Int. Ed. 2006, 45, 6366; (d) Tsogoeva, S. B.; Wei, S. Highly
enantioselective addition of ketones to nitroolefins catalyzed by new
thiourea-amine bifunctional organocatalysts. Chem. Commun. 2006, 1451;
(e) Seebach, D.; Beck, A. K.; Badine, D. M.; Limbach, M.; Eschenmoser,
A.; Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.; Linder, B. Are oxa-
zolidinones really unproductive, parasitic species in proline catalysis?
Thoughts and experiments pointing to an alternative view. Helv. Chim. Acta
2007, 90, 425.
12. Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H. Y.; Houk, K. N.
Acc. Chem. Res. 2004, 37, 558.
13. (a) Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericas, M. A. Toward an
artificial aldolase. Org. Lett. 2008, 10, 337. (b) Liu, Y. X.; Sun, Y.-N.; Tan,
H.-H.; Liu, W.; Tao, J.-C. Linear polystyrene anchored L-proline: New
recyclable organocatalysts for the aldol reaction in the presence of water.
Tetrahedron: Asymmetry 2007, 18, 2649; (c) Gryko, D.; Saletra, W. J. Orga-
nocatalytic asymmetric aldol reaction in the presence of water. Org. Biomol.
Chem. 2007, 5, 2148. (d) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Highly efficient and reusable dendritic catalysts derived from N-prolylsulfo-
namide for the asymmetric direct aldol reaction in water. Org. Lett. 2006,
8, 4417; (e) Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang, X.-L.; He, L. Highly
enantioselective direct aldol reaction catalyzed by cinchona derived primary
amines. Org. Biomol. Chem. 2007, 5, 2913; (f) Lacoste, E.; Vaique, E.; Ber-
lande, M.; Pianet, I.; Vincent, J.-M.; Landais, Y. Benzimidazole-
pyrrolidine=H þ (BIP=H þ), a highly reactive organocatalyst for asymmetric
processes. Eur. J. Org. Chem. 2007, 167; (g) Huang, J.; Zhang, X.;
Armstrong, D. W. Highly efficient asymmetric direct stoichiometric aldol
reactions on=in water. Angew. Chem. Int. Ed., 2007, 46, 9073; (h) Inoue,
H.; Kikuchi, M.; Ito, J.; Nishiyama, H. Chiral Phebox-rhodium complexes
as catalysts for asymmetric direct aldol reaction. Tetrahedron, 2008, 64, 493.