Organic Solvent-Free Direct Asymmetric Aldol Reactions Catalyzed by a Siloxy Serine Organocatalyst in Brine

Article abstract of DOI:10.1080/00397910902730937

A siloxy serine organocatalyst has been developed to catalyze direct asymmetric aldol reactions in aqueous saline media. The asymmetric aldol reactions between a selection of aromatic aldehydes and cyclohexanone afforded the products in good yields and en

Full text of DOI:10.1080/00397910902730937

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Organic Solvent–Free Direct
Asymmetric Aldol Reactions
Catalyzed by a Siloxy Serine
Organocatalyst in Brine
Yong-Chua Teo a & Peter Peng-Foo Lee a
a Natural Sciences and Science Education , National
Institute of Education, Nanyang Technological
University , Singapore
Published online: 03 Aug 2009.
To cite this article: Yong-Chua Teo & Peter Peng-Foo Lee (2009) Organic Solvent–Free
Direct Asymmetric Aldol Reactions Catalyzed by a Siloxy Serine Organocatalyst in
Brine, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 39:17, 3081-3091, DOI: 10.1080/00397910902730937
To link to this article: http://dx.doi.org/10.1080/00397910902730937
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Synthetic Communications1, 39: 3081–3091, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730937
Organic Solvent–Free Direct Asymmetric Aldol
Reactions Catalyzed by a Siloxy Serine
Organocatalyst in Brine
Yong-Chua Teo and Peter Peng-Foo Lee
Natural Sciences and Science Education, National Institute
of Education, Nanyang Technological University, Singapore
Abstract: A siloxy serine organocatalyst has been developed to catalyze direct
asymmetric aldol reactions in aqueous saline media. The asymmetric aldol
reactions between a selection of aromatic aldehydes and cyclohexanone afforded
the products in good yields and enantioselectivities (up to 92% ee).
Keywords: Asymmetric aldol, enantiomeric excess, b-hydroxy carbonyl
compounds, organocatalyst, serine
INTRODUCTION
Organocatalysis has recently emerged as a powerful synthetic metho-
dology for asymmetric synthesis.[1] The development of small organic
molecules that avoid the use of expensive and=or toxic metals as useful
catalysts in enantioselective reactions is attracting much interest. These
organocatalysts provide a ‘‘green’’ alternative to transition metals
because of their relative nontoxicity. In addition, they are easy to purify
and dispose, giving them an added economic advantage over transition-
metal catalysts.
The direct catalytic asymmetric aldol reaction[2] is one of the
most powerful carbon–carbon bond-forming reactions used for the
Received October 8, 2008.
Address correspondence to Yong-Chua Teo, Natural Sciences and Science
Education, National Institute of Education, Nanyang Technological University,
1 Nanyang Walk, Singapore 637616. E-mail: yongchua.teo@nie.edu.sg
3081

3082
Y.-C. Teo and P. P.-F. Lee
construction of enantiomerically enriched b-hydroxy carbonyl compounds
and their derivatives. The intense demand for stereoselective synthesis of
aldol products has been fueled by their application as key synthons in
numerous natural product syntheses as well as medicinal chemistry.[3]
Recently, organocatalytic reactions performed in the presence of water
or brine have been reported by a few research groups.[4] These reactions
can be catalyzed by a chiral primary or secondary amine that contains a
hydrophobic functional group.[5] Henceforth, the development of small
molecules that catalyze the asymmetric direct aldol in aqueous media
would be a favorable scenario from a green chemistry perspective.
RESULTS AND DISCUSSION
In this article, we disclose a siloxy serine catalyst that can catalyze the
direct asymmetric aldol reaction in aqueous saline media. The synthesis
of the siloxy serine organocatalyst was carried out according to the
synthetic route described in Scheme 1. It was readily accomplished in a
simple two-step protocol using commercially available starting materials
in good yield and purity.
In our endeavors to develop asymmetric protocols that are environ-
mentally clean and friendly, we got interested in the organocatalytic
direct asymmetric aldol reactions of ketones with commonly used
aldehyde acceptors. The reaction between cyclohexanone and 4-nitroben-
zaldehyde was chosen as the model reaction in our preliminary investiga-
tions. The results for the optimization studies are shown in Table 1.
In an initial experiment, the L-histidine (1)–catalyzed reaction
between cyclohexanone and 4-nitrobenzaldehyde in brine was investi-
gated. However, only a trace amount of the product was detected
(Table 1, entry 1). The reaction carried out using L-serine 2 in brine
did not afford any product after 2 days of stirring at room temperature
(entry 2). Based on these results, an attempt to protect the hydroxyl
group of commercially available Z-L-serine with tert-butyldiphenylchloro-
silane (TBDPSCl) to form TBDPS-L-serine 3 was initiated.
To our delight, the direct aldol reaction catalyzed by 10 mol% of the
TBDPS-L-serine 3 organocatalyst in the presence of brine (0.2 mL)
Scheme 1. Synthesis of siloxy serine organocatalyst.

Direct Asymmetric Aldol Reactions
3083
Table 1. Optimization studies on the siloxy-L-serine–catalyzed enantioselective
direct aldol reaction in aqueous mediuma
Entry
Catalyst
Solvent
Yield (%)b
anti=syn (%)c
ee (%)d
1
2
3
4
1
2
3
3
Brine
Brine
Brine
Brine
Trace
—
82
—
—
76:14
82:18
nd
nd
80
86
91
aUnless otherwise shown, the reaction was performed with aldehyde
(0.5 mmol), ketone (2.5 mmol), and catalyst (0.05 mmol) at room temperature
for 16–22 h.
bCombined yield of isolated diastereomers.
cDiastereoselectivity was determined by 1H NMR analysis of the reaction
mixture.
dEnantiomeric excess refers to the anti isomer and was determined by HPLC
analysis on a chiral phase.
afforded the product in a good yield of 82% and enantiomeric excess of
80% (entry 3). Henceforth, the hydrophobic effects of the TDBPS group
in the serine-derived organocatalyst were essential for the formation of a
reaction core and subsequent catalytic function of the organocatalyst in
the presence of brine. This result also illustrates that brine can be
employed as an environmentally friendly solvent for the induction of
diastereo- and enantiocontrol with the aldol reaction, proceeding in a
two-phase system. The optimum reaction condition was achieved with
10 mol% catalyst in the presence of 0.1 mL of brine, whereupon the aldol
product was isolated in an excellent yield of 91% and enantiomeric excess
of 86% (entry 4). A series of aldehydes was used to explore the generality
of this catalytic system in aqueous saline, and the results are summarized
in Table 2.
In most cases, the b-hydroxy carbonyl compounds were obtained
in good yields and enantioselectivities. The more reactive aldehydes
underwent the catalytic process to afford the products in good

3084
Y.-C. Teo and P. P.-F. Lee
Table 2. The asymmetric direct aldol reactiona catalyzed by the siloxy-L-serine
organocatalyst 3
Entry
1
Product
Time (h) Yield (%)b anti=syn (%)c ee (%)d
17
91
82:18
86
2
3
24
24
71
76
80:20
70:30
90
92
4
42
62
72:18
72
5
6
24
34
54
52
90:10
82:18
84
76
7
8
42
48
71
40
34:66
—
84
35
aUnless otherwise shown, the reaction was performed with aldehyde
(0.5 mmol), ketone (2.5 mmol) and siloxy serine catalyst 3 (0.05 mmol) in brine
(0.1 mL) at room temperature.
bCombined yield of isolated diastereomers.
cDiastereoselectivity was determined by 1H NMR analysis of the reaction
mixture.
dEnantiomeric excess refers to the anti isomer and was determined by HPLC
analysis on a chiral phase.

Direct Asymmetric Aldol Reactions
3085
enantioselectivities and good anti selectivity (Table 2, entries 1 to 4). The
direct aldol reaction of neutral aldehydes catalyzed by the siloxy-L-serine
catalyst also afforded the products in good enantioselectivities with mod-
erate yields (entries 5 and 6). Good enantioselectivities were also obtained
when cyclopentanone was employed as the donor, albeit with low diaster-
eoselectivities (entry 7). Although the aldol reaction of acetone and
4-nitrobenzaldehyde proceeded in the presence of brine, the enantioselec-
tivity and yield obtained was only moderate (entry 8). The stereochemis-
try of the b-hydroxy group of the aldol adducts 4 derived by the acyclic
siloxy-L-serine 3 catalysis was determined as S configuration by
chiral-phase, high-performance liquid chromatography (HPLC) analysis
and comparison with literature.[4]
EXPERIMENTAL
General Methods
Chemicals and solvents were either purchased from commercial
suppliers or purified by standard techniques. Analytical thin-layer
chromatography (TLC) was performed using Merck 60 F254
precoated silica-gel plate (0.2 mm thick). Subsequent to elution, plates
were visualized using ultraviolet (UV) radiation (254 nm) on
Spectroline model ENF-24061=F 254 nm. Flash chromatography was
performed using Merck silica gel 60 with AR-grade solvents. Proton
nuclear magnetic resonance spectra (1H NMR) were recorded on a
Bruker Avance DPX 400 spectrophotometer (CDCl3 as solvent). Che-
1
mical shifts for H NMR spectra are reported as d in units of parts per
million (ppm) downfield from SiMe4 (d 0.0) and relative to the signal
of chloroform-d (d 7.2600, singlet). Carbon nuclear magnetic
resonance spectra (13C NMR) are reported as d in units of parts per
million (ppm) downfield from SiMe4 (d 0.0) and relative to the signal
of chloroform-d (d 77.03, triplet). Infrared (IR) spectra were recorded
on a Bio-Rad FTS 165 Fourier transform (FT)–IR spectrometer.
HPLC was carried out using a Agilent 110 series LC–G1311A QUAT
pump, G1315B DAD detector, and integrator. All aldol reactions
were carried out under an atmosphere of air in a closed system.
Organic substrates cyclohexanone, cyclopentanone, 4-nitrobenzalde-
hyde, 3-nitrobenzaldehyde, 4-cyanobenzaldehyde, 4-bromobenzalde-
hyde, 2-naphthaldehyde tert-butyldiphenylchlorosilane, and Z-Ser-OH
were all commercially available and were used without any purification.
Benzaldehyde were purified by standard methods and distilled prior
to use.

3086
Y.-C. Teo and P. P.-F. Lee
General Procedure for the Synthesis of (2S)-2-Benzyloxycarbonyl
amino-3-(tert-butyl-diphenyl-silanyloxy)-propionic Acid, 3
Imidazole (3.8 g, 55.8mmol, 2.6 equiv) and TBDPSCl (6.0 mL, 23mmol,
1.1 equiv) were added to a dimethylformamide (DMF) solution (50 mL)
of (2S)-2-benzyloxycarbonylamino-3-hydroxy-propionic acid 3a (5.0g,
20.9 mmol) at 0ꢀC. The reaction was stirred for 20h at room temperature
and quenched by the addition of water and ether. The aqueous phase was
extracted with ether (3ꢁ 100 mL). The combined organic extracts were
dried with anhydrous MgSO4, and the solvent was removed under reduced
pressure. The crude siloxy ether product was purified by silica-gel column
chromatography (hexane–ethyl acetate 2:1) to afford 3b as a white solid
(7.3g, 73%).
Pd=C (4.89 g, 10 wt%, 4.6 mmol, 0.3 equiv) was added to a methanol
solution (100mL) of (2S)-2-benzyloxycarbonylamino-3-(tert-butyl-diphenyl-
silanyl oxy)-propionic acid 3b (7.3 g, 15.3 mmol) at room temperature. The
reaction mixture was stirred for 6 h at that temperature under a hydrogen
atmosphere in a closed system. The filtration of the inorganic materials
through celite and removal of methanol under reduced pressure afforded
the crude product. Purification by silica-gel chromatography (dichloro-
methane–methanol 9:1) afforded catalyst 3 as a white solid (4.1 g, 79%).
1H NMR (300 MHz, DMSO-d6): d (ppm) 0.98 (s, 9H), 3.35 (dd, J¼ 7.6,
3.2 Hz, 1H), 3.82 (dd, J¼ 10.8, 7.6Hz, 1H), 3.92 (dd, J¼ 10.4, 3.2 Hz,
1H), 7.40–7.47 (m, 6H), 7.65–7.68 (m, 4H); 13C NMR (100 MHz, DMSO-
d6): d (ppm) 19.3, 27.1, 56.7, 64.4, 128.2, 128.3, 130.2, 130.3, 133.1, 133.3,
135.7, 135.8, 168.3.
Representative Procedure for Asymmetric Direct Aldol Reaction:
Preparation of (2R,10S)-2-[Hydroxy-(4-nitro-phenyl)-
methyl]-cyclohexanone 4a
A catalytic amount of siloxyserine (0.0172 g, 0.05 mmol, 0.1 equiv) was
added to a vial containing 4-nitrobenzaldehyde (0.0760 g, 0.5 mmol,
1.0 equiv), cyclohexanone (0.26 mL, 2.5 mmol, 5 equiv), and brine
(0.1 mL) under air in a closed system. The reaction mixture was stirred
at room temperature for 17 h and subsequently poured into an extrac-
tion funnel that contained brine (5 mL) and water (5 mL). The reaction
vial was also washed with 10 mL ethyl acetate. The aqueous phase was
extracted with ethyl acetate (3 ꢁ 15 mL). The combined organic
extracts were dried with anhydrous MgSO4, and the solvent was
removed under reduced pressure. The crude aldol product was purified
by silica-gel column chromatography (hexane–ethyl acetate 4:1) to

Direct Asymmetric Aldol Reactions
3087
Table 3. 1H NMR (CDCL3-CHOH, d) of syn=anti diastereomers
1H NMR (CDCl3-CHOH, d)
Product
Syn
Anti
4a
4b
4c
4d
4e
4f
5.48 (d) (J ¼ 1.8 Hz)
5.50 (brs)
5.43 (brs)
4.89 (dd) (J ¼ 8.4 Hz)
4.92 (d) (J ¼ 8.4 Hz)
4.83 (d) (J ¼ 8.3 Hz)
4.75 (d) (J ¼ 8.5 Hz)
4.96 (d) (J ¼ 8.7 Hz)
4.79 (J ¼ 8.8 Hz)
5.30 (d) (J ¼ 2.6 Hz)
5.56 (brs)
5.39 (d) (J ¼ 2.3 Hz)
5.42 (brs)
4g
4.85 (J ¼ 8.9 Hz)
afford 4a as a white solid (0.1123 g, 91% yield). The diastereomeric
anti=syn ratio was determined by 1H NMR analysis of the reaction
mixture: d 5.48 (d, 1H, J ¼ 1.8 Hz, syn, minor), 4.89 (d, 1H, J ¼ 8.8 Hz,
anti, major). Enantiomeric excess was determined by HPLC with a
Chiralcel AD-H (hexane=i-PrOH ¼ 95=5, 1 mL=min, k ¼ 254 nm,
20ꢀC): tR ¼ 44.8 min (minor) and 60.5 min (major).
The aldol adducts 4a–h are all known compounds that exhibited
spectroscopic data identical to those reported in the literature. The dia-
stereomeric anti=syn ratio (Table 3) was determined by 1H NMR analysis
of the reaction mixture and comparison to known literature.[2k,4a–b,6]
The absolute configuration of aldol products was extrapolated
by comparison of the HPLC data with those of 4a–h, whose absolute
configurations are known.
Representative Data of (2R,10S)-2-[Hydroxy-(4-nitro-phenyl)-
methyl]-cyclohexanone 4a
White solid (112 mg, 91%); 1H NMR (400 MHz, CDCl3): d (ppm)
1.31–2.12 (m, 6H), 2.32–2.49 (m, 2H), 2.57–2.63 (m, 1H), 4.07 (s, 1H),
4.89 (d, J ¼ 8.4 Hz, 1H), 7.50 (d, J ¼ 8.7 Hz, 2H), 8.20 (d, J ¼ 8.6 Hz,
2H); 13C NMR (100 MHz, CDCl3): 24.7, 27.7, 30.8, 42.7, 57.2, 74.0,
123.5, 127.9, 147.6, 148.4, 214.8.
The diastereomeric anti=syn ratio was determined by 1H NMR
analysis of the reaction mixture: d 5.48 (d, 1H, J ¼ 1.8 Hz syn, minor),
4.89 (d, 1H, J ¼ 8.8 Hz, anti, major).
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H (hexane=i-PrOH ¼ 95=5, 1.0 mL=min, k ¼ 254 nm, 20ꢀC):
tR ¼ 44.8 min (minor) and 60.5 min (major).

3088
Y.-C. Teo and P. P.-F. Lee
The absolute of configuration of 4a was extrapolated by comparison
of the HPLC data to the literature[1–4] compound, whose absolute
configuration is known.
HPLC Data for Aldol Products 4b–h
(2R,10S)-2-[Hydroxy-(3-nitro-phenyl)-methyl]-cyclohexanone 4b
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 95=5, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 35.5 min
(major) and 47.0 min (minor).
(2R,10S)-4-[Hydroxy-(2-oxo-cyclohexyl)-methyl]-benzonitrile 4c
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 90=10, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 21.6 min
(minor) and 27.1 min (major).
(2R,10S)-2-[(4-Bromo-phenyl)-hydroxy-methyl]-cyclohexanone 4d
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 90=10, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 13.5 min
(minor) and 15.7 min (major).
(2R,10S)-2-(Hydroxy-naphthalen-2-yl-methyl)-cyclohexanone 4e
Enantiomeric excess was determined by HPLC with a Chiralcel AS-H
(hexane=i-PrOH ¼ 95=5, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 27.5 min
(major) and 32.1 min (minor).
(2R,10S)-2-(Hydroxy-phenyl-methyl)-cyclohexanone 4f
Enantiomeric excess was determined by HPLC with a Chiralcel AS-H
(hexane=i-PrOH ¼ 95=5, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 20.8 min
(major) and 22.5 min (minor).
(2R,10S)-2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclopentanone 4g
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 97=3, 1.0 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 71.9 min
(minor) and 76.9 min (major).

Direct Asymmetric Aldol Reactions
3089
(S)-4-Hydroxy-4-(4-nitro-phenyl)-butan-2-one 4h
Enantiomeric excess was determined by HPLC with a Chiralcel AS-H
(hexane=i-PrOH ¼ 60=40, 1 mL=min, k ¼ 254 nm, 20ꢀC): tR ¼ 9.2 min
(major) and 11.3 min (minor).
CONCLUSION
In conclusion, we have demonstrated an efficient asymmetric direct aldol
reaction catalyzed by a siloxy-L-serine organocatalyst in the presence of
brine via a two-phase system. Noteworthy features in this system include
(1) the direct aldol reaction proceeded in the presence of brine via a
two-phase system and with simple procedures without the need of an
organic cosolvent; (2) good enantioselectivities were attained in most
aldehydes; and (3) the siloxy serine catalyst 3 can be easily prepared eco-
nomically from commercially available sources, with both enantiomers
readily available. Further investigation on broadening the scope of the
siloxy serine organocatalyst is currently ongoing in our laboratory and
will be reported in due course.
ACKNOWLEDGMENT
We thank the National Institute of Education (RP5=06 TYC) and
Nanyang Technological University for their generous financial support.
REFERENCES
1. (a) Alexakis, A.; Bernardinelli, G.; Andrey, O. Asymmetric michael addition of
a-hydroxyketones to nitroolefins catalyzed by chiral diamine. Org. Lett. 2003,
5, 2559; (b) Barbas, C. F. III; Chowdari, N. S.; Suri, J. T. Asymmetric
synthesis of quaternary a- and b-amino acids and b-lactams via proline-
catalyzed Mannich reactions. Org. Lett. 2004, 6, 2507; (c) Dalko, P. I.;
Moisan, L. In the golden age of organocatalysis. Angew. Chem., Int. Ed. 2004,
43, 5138; (d) Berkssel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, 2005.
2. (a) List, B.; Lerner, R. A.; Barbas, C. F. III. Proline-catalyzed direct asym-
metric aldol reactions. J. Am. Chem. Soc. 2000, 122, 2395; (b) Sathivel, K.;
Notz, W.; Bui, T.; Barbas, C. F. III. Amino acid catalyzed direct asymmetric
aldol reactions: A bioorganic approach to catalytic asymmetric carbon-carbon
bond-forming reactions. J. Am Chem. Soc. 2001, 123, 5260; (c) Northrup, A.
B.; MacMillan, D. W. C. The first direct and enantioselective cross-aldol
reaction of aldehydes. J. Am. Chem. Soc. 2002, 124, 6798; (d) List, B.

3090
Y.-C. Teo and P. P.-F. Lee
Proline-catalyzed asymmetric reactions. Tetrahedron 2002, 28, 5573; (e) Tang,
Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Novel
small organic molecules for a highly enantioselective direct aldol reaction. J.
Am. Chem. Soc. 2003, 125, 5262; (f) Suzuki, N.; Hayashi, Y.; Shoji, M.;
Tsuboi, W. Application of high pressure induced by water-freezing to the
direct catalytic asymmetric three-component List–Barbas–Mannich reaction.
J. Am. Chem. Soc. 2003, 125, 11208; (g) Zhong, G. A facile and rapid route
to highly enantiopure 1,2-diols by novel catalytic asymmetric a-aminoxylation
of aldehydes. Angew. Chem., Int. Ed. 2003, 42, 4247; (h) Notz, W.; Tanaka, F.;
Barbas, C. F. III. Enamine-based organocatalysis with proline and diamines:
The development of direct catalytic asymmetric aldol, mannich, michael,
and Diels–Alder Reactions. Acc. Chem. Res. 2004, 37, 580; (i) Mahewald, R.
Modern Aldol reactions; Wiley-VCH: Weinheim, 2004; vols. 1–2; (j) Suri, J.
T.; Ramachary, D. B.; Barbas, C. F. III. Mimicking dihydroxy acetone
phosphate-utilizing aldolases through organocatalysis: A facile route to carbo-
hydrates and aminosugars. Org. Lett. 2005, 7, 1383; (k) Chen, J.-R.; Lu, H.-H.;
Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Readily tunable and bifunctional
L-prolinamide derivatives: design and application in the direct enantioselective
aldol reactions. Org. Lett. 2005, 7, 4543.
3. For reviews, see (a) Alcaide, B.; Almendros, P. The direct catalytic asymmetric
aldol reaction. Eur. J. Org. Chem. 2002, 10, 1595; (b) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Current progress in the asymmetric aldol addition reaction.
Chem. Soc. Rev. 2004, 33, 65; (c) Schetter, B.; Mahrwald, R. Modern aldol
methods for the total synthesis of polyketides. Ang. Chem. Int. Ed. 2006, 45,
7506; (d) Mukherjee, S.; Yang, J.-W.; Hoffmann, S.; List, B. Asymmetric
enamine catalysis. Chem. Rev. 2007, 107, 5471.
4. (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F. III. Organocatalytic direct asymmetric aldol reactions in water.
J. Am. Chem. Soc. 2006, 128, 734; (b) Hayashi, Y.; Sumiya, T.; Takashi, J.;
Gotoh, H.; Urushima, T.; Shoji, M. Highly diastereo- and enantioselective
direct aldol reactions in water. Angew. Chem., Int. Ed. 2006, 45, 958; (c) Mase,
N.; Wattanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. III.
Organocatalytic direct michael reaction of ketones and aldehydes with
b-nitrostyrene in brine. J. Am. Chem. Soc. 2006, 128, 4966; (d) Jiang, Z.-Q.;
Liang, Z.; Wu, X.-Y.; Lu, Y.-X. Asymmetric aldol reactions catalyzed by
tryptophan in water. Chem. Commun. 2006, 2801; (e) Teo, Y.-C. Direct
asymmetric aldol reactions catalyzed by a siloxy serine organocatalyst in
water. Tetrahedron: Asymmetry 2007, 18, 1155; (f) Huang, J.; Zhang, X.;
Armstrong, D. W. Highly efficient asymmetric direct stoichiometric aldol
reactions on=in water. Angew. Chem., Int. Ed. 2007, 46, 9073.
5. Lindstrom, M.; Anderson, F. Hydrophobically directed organic synthesis.
Angew. Chem., Int. Ed. 2006, 45, 548.
6. (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V.
Organocatalysis with proline derivatives: Improved catalysts for the
asymmetric Mannich, nitro-Michael and aldol reactions. Org. Biomol. Chem.
2005, 3, 84; (b) Yanagisawa, A.; Nakatsuka, Y.; Asakawa, K.; Wadamoto,

Direct Asymmetric Aldol Reactions
3091
M.; Kageyame, H.; Yamamoto, H. Catalytic asymmetric aldol reaction of
trimethoxysilyl enol ethers using 2,20-bis(di-p-tolylphosphino)-1,10-binaphthylꢂ
AgF complex. Bull. Chem. Soc. Jpn. 2001, 71, 1477; (c) Denmark, S. E.;
Stavenger, R. A.; Wong, K.; Su, X. Chiral phosphoramide-catalyzed aldol
additions of ketone enolates. Preparative aspects. J. Am. Chem. Soc. 1999,
121, 4982; (d) Denmark, S. E.; Stavenger, R. A.; Wong, K. Asymmetric aldol
additions catalyzed by chiral phosphoramides: Electronic effects of the
aldehyde component. Tetrahedron 1998, 54, 10389; (e) Notz, W.; List, B.
Catalytic asymmetric synthesis of anti-1,2-diols. J. Am. Chem. Soc. 2000,
122, 7386.