A highly efficient, large-scale, asymmetric direct aldol reaction employing simple threonine derivatives as recoverable organocatalysts in the presence of water

Article abstract of DOI:10.1002/ejoc.201001396

A one-step O-acylation of threonine resulted in a simple and readily available threonine-surfactant organocatalyst that could efficiently catalyze the direct asymmetric aldol reactions of cyclic and acyclic ketones with a series of aromatic aldehydes in t

Full text of DOI:10.1002/ejoc.201001396

FULL PAPER
DOI: 10.1002/ejoc.201001396
A Highly Efficient, Large-Scale, Asymmetric Direct Aldol Reaction Employing
Simple Threonine Derivatives as Recoverable Organocatalysts in the Presence
of Water
Chuanlong Wu,[a] Xiangkai Fu,*[a] and Shi Li[a]
Keywords: Synthetic methods / Asymmetric catalysis / Organocatalysis / Solvent effects / Aldol reactions
A one-step O-acylation of threonine resulted in a simple and
and enantiomeric excesses (Ͼ99%). The catalyst can be
readily available threonine-surfactant organocatalyst that
easily recovered and reused with no decrease of enantio-
could efficiently catalyze the direct asymmetric aldol reac- selectivity after six cycles. This novel catalyst can be ef-
tions of cyclic and acyclic ketones with a series of aromatic
aldehydes in the presence of water at room temperature with
good yields (up to 99%), diastereoselectivities (up to 99:1),
ficiently used in large-scale reactions, with the enantio-
selectivity being maintained at the same level, which offers
great possibilities for application in industry.
ids or amino acid surrogates were employed in polar
solvents, such as N,N-dimethylformamide (DMF),
DMSO,[5a–5f] and N-methyl-2-pyrrolidinone (NMP),[5g]
owing to the solubility, however, these polar solvents often
created added hurdles for product isolation. Use of water
clearly has many advantages, such as its low cost, safety,
and environmentally benign nature, however, the vast ma-
jority of organocatalytic reactions would yield racemic
products if the reactions were carried out in the presence of
water.[5f–5g] Recently, it was shown by the groups of Takabe,
Barbas, Hayashi, Noto, and others that the direct asymmet-
ric aldol reaction and the Michael reaction could both be
catalyzed by hydrophobic proline derivatives in the presence
of water.[6] Our group recently also reported that 4-phen-
oxy-substituted and 4-tert-butyldimethylsiloxy-substituted
prolinamides catalyze direct aldol reactions between cyclic
ketones and aromatic aldehydes in the presence of water.[7]
The groups of Lu and Teo reported that the siloxy the-
ronine and serine derivatives are highly efficient organocat-
alysts for the asymmetric aldol reactions of ketones in the
presence of water. Although these amino acids were not ef-
ficient organocatalysts in the direct aldol reactions between
cyclohexanone and benzaldehyde in water, probably be-
cause these amino acids are dissolved in the water phase
and are thereby separated from the hydrophobic reactants
of cyclohexanone and 4-nitrobenzaldehyde, their hydro-
phobic derivatives (e.g., O-TBS-threonine) proved to be
very efficient catalysts. The desired aldol products were ob-
tained in excellent yields (up to 99%), and with nearly per-
fect enantiomeric control (up to 99% ee).[8] However, it
should be noted that among the reported asymmetric or-
ganocatalysts, most were prepared with complex pro-
cedures, required time-consuming chromatographic purifi-
cation techniques, and/or required expensive reagents,[9]
Introduction
In spite of the remarkable advances in asymmetric aldol
reactions[1] used for constructing C–C bonds, there contin-
ues to be increasing demand for new, inexpensive, simple,
and efficient organocatalysts. Asymmetric organocatalysis
has progressed at an astonishing pace in recent years.[2]
A
wide range of small organic molecules, including proline[3]
and various other chiral pyrrolidine derivatives,[4] have been
shown to be efficient catalysts for asymmetric aldol reac-
tions. Hayashi and Cordova demonstrated that acyclic
amino acids or small peptides could effect direct aldol reac-
tions in dimethyl sulfoxide (DMSO) (in the presence of a
little water).[5a–5f] However, a number of shortcomings have
also been realized. One of the major limitations of using
organocatalyst-catalyzed reactions is the high catalyst load-
ing (20–30 mol-%) that is generally required to complete the
transformation within reasonable timescales. This raises
cost concerns when large amounts of chiral materials are
used for large-scale syntheses in industrial applications.
Therefore, the design and development of highly active or-
ganocatalysts that enable lower catalyst loading has proved
to be a significant goal, however, only limited success has
been achieved so far. Moreover, it was noted that the vast
majority of organocatalyzed processes involving amino ac-
[a] College of Chemistry and Chemical Engineering Southwest
University, Research Institute of Applied Chemistry Southwest
University, The Key Laboratory of Applied Chemistry of
Chongqing Municipality; Key Laboratory of Eco-environments
in Three Gorges Reservoir Region Ministry of Education
Chongqing,
400715 Chongqing, P. R. of China
Fax: +86-23-6825-4000
E-mail: fxk@swu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001396.
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X. Fu et al.
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which creates added hurdles for industrial production, so to be good chiral structural scaffolds, because the hydroxyl
these organocatalysts were often only used in research or sulfhydryl group allow various hydrophobic groups, both
laboratories. Therefore, the development of new and effec- alkyl and acyl, to be easily attached. We developed a direct
tive asymmetric organocatalysts from natural chiral pool one-step synthesis of novel and simple acylated derivatives
compounds, using simple preparation procedures and inex- of cysteine, serine, and threonine 1a–f with acyl chlorides
pensive reagents, is urgently needed. An alternative strategy at room temperature in trifluoroacetic acid on a large scale.
is to design recyclable and reusable organocatalysts, and ef- Furthermore, no protecting groups or chromatographic
forts have been made on organocatalyst recycling using techniques were involved in the course of synthesis.[14]
polymer supports,[10] ionic liquid supports,[11] and fluorous
The organocatalyzed aldol reaction was carried out using
chemistry.[12] Herein, we wish to report a new, simple, recov- cyclohexanone and 4-nitrobenzaldehyde as a model reac-
erable, and reusable threonine-surfactant organocatalyst tion to investigate different parameters, such as the cata-
that promotes aldol reactions while achieving a respectable lysts, the stoichiometry of reactants, and loading of the cat-
level of enantioselectivity; this catalyst can be used in large- alysts. In our initial investigation, cysteine, serine, and thre-
scale reactions with the enantioselectivity being maintained onine, and their derivatives 1a–f were screened as catalysts.
at the same level.
As seen in the summarized results in Table 1, whereas nei-
ther natural cysteine, serine, nor threonine were efficient or-
ganocatalysts in water (Table 1, entries 1–3), all the deriva-
tive catalysts 1a–f catalyzed the asymmetric direct aldol re-
action of 4-nitrobenzaldehyde and cyclohexanone to give
the product in good yields (93–99%) with a range of ee
values (90–98% ee for anti) in the presence of water
Results and Discussion
The use of threonine and serine derivatives has been pop-
ular in the design of compounds that deliver improved cata-
lytic activity and stereoselectivity. The groups of Barbas,[5g]
Lu, and Teo[8] reported the use of a series of threonine and
serine based organocatalysts for the direct asymmetric aldol
reactions of various aromatic aldehydes and ketones, with
impressive results. Moreover, they found that a subtle
change in catalyst structure may effect the catalytic per-
formance, especially for systems in which natural cysteine[5f]
derivatives were not efficient. With this knowledge in mind,
we investigated some novel cysteine, serine, and threonine
based organocatalysts 1a–f (Figure 1) with the aim of de-
veloping a practical process for asymmetric aldol reactions.
The group of Hansen reported a direct O-acylation of
trans-4-hydroxy-l-proline with acyl chlorides in trifluoro-
acetic acid in a single step on a large scale. The fact that
no protecting groups or chromatographic techniques were
involved in the synthetic process recently prompted interest
in the synthesis.[14c–14e] With this knowledge in mind, we
envisaged that incorporation of a hydrophobic group into
a natural amino acid that is usually hydrophilic could gen-
erate a surfactant organocatalyst that may interact favor-
ably with organic substrates in aqueous media due to its
Table 1. Screening of organocatalysts.[a]
Entry
Catalyst
Catalyst
loading [%]
Time Yield [%][b]
[h]
dr
ee [%][c]
(anti/syn)[c]
1
2
3
4
5
6
7
8
9
l-Cys
l-Ser
l-Thr
1a
1b
1c
1d
1e
1f
20
20
20
10
10
10
10
10
10
48
48
48
14
14
10
10
10
10
–
–
–
93
95
95
96
96
99
–
–
–
–
–
–
90
92
92
94
96
98
77:23
85:15
94:6
92:8
94:6
94:6
[a] Reagents and conditions: 4-nitrobenzaldehyde (1 mmol), cyclo-
hexanone (2 mmol), catalyst (0.1 mmol), water (0.5 mL), room
temperature. [b] Isolated yield. [c] Determined by chiral HPLC
surfactant nature.[13] Cysteine, serine, and threonine seem analysis (AD-H column).
Figure 1. Cysteine, serine, and threonine based organocatalysts.
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Asymmetric Aldol Reaction with Threonine Derivatives
(Table 1, entries 4–9). Among the six acylated derivatives,
To test the substrate generality of this organocatalyzed
the catalysts containing the tert-butylphenyl group gave the direct aldol reaction, the reactions of various aromatic alde-
best yield (99%) and enantioselectivity (98% ee for anti). hydes with cyclohexanone were studied under the optimized
The threonine-based organocatalyst 1f was found to be the conditions. The results are summarized in Table 3. It can be
most efficient catalyst (Table 1, entry 9).
seen that a wide range of aromatic aldehydes can effectively
Using water as solvent and 1f as catalyst, the effects of participate in the aldol reaction, and aldol adducts 2–16,
ketone and catalyst loading on the reaction of 4-nitrobenz- derived from their corresponding aromatic aldehydes and
aldehyde and cyclohexanone was investigated (Table 2). cyclohexanone, could be accessed. In the presence of only
When 10 mol-% 1f was used, the reaction could be ac- 5 mol-% catalyst 1f and water (0.5 mL), most reactions be-
celerated by increasing the amount of ketone from 1 to tween cyclohexanone and various aromatic aldehydes af-
4 equiv., however, the dr and ee values were not improved forded the aldol products in excellent yields and nearly per-
(Table 2, entries 1–3). The aldol product could be obtained fect ee values. In general, the reaction between cyclohexan-
in high yield with good stereoselectivity, even with only one and aromatic aldehydes bearing electron-withdrawing
2 equiv. of cyclohexanone. The effect of catalyst loading substituents furnished β-hydroxy carbonyl aldol products in
was also investigated using 2 equiv. of cyclohexanone. excellent yields (94–99%) and enantioselectivities (97–99%
When 2 mol-% catalyst was used (Table 2, entry 5), the reac- ee for anti isomer) within 8–12 h, especially p-nitrobenzal-
tion was slow and the ee value was slightly lower than that dehyde and o-nitrobenzaldehyde (Table 3, entries 1 and 2,
using 5 mol-% catalyst (Table 2, entry 4). Noticeably, by 99:1 anti/syn ratio and Ͼ99% ee for anti isomers; Table 3,
using only 5 mol-% of catalyst, after 8 h the desired aldol entries 1–8). In contrast, longer reaction times (20 h) were
product was obtained in 99% yield and with 99% ee required for aromatic aldehydes containing an electron-
(Table 2, entry 4). Thus, the optimized catalyst loading was donating groups, and the reactions gave comparatively low
chosen as 5 mol-% 1f. Some aldol reactions have been per- yields (83–89%), but without decreasing the enantio-
formed under aqueous conditions, with the presence of selectivities, especially with p-tolualdehyde (Table 3, entry
water reported to increase the reactivity and stereoselecti- 11, 99:1 anti/syn ratio and Ͼ99% ee, and Table 3, entries 9–
vity,[6] therefore, the influence of the amount of water was 11). This can be explained by the fact that electron-with-
also investigated. When the reaction was carried out under drawing groups enhance the electrophilicity of carbonyl car-
neat conditions, the reaction was fast and the ee value was bons in aldehydes, which facilitates the reaction, whereas
slightly lower (Table 2, entry 6). When the amount of water electron-donating groups reduce the electrophilicity. More-
was increased from 0.1 to 0.5 mL, the reaction gave the al- over, the direct aldol reaction of neutral aldehydes catalyzed
dol product with a high enantioselectivity of 99% ee by the threonine derivative, organocatalyst 1f, also afforded
(Table 2, entry 4) and excellent diastereoselectivities ranging the aldol products with high enantioselectivities and dia-
from 91:9 to 99:1 (Table 2, entries 7, 8, and 4). When the stereoselectivities, especially with the 2-naphthyl aldehyde
amount of water was increased from 0.8 mL to 1.0 mL, the
direct aldol reaction catalyzed by catalyst 1f took place
smoothly with excellent enantioselectivity (Table 2, entries
9–10).
Table 3. Direct aldol reactions catalyzed by organocatalyst 1f in the
presence of water.[a]
Table 2. Effects of ketone, catalyst loading and the amount of water
on the organocatalyzed direct aldol reaction.[a]
Entry Product
R
Time Yield[b]
dr[c]
ee[c]
[h]
[%]
(anti/syn)
[%]
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
p-NO2-C6H4
o-NO2-C6H4
m-NO2-C6H4
p-CN-C6H4
p-CF3-C6H4
p-Cl-C6H4
o-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
m-MeO-C6H4
p-Me-C6H4
2-naphthyl
1-naphthyl
Ph
8
8
8
8
8
12
12
12
20
20
20
20
20
24
8
99
98
99
98
96
94
95
95
89
86
83
93
90
89
96
99:1
99:1
96:4
95:5
92:8
95:5
90:10
96:4
93:7
93:7
99:1
97:3
98:2
94:6
81:19
99
99
99
98
97
98
98
98
97
Entry Ketone Catalyst Water Time Yield[b]
dr[c]
ee[c]
[equiv.]
[mol-%]
[mL]
[h]
[%]
(anti/syn)
[%]
1
2
3
4
5
6
7
8
9
10
1
2
4
2
2
2
2
2
2
2
10
10
10
5
2
5
5
5
5
5
0.5
0.5
0.5
0.5
0.5
–
0.1
0.2
0.8
1.0
24
8
6
8
18
8
8
8
18
24
90
99
99
99
94
99
99
99
95
90
91:9
94:6
94:6
99:1
90:10
83:17
91:9
92:8
93:7
93:7
96
98
97
99
97
95
97
98
98
98
9
10
11
12
13
14
15
98
Ͼ99
Ͼ99
98
98
98
4-pyridinyl
[a] Reagents and conditions: aldehyde (1 mmol), cyclohexanone
(2 mmol), 1f (0.05 mmol), water (0.5 mL), room temperature. [b]
Isolated yield. [c] Determined by chiral HPLC analysis (AD-H,
OD-H columns).
[a] Reagents and conditions: 4-nitrobenzaldehyde (1 mmol), cyclo-
hexanone, catalyst 1f, water, room temperature. [b] Isolated yield.
[c] Determined by chiral HPLC analysis (AD-H column).
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(Table 3, entry 12, 97:3 anti/syn ratio and Ͼ99% ee, and Table 4. Direct asymmetric aldol reactions between ketones and
aromatic aldehydes in the presence of water, catalyzed by 1f.[a]
Table 3, entries 12–15). All the reactions of cyclohexanone
with aromatic aldehydes provided the corresponding prod-
ucts with excellent enantioselectivities (97–99% ee for anti
isomers) and excellent diastereoselectivities(anti/syn 81:19
to 99:1; Table 3, entries 1–15).
The feasibility of using other cyclic and acyclic ketones
as aldol donors was then examined. As shown in Table 4,
when cyclopentanone was used as an aldol donor, a good
yield of 92–99% with excellent ee (95–98%) for the anti
isomer were received, however, the diastereomeric ratio ob-
tained was only 55:45 to 62:38 (anti/syn) (Table 4, entries
1–4). However, when 4-methylclohexanone and tetrahydro-
4H-pyran-4-one were used as aldol donors, not only were
excellent enantioselectivities obtained, but excellent dia-
stereoselectivities were also achieved (Table 4, entries 5–6).
We also examined the feasibility of using acyclic ketones,
such as hydroxyacetone and acetone, as aldol donors. Al-
though longer reaction times were required in comparison
with cyclic ketones, satisfactory results were obtained. The
threonine derivative organocatalyst 1f also catalyzed direct
syn-aldol reactions of hydroxyacetone (Table 4, entries 7–
9) under neat conditions, and the syn-aldol products were
obtained in high yields (up to 97%) with excellent enantio-
selectivities (up to 99% ee for syn-isomers). Furthermore,
when the aldol reaction of chlorobenzaldehyde with acetone
was conducted in the presence of 5 mol-% organocatalyst
1f the aldol products were obtained in high yields (86–89%)
with high enantioselectivities (95–97% ee) (Table 4, entries
10 and 11). All the reactions of other cyclic and acyclic
ketones with aromatic aldehydes provided the correspond-
ing aldol products with excellent enantioselectivities (95–
99%) and good yields (86–99%) (Table 4, entries 1–11).
To verify that the threonine derivative organocatalyst 1f
could be recovered and reused, we performed a recycling
study of 1f using the aldol reaction between cyclohexanone
and 4-nitrobenzaldehyde as a model (Table 5). The catalyst
1f could be easily recovered from the reaction mixture after
completion of the reaction upon acid treatment; the aldol
product was extracted with diethyl ether (Et2O) and the or-
ganic solution was evaporated to obtain the aldol product.
The catalyst 1f, which was retained in the acidic aqueous
layer, was obtained as a white suspension upon addition of
an equivalent amount of triethylamine (Et3N). The suspen-
sion was filtered under vacuum and the white crystals were
used directly in subsequent reaction cycles without adding
any new catalyst. In each reuse, the same amounts of sub-
strates were used, and the recovered catalyst 1f retained es-
sentially its catalytic activity without further purification.
No decrease in the enantioselectivity was observed over six
cycles (Table 5).
Large-scale asymmetric aldol reactions were then per-
formed with 25 mmol of aromatic aldehydes and 2 equiv. of
ketones. The same catalyst loading of 5 mol-% as used in
the experimental scale was used. The large-scale experi-
ments proceeded smoothly using the same procedure as for
the experimental-scale reactions. As can be seen from the
results summarized in Table 6, the enantioselectivities were
[a] Reagents and conditions: aldehyde (1 mmol), ketones (2 mmol),
1f (0.05 mmol), water (0.5 mL), room temperature. [b] Isolated
yield. [c] Determined by chiral HPLC analysis (AD-H, OD-H col-
umns). [d] Reaction performed at 0 °C with a nitrobenzaldehyde/
hydroxyacetone/catalyst ratio of 1:2:0.05. [e] Reaction performed at
room temperature with an aldehyde/acetone/catalyst/water ratio of
1:100:0.05:11.
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Asymmetric Aldol Reaction with Threonine Derivatives
Table 5. The recycling and reuse of catalyst 1f.[a]
which is a robust and effective catalyst for highly enantiose-
lective aldol reactions. A wide range of aromatic aldehydes
with cyclic and acyclic ketones can effectively participate in
the direct aldol reactions. The electronic effect of the sub-
stituents in substituted benzaldehydes has been discussed.
Noteworthy features of this catalysis system are (1) the di-
rect aldol reactions proceeded in the presence of water using
simple procedures; (2) the direct S-acylation of cysteine,
and O-acylation of serine and threonine to give organocata-
lysts 1a–f can be economically prepared easily in a single
step from commercially available sources, with both
enantiomers being readily available; (3) 5 mol-% catalyst 1f
was sufficient to furnish the aldol products in excellent
yields (up to 99%) and enantioselectivities (up to 99%); (4)
the catalyst can be readily recovered and reused without
significant loss of catalytic activity or stereoselectivity; (5)
notably, this organocatalyzed direct asymmetric aldol reac-
tion can be performed on a large scale, with the enantio-
selectivity being maintained at the same level, which offers
great possibilities for applications in industry.
Run
Time [h]
Yield [%][b]
dr (anti/syn)[c]
ee [%][c]
1
2
3
4
5
6
8
8
8
10
24
48
99
98
98
98
97
98
99:1
98:2
98:2
97:3
98:2
97:3
99
99
98
98
98
98
[a] Reagents and conditions: 4-nitrobenzaldehyde (10 mmol), cyclo-
hexanone (20 mmol), water (5 mL), room temperature. [b] Isolated
yield. [c] Determined by chiral HPLC analysis (AD-H column).
maintained at the same level for the large-scale reactions.
Thus, the threonine derivative organocatalyst 1f is not only
simple and easily prepared by a one-step procedure, but the
enantioselectivities are maintained at the same level for the
large-scale aldol reactions, which offers great possibilities
for applications in industry.
Table 6. Large-scale asymmetric aldol reactions.[a]
Experimental Section
General Remarks: All reagents are commercial products. The reac-
tions were monitored by thin layer chromatography (TLC). Col-
umn and preparative TLC purifications were carried out using sil-
ica gel. Flash column chromatography was performed on silica gel
(200–300 mesh). NMR spectra were recorded with a 300 MHz in-
strument (Bruker Avance 300 spectrometer). Chemical shifts (δ) are
given in ppm relative to TMS as the internal reference, coupling
constants (J) in Hz. IR spectra were recorded with a Bruker Tensor
27 FTIR spectrometer. Melting points were measured with a digital
melting point apparatus (TAQ100). Mass spectra (MS) were mea-
sured with a Bruker HCT mass spectrometer. Analytical high-per-
formance liquid chromatography (HPLC) was carried out with an
Agilent 1200 instrument using Chiralpak AD (4.6 mmϫ250 mm)
or Chiralcel OD-H (4.6 mmϫ250 mm) columns. Optical rotations
¯
were measured with a JASCO P1010 Polarimeter at λ = 589 nm.
Direct S-Acylation of Cysteine, and O-Acylation of Serine and
Threonine to give Organocatalysts 1a–f. General Experimental Pro-
cedure:[14] A 500 mL round-bottomed flask was charged with TFA
(120 mL) and placed in an ice/water bath. Powdered amino acid
(cysteine, serine or threonine; 250 mmol, dried at 70–75 °C for
24 h) was added in small portions under vigorous stirring to give
a viscous solution (leaving some small pieces of undissolved mate-
rial). The reaction mixture was stirred for 15 min, and then re-
moved from the ice/water bath. After 5 min of stirring, acyl chlo-
ride (375 mmol) was added in one portion. The reaction flask was
fitted with a loose glass stopper and the reaction mixture was
stirred at room temperature without any external temperature ad-
justment for 6 h, giving a clear and colorless solution. The reaction
flask was then cooled in an ice/water bath and Et2O (360 mL) was
added under vigorous stirring over a period of 20 min, slowly at
first. The resulting white suspension was stirred at 0–5 °C for
15 min after complete addition, and then filtered under vacuum.
The crystals were washed with two portions of Et2O and dried at
room temperature for 23 h in a ventilated hood to give S-acylated
cysteine, and O-acylated serine and threonine hydrochloride. The
hydrochloride salts were dissolved in water, an equivalent amount
[a] Reagents and conditions: 4-nitrobenzaldehyde (25 mmol), cyclo-
hexanone (50 mmol), water (12.5 mL), room temperature. [b] Iso-
lated yield. [c] Determined by chiral HPLC analysis (AD-H col-
umn).
Conclusions
The results of the investigation demonstrate that the di-
rect O-acylation of threonine leads to organocatalyst 1f, of triethylamine (Et3N) was added, and the resulting white suspen-
Eur. J. Org. Chem. 2011, 1291–1299
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X. Fu et al.
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sion was stirred at room temperature for 10 min after complete
addition, and then filtered under vacuum. The white crystals were
washed with two portions of H2O and dried to give the acylated
cysteine, serine or threonine-derived organocatalysts. These essen-
tially pure materials were used for the next step without further
purification.
reaction was quenched with saturated NH4Cl (8 mL), extracted
with EtOAc (3ϫ 10 mL), and dried with Na2SO4. Purification by
flash chromatography afforded the corresponding pure products.
(2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one (2):[7]
Yield 241.8 mg (0.97 mmol, 97%); anti/syn = 99:1, enantiomeric
excess: 99% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 20:80; 0.5 mL/min; 20 °C;
λ = 254 nm) tR = 42.5 min (anti, major) and tR = 32.8 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.7 Hz, 2
H, Ar-H), 7.51 (d, J = 8.7 Hz, 2 H, Ar-H), 4.90 (dd, J = 8.4, 3.0 Hz,
1 H), 4.09 (d, J = 3.0 Hz, 1 H), 2.65–2.45 (m, 2 H), 2.36 (td, J =
13.2, 5.7 Hz, 1 H), 2.17–2.06 (m, 1 H), 1.87–1.78 (m, 1 H), 1.67–
1.51 (m, 3 H), 1.45–1.31 (m, 1 H) ppm.
S-(tert-Butyl)-L-cysteine (1a): Yield 47.21 g (230 mmol, 92%); white
microcrystals; m.p. 145–146 °C; [α]2D0 = –13.1 (c = 1, MeOH). 1H
3
NMR (300 MHz, DMSO): δ = 1.19 (s, 9 H, CH3), 3.36–3.38 (d, J
3
= 5.4 Hz, 2 H, SCH2), 4.06 (d, J = 5.1 Hz, 1 H, NCH) ppm. 13C
NMR (75 MHz, DMSO): δ = 27.2, 28.2, 46.5, 51.9, 169.4,
204.6 ppm. MS (ESI): calcd. for C8H15NO3S 205.27; found 205.46.
IR (KBr): ν = 2970, 1766, 1680, 1501, 1479, 1200, 933 cm–1.
˜
(2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexan-1-one (3):[7]
Yield 244.3 mg (0.98 mmol, 98%); anti/syn = 99:1, enantiomeric
excess: 99% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak OD-H column; iPrOH/hexane = 5:95; 0.5 mL/min; 20 °C; λ
= 254 nm) tR = 41.9 min (anti, major) and tR = 50.7 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 8.1 Hz, 1
H, Ar-H), 7.77 (d, J = 7.8 Hz, 1 H, Ar-H), 7.63 (t, J = 7.5 Hz, 1
H, Ar-H), 7.43 (t, J = 7.8 Hz, 1 H, Ar-H), 5.45 (d, J = 6.6 Hz, 1
H), 3.90 (br., 1 H), 2.82–2.70 (m, 1 H), 2.50–2.40 (m, 1 H), 2.34
(td, J = 12.3, 5.7 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.90–1.55 (m, 4
H) ppm.
S-(4-tert-Butylphenyl)-L-cysteine (1b): Yield 66.82 g (237.5 mmol,
95%); white microcrystals; m.p. 144–145 °C; [α]2D0 = –25.8 (c = 0.1,
MeOH). 1H NMR (300 MHz, DMSO): δ = 1.30–1.31 (d, J =
2.6 Hz, 9 H, CH3), 3.60–3.62 (d, J = 5.5 Hz, 2 H, SCH2), 4.67 (br.
s, 1 H, NCH), 7.52 (d, 3J = 5.8 Hz, 2 H, Ph-H), 7.87 (d, J = 5.9 Hz,
2 H, Ph-H) ppm. 13C NMR (75 MHz, DMSO): δ = 31.3, 35.2, 37.8,
51.6, 125.8, 128.4, 129.6, 157.2, 167.6, 169.6 ppm. MS (ESI): calcd.
for C H NO S 281.37; found 281.51. IR (KBr): ν = 2968, 1756,
˜
14 19
3
1737, 1601, 1575, 1493, 1415 cm–1.
O-(tert-Butyl)-L-serine (1c): Yield 44.94 g (237.5 mmol, 95%); white
microcrystals; m.p. 115–116 °C; [α]2D0 = –37.3 (c = 1, MeOH). 1H
3
(2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexan-1-one (4):[7]
Yield 246.8 mg (0.99 mmol, 99%); anti/syn = 96:4, enantiomeric
excess: 99% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 20:80; 0.5 mL/min; 20 °C;
λ = 254 nm) tR = 41.9 min (anti, major) and tR = 32.4 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.7 Hz, 2
H, Ar-H),7.51 (d, J = 8.7 Hz, 2 H, Ar-H), 4.90 (dd, J = 8.4, 3.0 Hz,
1 H), 4.09 (d, J = 3.0 Hz, 1 H), 2.65–2.45 (m, 2 H), 2.36 (td, J =
13.2, 5.7 Hz, 1 H), 2.17–2.06 (m, 1 H), 1.87–1.78 (m, 1 H), 1.67–
1.51 (m, 3 H), 1.45–1.31 (m, 1 H) ppm.
NMR (300 MHz, DMSO): δ = 1.16 (s, 9 H, CH3), 3.84 (ddd, J =
3.0, 4.2, 3.4 Hz, 1 H, 3-H), 4.32–4.34 (m, 2 H, OCH2) ppm. 13C
NMR (75 MHz, DMSO): δ = 27.1, 38.7, 51.6, 61.2, 168.7,
177.3 ppm. MS (ESI): calcd. for C8H15NO4 189.21; found 189.50.
IR (KBr): ν = 2976, 1727, 1631, 1504, 1368, 1150 cm–1.
˜
O-(4-tert-Butylphenyl)-L-serine (1d): Yield 63.67 g (240 mmol,
96%); white microcrystals; m.p. 112–113 °C; [α]2D0 = –7.9 (c = 1,
MeOH). 1H NMR (300 MHz, DMSO): δ = 1.31 (s, 9 H, CH3),
4.46 (br. s, 1 H, NCH), 4.68 (m, 2 H, OCH2), 7.55 (d, 3J = 8.4 Hz,
2 H, Ph-H), 8.00 (d, 3J = 8.4 Hz, 2 H, Ph-H) ppm. 13C NMR
(75 MHz, DMSO): δ = 31.2, 35.3, 51.8, 62.7, 125.8, 126.6, 130.1,
157.2, 165.5, 168.7 ppm. MS (ESI): calcd. for C14H19NO4 265.33;
(2S,10R)-2-[(4-Cyanophenyl)hydroxymethyl]cyclohexan-1-one (5):[7]
Yield 224.7 mg (0.98 mmol, 98%); anti:syn = 95:5, enantiomeric
excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 20:80; 0.5 mL/min; 20 °C;
λ = 254 nm) tR = 22.5 min (anti, major) and tR = 18.1 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.1 Hz, 2
H, Ar-H), 7.45 (d, J = 8.1 Hz, 2 H, Ar-H), 4.85 (dd, J = 8.1, 3.0 Hz,
1 H), 4.11 (d, J = 3.0 Hz, 1 H), 2.65–2.44 (m, 2 H), 2.37 (td, J =
12.9, 6.0 Hz, 1 H), 2.17–2.06 (m, 1 H), 1.88–1.77 (m, 1 H), 1.72–
1.47 (m, 3 H), 1.44–1.31 (m, 1 H) ppm.
found 265.51. IR (KBr): ν = 2968, 1754, 1722, 1601, 1575, 1493,
˜
1415, 1157 cm–1.
O-(tert-Butyl)-L-threonine (1e): Yield 47.76 g (234 mmol, 94%);
white microcrystals; m.p. 110–111 °C; [α]2D0 = –13.3 (c = 1, MeOH).
1H NMR (300 MHz, DMSO): δ = 1.12 (s, 9 H, CH3), 1.20–1.24
3
(d, J = 6.9 Hz, 3 H, CH3), 4.20 (br. s, 1 H, NCH), 5.24–5.27 (dq,
3J = 2.7, 6.3 Hz, 1 H, OCH) ppm. 13C NMR (75 MHz, DMSO): δ
= 16.2, 26.6, 38.3, 55.4, 67.8, 168.4, 176.3 ppm. MS (ESI): calcd.
for C9H17NO4 203.24; found 203.51. IR (KBr):ν = 2968, 1754,
˜
(2S,10R)-2-{Hydroxy[4-(trifluoromethyl)methyl]}cyclohexan-1-one
(6):[7] Yield 261.4 mg (0.96 mmol, 96%); anti/syn = 92:8, enantio-
meric excess: 97% (anti diastereomer) determined by HPLC (Daicel
Chiralpak AD-H column; iPrOH/hexane = 10:90; 0.5 mL/min,
20 °C, λ = 254 nm) tR = 34.4 min (anti, major) and tR = 26.9 min
(anti, minor). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.55 (m, 3 H,
ArH), 7.40 (t, J = 7.2 Hz, 1 H, ArH), 5.30 (d, J = 9.3 Hz, 1 H),
4.03 (t, J = 3.0 Hz, 1 H), 2.81–2.69 (m, 1 H), 2.55–2.45 (m, 1 H),
2.37 (td, J = 12.9, 4.8 Hz, 1 H), 2.15–2.03 (m, 1 H), 1.81–149 (m,
3 H), 1.48–1.23 (m, 1 H) ppm.
1722, 1588, 1493, 1415, 1156 cm–1.
O-(4-tert-Butylphenyl)-L-threonine (1f): Yield 62.85 g (225 mmol,
90%); white microcrystals; m.p. 97–100 °C; [α]2D0 = –18.0 (c = 1,
MeOH). 1H NMR (300 MHz, DMSO): δ = 1.28 (s, 9 H, CH3),
1.42–1.44 (d, 3J = 6.6 Hz, 3 H, CH3), 4.31 (br. s, 1 H, NCH), 5.51–
3
3
5.54 (dq, J = 3.0, 6.5 Hz, 1 H, 3-H, OCH), 7.51 (d, J = 8.2 Hz,
2 H, Ph-H), 8.01 (d, 3J = 8.3 Hz, 2 H, Ph-H) ppm. 13C NMR
(75 MHz, DMSO): δ = 31.2, 35.3, 56.0, 69.0, 125.8, 126.7, 130.2,
157.2, 164.9, 168.8 ppm. MS (ESI): calcd. for C15H21NO4 279.33;
found 279.52. IR (KBr): ν = 2968, 1754, 1722, 1601, 1575, 1493,
˜
(2S,10R)-2-[(4-Chlorophenyl)hydroxymethyl]cyclohexan-1-one (7):[7]
Yield 224.4 mg (0.94 mmol, 94%); anti/syn = 95:5, enantiomeric
1415, 1157 cm–1.
Typical Procedure for Asymmetric Aldol Reactions of Ketones with excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
Aldehydes: To a mixture of catalyst 1f (13.97 mg, 0.05 mmol) and
ketone (2.0 mmol), were added aldehyde (1.0 mmol) and water
(0.5 mL). The resulting mixture was stirred at room temperature
and the reaction was monitored by TLC. After completion, the
ralpak AD-H column; iPrOH/hexane = 10:90; 0.5 mL/min, 20 °C,
λ = 221 nm) tR = 39.2 min (anti, major) and tR = 33.4 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.34 (d, J = 8.4 Hz, 2
H, ArH), 7.28 (d, J = 8.4 Hz, 2 H, ArH), 4.76 (dd, J = 8.7, 2.7 Hz,
1296
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1291–1299

Asymmetric Aldol Reaction with Threonine Derivatives
1 H), 3.99 (d, J = 3.0 Hz, 1 H), 2.61–2.44 (m, 2 H), 2.35 (td, J =
12.9, 5.4 Hz, 1 H), 2.15–2.05 (m, 1 H), 1.85–1.75 (m, 1 H), 1.70–
1.50 (m, 3 H), 1.37–1.20 (m, 1 H) ppm.
excess: 96% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 5:95; 1.0 mL/min, 20 °C, λ
= 254 nm) tR = 45.9 min (anti, major) and tR = 36.7 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.24–8.27 (m, 1 H, ArH),
7.84–7.89 (m, 1 H, ArH), 7.81 (d, J = 8.1 Hz, 1 H, ArH), 7.57 (d,
J = 6.3 Hz, 1 H, ArH), 7.45–7.53 (m, 3 H, ArH), 5.58 (dd, J = 8.7,
2.9 Hz, 1 H), 4.15 (d, J = 2.9 Hz, 1 H), 2.95–3.04 (m, 1 H), 2.49–
2.54 (m, 1 H), 2.35–2.45 (m, 1 H), 2.05–2.12 (m, 1 H), 1.61–1.74
(m, 2 H), 1.33–1.51 (m, 3 H) ppm.
(2S,10R)-2-[(2-Chlorophenyl)hydroxymethyl]cyclohexan-1-one (8):[7]
Yield 226.8 mg (0.95 mmol, 95%); anti/syn = 90:10, enantiomeric
excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak OD-H column; iPrOH/hexane = 5:95; 1.0 mL/min, 20 °C, λ
= 221 nm) tR = 9.7 min (anti, major) and tR = 12.3 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.56 (dd, J = 7.6, 1.6 Hz,
1 H, ArH), 7.21–7.37 (m, 3 H, ArH), 5.35 (dd, J = 8.0, 3.6 Hz 1
H), 2.65–2.71 (m, 1 H), 3.88 (s, 1 H), 2.46–2.49 (m, 1 H), 2.31–2.39
(m, 1 H), 2.05–2.13 (m, 1 H), 1.53–1.84 (m, 5 H) ppm.
(2S,10R)-2-[(4-Bromophenyl)hydroxymethyl]cyclohexan-1-one (9):[7]
Yield 269.0 mg (0.95 mmol, 95%); anti/syn = 96:4, enantiomeric
excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 10:90; 0.5 mL/min, 20 °C,
λ = 220 nm) tR = 43.1 min (anti, major) and tR = 35.5 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 8.1 Hz, 2
H, ArH), 7.20 (d, J = 8.7 Hz, 2 H, ArH), 4.75 (dd, J = 8.7, 2.7 Hz,
1 H), 3.99 (d, J = 3.0 Hz, 1 H), 2.61–2.44 (m, 2 H), 2.35 (td, J =
12.9, 6.3 Hz, 1 H), 2.15–2.04 (m, 1 H), 1.85–1.75 (m, 1 H), 1.70–
1.50 (m, 3 H), 1.37–1.20 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(phenyl)methyl]cyclohexan-1-one (15):[7] Yield
171.6 mg (0.84 mmol, 84%); anti/syn = 94:6, enantiomeric excess:
97% (anti diastereomer) determined by HPLC (Daicel Chiralpak
OD-H column; iPrOH/hexane = 10:90; 0.5 mL/min, 20 °C, λ =
220 nm) tR = 19.6 min (anti, major) and tR = 30.6 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H, PhH),
4.80 (d, J = 9.0 Hz, 1 H), 4.00 (m, 1 H), 2.70–2.56 (m, 1 H), 2.55–
2.44 (m, 1 H), 2.34 (td, J = 12.3, 5.4 Hz, 1 H), 2.16–2.03 (m, 1 H),
1.87–1.73 (m, 1 H), 1.72–1.50 (m, 3 H), 1.40–1.22 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(pyridin-4-yl)methyl]cyclohexan-1-one (16):[7]
Yield 197.0 mg (0.96 mmol, 96%); anti/syn = 81:19, enantiomeric
excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 10:90; 1.0 mL/min, 20 °C,
λ = 254 nm) tR = 27.5 min (anti, major) and tR = 25.0 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.53–8.55 (d, J = 6.0 Hz,
2 H), 7.25–7.28 (d, J = 6.0 Hz, 2 H), 4.80 (d, J = 8.4 Hz, 1 H),
4.29 (br., 1 H), 2.31–2.63 (m, 3 H), 2.07–2.12 (m, 1 H), 1.81–1.84
(m, 1 H), 1.61–1.1.71 (m, 4 H), 1.30–1.41 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(4-methoxyphenyl)methyl]cyclohexan-1-one
(10):[7] Yield 208.5 mg (0.89 mmol, 89%); anti/syn = 93:7, enantio-
meric excess: 97% (anti diastereomer) determined by HPLC (Daicel
Chiralpak AD-H column; iPrOH/hexane = 10:90; 0.8 mL/min,
20 °C, λ = 221 nm) tR = 32.5 min (anti, major) and tR = 30.8 min
(anti, minor). 1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.4 Hz,
2 H, ArH), 6.90 (d, J = 8.8 Hz, 2 H, ArH), 4.76 (d, J = 7.6 Hz, 1
H), 3.94 (s, 1 H), 3.83 (s, 3 H), 2.34–2.65 (m, 3 H), 2.08–2.14 (m,
1 H), 1.55–1.82 (m, 6 H), 1.20–1.40 (m, 2 H) ppm.
(2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclopentan-1-one (17):[7]
Yield 232.9 mg (0.99 mmol, 99%); anti/syn = 56:44, enantiomeric
excess: 95% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 5:95; 1.0 mL/min, 20 °C, λ
= 254 nm) tR = 58.4 min (anti, major) and tR = 55.4 min (anti,
minor); tR = 30.8 min (syn, major) and tR = 43.9 min (syn, minor).
1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.7 Hz, 2 H, ArH),
7.54 (d, J = 9.0 Hz, 2 H, ArH), 4.85 (d, J = 9.2 Hz, 1 H), 4.76
(s, 1 H), 2.54–2.18 (m, 3 H), 2.08–1.95 (m, 1 H), 1.81–1.48 (m, 3
H) ppm.
(2S,10R)-2-[Hydroxy(3-methoxyphenyl)methyl]cyclohexan-1-one
(11):[7] Yield 201.5 mg (0.86 mmol, 86%); anti/syn = 93:7, enantio-
meric excess: 96% (anti diastereomer) determined by HPLC (Daicel
Chiralpak AD-H column; iPrOH/hexane = 10:90; 0.5 mL/min,
20 °C, λ = 221 nm) tR = 56.3 min (anti, major) and tR = 51.1 min
(anti, minor). 1H NMR (300 MHz, CDCl3): δ = 7.28–7.33 (m, 1 H,
ArH), 6.80–7.00 (m, 3 H, ArH), 4.80 (d, J = 8.7 Hz, 1 H), 3.85 (s,
3 H), 2.30–2.75 (m, 3 H), 2.00–2.15 (m, 1 H), 1.55–1.90 (m, 4 H),
1.20–1.40 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(4-tolyl)methyl]cyclohexan-1-one (12):[7] Yield
181.2 mg (0.83 mmol, 83%); anti/syn = 99:1, enantiomeric excess:
Ͼ99% (anti diastereomer) determined by HPLC (Daicel Chiralpak
AD-H column; iPrOH/hexane = 10:90; 0.5 mL/min, 20 °C, λ =
221 nm) tR = 32.8 min (anti, major) and tR = 44.5 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 7.18 (dd, J = 17.1,
8.4 Hz, 4 H, ArH), 4.75 (dd, J = 9.0, 2.7 Hz, 1 H), 3.91 (d, J =
2.7 Hz, 1 H), 2.66–2.54 (m, 1 H), 2.51–2.43 (m, 1 H), 2.35 (td, J =
13.2, 6.0 Hz, 1 H), 2.34 (s, 3 H), 2.14–2.03 (m, 1 H), 1.82–1.72 (m,
1 H), 1.70–1.50 (m, 3 H), 1.38–1.18 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(2-naphthyl)methyl]cyclohexan-1-one (13):[7,8a]
Yield 236.3 mg (0.93 mmol, 93%); anti/syn = 97:3, enantiomeric
excess: Ͼ99% (anti diastereomer) determined by HPLC (Daicel
Chiralpak OD-H column; iPrOH/hexane = 10:90; 1.0 mL/min,
20 °C, λ = 221 nm) tR = 15.7 min (anti, major) and tR = 22.2 min
(anti, minor). 1H NMR (300 MHz, CDCl3): δ = 7.70–7.90 (m, 4 H,
ArH), 7.40–7.55 (m, 3 H, ArH), 5.01 (d, J = 8.7 Hz, 1 H), 4.10 (s,
1 H), 2.71–2.78 (m, 1 H), 2.37–2.55 (m, 2 H), 2.09–2.14 (m, 1 H),
1.52–1.80 (m, 5 H), 1.28–1.42 (m, 2 H) ppm.
(2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclopentan-1-one (18):[7]
Yield 230.5 mg (0.98 mmol, 98%); anti/syn = 55:45, enantiomeric
excess: 98% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak OD-H column; iPrOH/hexane = 5:95; 1.0 mL/min, 20 °C, λ
= 254 nm) tR = 39.8 min (anti, major) and tR = 43.2 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.00 (dd, J = 8.0, 0.8 Hz,
1 H, ArH), 7.89 (d, J = 8.0 Hz, 1 H, ArH), 7.66 (t, J = 8.0 Hz, 1
H, ArH), 7.44 (t, J = 8.0 Hz, 1 H, ArH), 5.21 (d, J = 7.2 Hz, 1 H),
2.90 (br., 1 H), 2.68 (d, J = 7.6 Hz, 1 H), 2.19–2.38 (m, 2 H),1.70–
2.03 (m, 4 H) ppm.
(2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclopentan-1-one (19):[7]
Yield 232.9 mg (0.99 mmol, 99%); anti/syn = 75:25, enantiomeric
excess: 96% (anti diastereomer) determined by HPLC (Daicel Chi-
ralpak AD-H column; iPrOH/hexane = 8:92; 1.0 mL/min, 20 °C, λ
= 254 nm) tR = 29.4 min (anti, major) and tR = 43.3 min (anti,
minor). 1H NMR (300 MHz, CDCl3): δ = 8.17–8.18 (m, 1 H, ArH),
8.10 (ddd, J = 8.1, 2.3, 1.1 Hz, 1 H, ArH), 7.62–7.65 (m, 1 H,
ArH), 7.47 (t, J = 7.9 Hz, 1 H, ArH), 4.77 (d, J = 9.3 Hz, 1 H),
4.72 (s, 1 H), 2.16–2.47 (m, 3 H), 1.92–2.01 (m, 1 H), 1.61–1.78 (m,
2 H), 1.50–1.55 (m, 1 H) ppm.
(2S,10R)-2-[Hydroxy(4-chlorophenyl)methyl]cyclopentan-1-one
(20):[6e] Yield 206.7 mg (0.92 mmol, 92%); anti/syn = 61:39, enan-
(2S,10R)-2-[Hydroxy(1-naphthyl)methyl]cyclohexan-1-one (14):[7,8a] tiomeric excess: 95 % (anti diastereomer) determined by HPLC
Yield 228.9 mg (0.90 mmol, 90%); anti/syn = 98:2, enantiomeric
(Daicel Chiralpak AD-H column; iPrOH/hexane = 5:95; 1.0 mL/
Eur. J. Org. Chem. 2011, 1291–1299
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1297

X. Fu et al.
FULL PAPER
min, 20 °C, λ = 220 nm) tR = 36.9 min (anti, major) and tR
=
δ = 7.47 (s, 1 H, ArH), 7.19 (m, 1 H, ArH), 7.13 (d, J = 7.2 Hz, 1
29.9 min (anti, minor). 1H NMR (300 MHz, CDCl3): δ = 7.32 (dd, H, ArH), 7.09 (m, 1 H, ArH), 5.50 (m, 1 H), 3.66 (br., 1 H), 2.75
J = 22.8, 8.4 Hz, 4 H, ArH), 5.23 (br. s, 1 H), 4.63 (s, 1 H), 2.90
(t, J = 13.2 Hz, 1 H), 1.22–2.38 (m, 6 H) ppm.
(t, J = 4.6 Hz, 2 H), 2.21 (s, 3 H) ppm.
Procedure for Catalyst Recovery: To a mixture of catalyst 1f
(0.1397 g, 0.5 mmol) and cyclohexanone (20 mmol), were added 4-
nitrobenzaldehyde (1.512 g, 10 mmol) and water (5 mL). The mix-
ture was stirred at room temperature as specified in Table 5. The
reaction mixture was quenched with aqueous HCl (0.5 mmol,
6 mol/L) and then diluted with diethyl ether (25 mL) and the reac-
tion mixture was vigorous stirred for 5 min. The reaction mixture
was placed in an ethanol bath for 1 h (–20 °C), then the organic
layer was concentrated in vacuo to afford the crude aldol product,
which was purified by column chromatography (ethyl acetate/hex-
ane = 1:10 to 1:2). To the catalyst 1f, which remained in the acidic
aqueous layer, was added triethylamine (0.55 mmol), and the re-
sulting white suspension was stirred at room temperature for
10 min after addition, and then filtered under vacuum. The white
crystals of 1f could be recycled to catalyze the aldol reaction with-
out adding any new catalyst.
(2S,4S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]-4-methylcyclohexan-
1-one (21):[6e] Yield 258.0 mg (0.98 mmol, 98%); anti/syn = 95:5;
enantiomeric excess: 97% (anti diastereomer) determined by HPLC
(Daicel Chiralpak AD-H column; iPrOH/hexane = 10:90; 1.0 mL/
min, 20 °C, λ = 254 nm) tR = 36.3 min (anti, major) and tR
=
1
41.3 min (anti, minor). H NMR (300 MHz, CDCl3): δ = 8.21 (d,
J = 8.8 Hz, 2 H, ArH), 7.51 (d, J = 8.8 Hz, 2 H, ArH), 4.94 (dd,
J = 8.4, 2.4 Hz, 1 H), 3.96 (d, J = 2.8 Hz, 1 H), 2.38–2.78 (m, 3
H), 1.26–2.11 (m, 5 H), 1.06 (d, J = 6.8 Hz, 3 H) ppm.
(S)-3-[(R)-Hydroxy(4-nitrophenyl)methyl]tetrahydropyran-4-one
(22):[6e] Yield 243.7 mg (0.97 mmol, 97%); anti/syn = 96:4, enantio-
meric excess: 98% (anti diastereomer) determined by HPLC (Daicel
Chiralpak AD-H column; iPrOH/hexane = 5:95; 1.0 mL/min,
20 °C, λ = 254 nm) tR = 23.0 min (anti, major) and tR = 27.1 min
(anti, minor). 1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz,
2 H, ArH), 7.53 (d, J = 8.8 Hz, 2 H, ArH), 4.99 (d, J = 8.0 Hz, 1
H), 4.19–4.25(m, 1 H), 3.70–3.85 (m, 3 H), 3.42–3.49 (m, 1 H),
2.88–2.94 (m, 1 H), 2.64–2.70 (m, 1 H), 2.50–2.57 (m, 1 H) ppm.
(3R,4S)-3,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one (23):[6g] Yield
218.4 mg (0.97 mmol, 97%); anti/syn = 20:80, enantiomeric excess:
97% (syn diastereomer) determined by HPLC (Daicel Chiralpak
AD-H column; iPrOH/hexane = 20:80; 0.8 mL/min, 25 °C, λ =
254 nm) tR = 21.7 min (syn, major) and tR = 16.2 min (syn, minor).
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 8.8 Hz, 2 H, ArH),
7.63 (d, J = 8.8 Hz, 2 H, ArH), 5.20–5.22 (m, 1 H), 4.40–4.42 (m,
1 H), 3.71 (d, J = 4.6 Hz, 1 H), 2.68 (d, J = 8.1 Hz, 1 H), 2.36–
2.43 (m, 1 H), 2.36 (s, 3 H) ppm.
General Procedure for Large-Scale Aldol Reactions: To a mixture
of catalyst 1f (0.3492 g, 1.25 mmol) and ketone (50 mmol), were
added aromatic aldehyde (25 mmol) and water (12.5 mL). The re-
sulting mixture was stirred at room temperature and the reaction
was monitored by TLC. The reaction was then quenched with satu-
rated NH4Cl (30 mL), extracted with EtOAc (3ϫ 60 mL), and
dried with Na2SO4. Purification by flash chromatography afforded
the corresponding pure products.
Supporting Information (see footnote on the first page of this arti-
1
cle): Synthesis and H and 13C NMR spectra of catalysts 1a–f.
Acknowledgments
(3R,4S)-3,4-Dihydroxy-4-(2-nitrophenyl)butan-2-one (24):[6g] Yield
213.9 mg (0.95 mmol, 95%); anti/syn = 5:95, enantiomeric excess:
99% (syn diastereomer) determined by HPLC (Daicel Chiralpak
AD-H column; iPrOH/hexane = 20:80; 0.8 mL/min, 25 °C, λ =
254 nm) tR = 14.0 min (syn, major) and tR = 12.9 min (syn, minor).
1H NMR (300 MHz, CDCl3): δ = 8.09–8.11 (dd, J = 8.0, 0.8 Hz,
1 H, ArH), 7.79–7.81 (d, J = 8.0 Hz, 1 H, ArH), 7.70–7.74 (t, J =
8.0 Hz, 1 H, ArH), 7.48–7.53 (t, J = 8.0 Hz, 1 H, ArH), 5.89 (m,
1 H), 4.45–4.56 (m, 1 H), 2.51 (s, 3 H) ppm.
Authors are grateful to the Southwest University of China for fin-
ancial support.
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Received: October 12, 2010
Published Online: January 12, 2011
Eur. J. Org. Chem. 2011, 1291–1299
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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