Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

Article abstract of DOI:10.1016/j.tet.2007.09.027

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cy

Full text of DOI:10.1016/j.tet.2007.09.027

Tetrahedron 63 (2007) 11886–11892
Highly stereoselective direct aldol reactions catalyzed by
(S)-NOBIN-L-prolinamide
*
Alessio Russo, Giovanna Botta and Alessandra Lattanzi
Dipartimento di Chimica, Universitaꢀ di Salerno, Via Ponte don Melillo, 84084-I Fisciano, Italy
Received 18 June 2007; revised 28 August 2007; accepted 13 September 2007
Available online 22 September 2007
Abstract—(S)-NOBIN-L-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic alde-
hydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones
furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).
Ó 2007 Elsevier Ltd. All rights reserved.
R
O
1. Introduction
R
N
The stereoselective aldol reaction plays a fundamental role
among the carbon–carbon bond forming transformations as
a key step in natural product synthesis and for the rapid ac-
cess to polyoxygenated compounds.1 After the discovery by
List and co-workers that L-proline catalyzes the enantio-
selective intermolecular direct aldol reaction,2 a significant
amount of work has been undertaken to improve the effi-
ciency and increase the scope of the organocatalyzed aldol
reaction. Thus, a rapid development of asymmetric method-
ologies employing cyclic and linear unmodified ketones
with different aldehydes has been observed.3 Several orga-
nocatalysts have been synthesized mainly by modifying
the acidic moiety of L-proline and the most efficient deriva-
tives are those having groups, which can be involved in hy-
drogen bonding interactions.4 According to the mechanism
proposed for this reaction, the enamine derived from the
condensation of acetone with proline4a (TS-1) or proline-
based organocatalysts as amides4c,e (TS-2) forms rigid
transition states where the stereochemistry of the novel
carbon–carbon bond is regulated through hydrogen bonding
interactions with the carbonyl group of the approaching
aldehyde (Fig. 1). Hence, the presence of acidic protons in
the organocatalyst is an important structural feature for the
development of more efficient proline-derived promoters.
N
O
H
N
H
R
O
H
O
O
O
H
H
R
TS-1
TS-2
Figure 1. Transition states for proline and prolinamides catalyzed aldol
reactions.
of prolinamides having (S)- and (R)-NOBIN ligands as the
amide portion in the direct aldol reaction (Fig. 2).6 These
compounds, easily obtained from N-benzyloxy-L-proline,6
were designed with the intention of synthesizing more reac-
tive promoters with the presence of better H-bond donors in
the phenolic OH and amidic NH groups, and to enhance the
stereocontrol due to the axial element of chirality.
Diastereoisomer 2 proved to be a better catalyst than 1 in the
reaction of acetone and different aldehydes, showing the
O
O
N
N
N
H
N
H
H
H
HO
HO
1, L-Pro-Ra-NOBIN
2, L-Pro-Sa-NOBIN
Axial chirality in proline-based compounds has been intro-
duced as BINAM mono- and bis-prolinamides, which were
successfully employed under different conditions in direct
aldol reactions.5 We have recently reported the employment
O
N
N
H
H
H3CO
3
Keywords: Organocatalysis; Aldol reactions; NOBIN; Prolinamides.
* Corresponding author. Tel.: +39 089 969563; e-mail: lattanzi@unisa.it
Figure 2. NOBIN-based prolinamides.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.027

A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
11887
matching combination of L-proline with axial (S)-configured
NOBIN. Unexpectedly high reactivity of 2 was observed
when carrying out the reaction in the unusual hexane and
this enabled reactions with a low loading of 2 (5 mol %)
and of acetone (3 equiv) with respect to the aldehyde. Al-
though the products were isolated in good to high yields,
the enantioselectivity ranged from 53 to 77% ee. The pres-
ence of an OH group in catalyst 2 was important, which is
likely to be involved as a H-bond donor. In fact, the reaction
performed using 3, the O-methylated enantiomer of 2, fur-
nished the product in high yield, but with a significantly
lower ee.
the conversion and the aldol product was isolated in 78% ee
(entry 2). Higher conversion was observed when adding
1.1 equiv of water (entry 3), while 4.5 or 9 equiv afforded
a maximum of 41% yield, but the enantioselectivity slightly
decreased (entries 4 and 5). These experiments showed that
the presence of water is beneficial for both the activity and
the asymmetric induction in a more restricted molar range
when compared to L-proline.9a,d It is likely that the amount
of water added, in order to regulate the activity, is related to
the structure of the proline-based organocatalysts. This is sim-
ilar to what happens to reactions catalyzed by enzymes in or-
ganic solvents, where the water content is known to modulate
their activity and stereoselectivity.11 With the optimum
amount of water additive (1.1 equiv), THF and DME were ex-
amined as alternative ethereal solvents, but they gave unsatis-
factory results when compared to dioxane (entries 6 and 7). It
must be noted that the reaction performed in the polar protic
methanol and in the absence of water furnished racemic aldol
product in moderate yield (entry 8). Predictably, methanol
was highly competitive with the catalyst as a H-bond donor
in activating the aldehyde through an unselective pathway.
Carrying out the reaction using 5 mol % of TFA as acid addi-
tive and 10 mol % of 2 in dioxane (entry 9) had a detrimental
effect on the reaction (compare with entry 1) even in the pres-
ence of water (entry 10).
Herein, we report a more in-depth investigation on the aldol
reactions catalyzed by compound 2. An improvement of the
enantioselectivity was achieved for acetone as donor under
different conditions and the scope of the reaction was
extended to different ketones achieving excellent levels of
diastereo- and enantioselectivity.7
2. Results and discussion
It has been shown that the presence of acid and basic additives
affected the outcome of organocatalyzed direct aldol reac-
tions.8 Depending on the amount, addition of water to the
reaction solvent improved the activity and asymmetric induc-
tion of L-proline9 and other derivatives5e as catalysts. We
therefore investigated the effect of different equivalents of wa-
ter in the model reaction of acetone and p-nitrobenzaldehyde
at room temperature catalyzed by 5 mol % of compound 2
(Table 1). Amongst the solvents to be examined, dioxane
was chosen for this investigation.10 Anhydrous conditions fur-
nished the product in low yield and 65% ee (entry 1). The ad-
dition of 0.5 equiv of water to the reaction mixture doubled
Using 1.1 equiv of water and working at 4 ꢀC in dioxane,
some representative aldol products were obtained in good
yield using 5 mol % of catalyst, but in higher ee with respect
to the use of hexane as the solvent6 (entries 11–13).
Under the same conditions cyclic ketones were studied as
donors employing 10 mol % of catalyst 2 (Table 2).
Table 2. Direct aldol reaction of cyclic ketones and aromatic aldehydes cat-
alyzed by 2 at 4 ꢀC in dioxane and in the presence of 1.1 equiv of watera
Table 1. Direct aldol reaction of acetone and aromatic aldehydes catalyzed
by 2 in different conditions using water as an additivea
O
OH
O
2 (10 mol%)
O
H2O (1.1 equiv)
+
R
O
H
R
O
OH
O
dioxane, 4 °C
+
2 (5 mol%)
X
H
R
R
X
4
6
dioxane
4
5
Entry
R
X
T (h) Yieldb drc (%,
eed (%)
Entry
R
H2O (equiv) T (ꢀC) t (h) Yieldb (%) eec (%)
(%)
anti/syn)
1
2
3
4
p-NO2C6H4
—
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
24 11
27 30
20 37
24 41
23 41
21 13
23 27
46 46
25 13
28 <5
70 77
88 74
129 88
65
78
78
76
72
75
54
3
47
—
1
p-NO2C6H4
p-NO2C6H4
o-NO2C6H4
2,6-Cl2C6H3
p-CNC6H4
p-CF3C6H4
p-ClC6H4
CH2
CH2
CH2
CH2
CH2
CH2 113
CH2 166
CH2 120
65
96
63
72
94
86
42
50
78
61
71
26
60
99
98
82
90
40
31
64
50
98/2
87/13
95/5
92
71f
90
p-NO2C6H4 0.55
p-NO2C6H4 1.1
p-NO2C6H4 4.5
p-NO2C6H4 9.0
p-NO2C6H4 1.1
p-NO2C6H4 1.1
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4 1.1
p-NO2C6H4 1.1
o-NO2C6H4 1.1
2,6-Cl2C6H3 1.1
2e
3
4
5
6
7
8
9
10
11
12
13
14
15
16
>99/<1 95
5
98/2
99/1
98/2
95/5
96/4
35/65
44/56
>99/<1 70
>99/<1 94
97/3
97/3
93
91
93
90
79
92(62)
90(56)
6d
7e
8f
—
—
o-ClC6H4
5-Nitrofuran-2-yl CH2
9g
10g
11h
12h
13h
24
48
75
48
p-NO2C6H4
o-NO2C6H4
p-NO2C6H4
p-NO2C6H4
o-NO2C6H4
p-CNC6H4
p-CF3C6H4
—
—
O
S
S
S
80 (70)i
79 (71)i
93 (77)i
4
4
96
192
160
160
93
90
a
Reaction conditions: 4 (0.2 mmol), acetone (0.6 mmol), solvent (400 mL).
Yield of isolated product after flash chromatography.
Determined by HPLC on Chiralpak AS-H column. Absolute configuration
was determined by comparison of the HPLC retention times with those in
the literature.
The reaction was carried out in THF.
The reaction was carried out in dimethoxyethane (DME).
The reaction was carried out in methanol.
b
c
S
>99/<1 90
a
Reaction conditions: 4 (0.2 mmol), acetone (0.6 mmol), H2O (0.22 mmol),
solvent (200 mL).
Yield of isolated aldol products (anti/syn) after flash chromatography.
The anti/syn ratio was determined by 1H NMR analysis on the crude
reaction mixture.
Determined by HPLC on chiral columns. ee in parenthesis for syn-isomer.
Catalyst 3 was used.
The opposite enantiomer of the anti-6 was obtained.
d
e
f
b
c
g
h
i
d
e
f
The reaction was carried out with 10 mol % of 2 and 5 mol % of TFA.
The reaction was carried out using 200 mL of solvent.
ee in parenthesis was achieved in hexane as reported in Ref. 6.

11888
A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
The aldol product obtained from the reaction of p-nitrobenz-
aldehyde and cyclohexanone was recovered in excellent
diastereoisomeric ratio and high ee for the anti adduct
(entry 1).
O
N
N
H
O
H
O
In order to check if under these modified conditions the phe-
nolic OH group of catalyst 2 was involved in the process, the
reaction was performed using catalyst 3 (entry 2). The con-
version to the aldol product was remarkably reduced and
both the diastereo- and the enantioselectivity were signifi-
cantly lowered, which confirmed6 the importance of the
OH group in promoting the reaction and controlling the
stereoselectivity. Excellent anti/syn ratio and ee higher
than 90% for the anti-isomer were generally achieved
(entries 4–9). The anti/syn ratio was marginally decreased
to 95/5 when reacting ortho substituted aromatic aldehydes
(entries 3 and 8), but the asymmetric induction was main-
tained at high levels. Heteroaromatic aldehydes are also
suitable substrates (entry 9). When reacting cyclopentanone
the conversion to the products improved and a slight prefer-
ence for the syn-isomer was observed (entries 10 and 11).
Nevertheless, the anti-aldol was recovered in high ee. Tetra-
hydropyran-4-one reacted much faster than tetrahydro-4H-
thiopyran-4-one with p-nitrobenzaldehyde (entries 12 and
13).12 In both cases the anti-isomer was exclusively ob-
tained, but only the thio-derivative showed appreciable ee.
Although being a relatively unreactive ketone, tetrahydro-
4H-thiopyran-4-one furnished different aldol products in
satisfactory yields, excellent diastereoselectivity and high
enantioselectivity (entries 14–16). These products are syn-
thetically useful building blocks13 since they can be con-
verted to 3-pentanone derivatives, which are difficult to
prepare by direct aldol reaction of the linear ketone with
high stereocontrol.14 Finally, two more challenging linear
ketones15 were reacted to ascertain the degree of regio-
and stereocontrol with model p-nitrobenzaldehyde (Table 3).
In the case of a-methoxyacetone (entry 1) reasonable regio-
selectivity in favor of isomers 7 as well as comparable anti-
diastereoselectivity were observed. anti-7 was recovered in
84% ee. Unreactive a-chloroacetone16 furnished the aldols
in modest yield, but with excellent regio- and diastereoselec-
tivity and anti-7 was obtained in 85% ee (entry 2). These re-
sults showed that linear ketones, although more flexible
donors, can be successfully converted in high regio- and
H
H
Figure 3. Plausible transition state for the direct aldol reaction catalyzed
by 2.
diastereoselective control to anti-isomers with fairly good
level of enantioselectivity.
On the basis of experimental results, the high stereocontrol
observed when using catalyst 2 can be rationalized by invok-
ing the transition state depicted in Figure 3, which is similar
to transition state TS-2 previously suggested by Gong et al.4c
(Fig. 1). Both NH and OH groups take part in the activation
of the aldehyde as H-bond donors and the new C–C bond is
formed by the attack of enamine from its Re face onto the
Re face of aldehyde.
3. Conclusion
Under optimized conditions, which required the presence of
water as additive,17 (S)-NOBIN-L-prolinamide 2 was shown
to be a highly stereoselective catalyst in direct aldol reac-
tions of linear and cyclic ketones with aromatic aldehydes.
anti-Aldols were generally isolated in excellent diastereo-
selectivity and high ee. Although the activity of catalyst 2
decreased when using non-activated aromatic aldehydes, it
can be used at 5–10 mol % loading and only a slight excess
of the ketone with respect to the aldehyde is required. From
a practical and economic point of view these reaction condi-
tions are convenient with respect to most of the organocata-
lyzed protocols where a large excess of ketones is used.
4. Experimental
4.1. General
All reactions requiring dry or inert conditions were con-
ducted in flame dried glassware under a positive pressure
of nitrogen. Reactions were monitored by thin layer chroma-
tography (TLC) on Merck silica gel plates (0.25 mm) and vi-
sualized by UV light or by a 10% H2SO4/ethanol spray test.
Flash chromatography was performed on Merck silica gel
(60, particle size: 0.040–0.063 mm). 1H NMR and 13C
NMR spectra were recorded on Bruker DRX 400 and Bruker
DRX 300 spectrometers at room temperature in CDCl3 as
solvent. Chemical shifts are reported relative to the residual
solvent peaks (CHCl3: dH¼7.26 and dC¼77.0). Optical rota-
tions were performed on a Jasco Dip-1000 digital polarime-
ter using the Na lamp. All commercially available reagents
were purchased from Aldrich. Petrol ether (PE) refers to
light petroleum ether (bp 40–60 ꢀC). The absolute configura-
tions were determined by comparison with optical rotations
and/or HPLC retention times using Daicel Chiralcel OD and
Daicel Chiralpak AD and AS-H columns, as reported in the
Table 3. Direct aldol reaction of linear ketones and p-nitrobenzaldehyde cat-
alyzed by 2 at 4 ꢀC in dioxane and in the presence of 1.1 equiv of watera
OH
O
2 (20 mol%)
O
OH
O
O
+
+
H2O (1.1 equiv)
X
X
R
R
H
R
dioxane, 4 °C
X
7
4
8
Entry X
Regioselectivitye t (h) Yieldb drc of 7
(7/8) of 7 (%) (%, anti/syn)
eed of 7 (%)
1
OCH3 85/15
Cl 95/5
168 62
182 41
84/16
95/5
84
85
2e
a
Reaction conditions:
(0.22 mmol), solvent (200 mL).
Yield of isolated aldol products (7 and 8) after flash chromatography.
The anti/syn ratio was determined by 1H NMR analysis on the crude
reaction mixture.
4
(0.2 mmol), acetone (0.6 mmol), H2O
b
c
d
e
Determined by HPLC on chiral columns.
The regioisomeric ratio was determined by 1H NMR analysis on the crude
reaction mixture.

A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
11889
literature. Synthesis and spectral data of organocatalysts 1–3
were previously reported.6
CDCl3): d 1.55–1.90 (m, 4 H, 2 CH2), 2.06–2.15 (m, 1H,
one proton of CH2), 2.34 (td, J¼12.3, 5.7 Hz, 1H, CH),
2.40–2.50 (m, 1H, CH), 2.70–2.82 (m, 1H, CH), 3.90 (br s,
1H, OH), 5.45 (d, J¼6.6 Hz, 1H, CHOH), 7.43 (t,
J¼7.8 Hz, 1H, ArH), 7.63 (t, J¼7.5 Hz, 1H, ArH), 7.77 (d,
J¼7.8 Hz, 1H, ArH), 7.84 (d, J¼8.1 Hz, 1H, ArH). The ee
was determined by HPLC with Chiralpak AD column (90/
10 hexane/2-propanol), 254 nm, 0.5 mL/min, tr¼59.4 min
(major), tr¼63.0 min (minor).
4.2.6. (2S,10R)-2-(Hydroxy-(2,6-dichlorophenyl)methyl)-
cyclohexan-1-one (Table 2, entry 4).4i [a]D22 ꢁ24.7
(c¼2.12, CHCl3), 95% ee. anti-Isomer: 1H NMR
(300 MHz, CDCl3): d 1.24–1.68 (m, 4H, 2 CH2), 1.71–
1.77 (m, 1H, one proton of CH2), 2.03–2.08 (m, 1H, one pro-
ton of CH2), 2.38–2.49 (m, 2H, CH2), 3.42–3.49 (m, 1H,
CH), 3.65 (d, J¼4.2 Hz, 1H, OH), 5.80 (dd, J¼4.2 Hz, 1H,
CHOH), 7.11–7.31 (m, 3 H, ArH). The ee was determined
by HPLC with Chiralpak AS-H column (95/5 hexane/
2-propanol), 220 nm, 0.5 mL/min; tr¼29.1 min (major),
tr¼23.3 min (minor).
4.2.7. (2S,10R)-2-(Hydroxy-(p-cyanophenyl)methyl)-
cyclohexan-1-one (Table 2, entry 5).3v,w [a]D25 +9.7
(c 1.28, CHCl3), 93% ee. anti-Isomer: 1H NMR (300 MHz,
CDCl3): d 1.31–1.44 (m, 1H, one proton of CH2), 1.47–
1.72 (m, 3H, CH2 and one proton of CH2), 1.77–1.88 (m,
1H, one proton of CH2), 2.06–2.17 (m, 1H, one proton of
CH2), 2.37 (td, J¼12.9, 6.0 Hz, 1H, CH), 2.44–2.65 (m,
2H, CH2), 4.11 (d, J¼3.0 Hz, 1H, OH), 4.85 (dd, J¼8.1,
3.0 Hz, 1H, CHOH), 7.45 (d, J¼8.1 Hz, 2H, ArH), 7.65 (d,
J¼8.1 Hz, 2H, ArH). The ee was determined by HPLC
with Chiralpak AD column (80/20 hexane/2-propanol),
254 nm, 0.5 mL/min, tr¼46.6 min (major), tr¼37.9 min
(minor).
4.2. General procedure for the aldol reaction
In a capped vial, catalyst 2 (7.6 mg, 0.02 mmol), aldehyde
(0.2 mmol), dry dioxane (200 mL), and H2O (4.0 mL) were
added at room temperature. The reaction was cooled to
+4 ꢀC, then the ketone (0.6 mmol) was added and the mix-
ture was stirred at +4 ꢀC. After monitoring by TLC, the mix-
ture was directly purified by flash chromatography eluting
with PE/AcOEt 9/1 to 7/3 mixtures to provide the aldol ad-
duct. Spectral data of aldols were identical to those previ-
ously reported.4c–e,g,9d,15,18 The enantiomeric excess of
aldols was determined by chiral HPLC analysis using Daicel
Chiralcel OD and Daicel Chiralpak AD and AS-H columns
according to the literature.4c,e,g,9d,18
4.2.1. (R)-4-Hydroxy-4-(p-nitrophenyl)-butan-2-one (Ta-
ble 1, entry 11).4e [a]D29 +25.6 (c 0.38, CHCl3), 80% ee. 1H
NMR (300 MHz, CDCl3): d 2.21 (s, 3H, CH3CO), 2.86–2.90
(m, 2H, CH2CO), 3.56 (d, J¼3.2 Hz, 1H, OH), 5.22–5.26
(m, 1H, CHOH), 7.52 (d, J¼7.0 Hz, 2H, ArH), 8.20 (d,
J¼7.0 Hz, 2H, ArH). The ee was determined by HPLC
with Chiralpak AS-H column (70/30 hexane/2-propanol),
254 nm, 1.0 mL/min, tr¼13.0 min (major), tr¼16.3 min
(minor).
4.2.2. (R)-4-Hydroxy-4-(o-nitrophenyl)-butan-2-one (Ta-
ble 1, entry 12).4e [a]D31 +14.0 (c 0.95, CHCl3), 79% ee. 1H
NMR (300 MHz, CDCl3): d 2.22 (s, 3H, CH3CO), 2.85–2.90
(m, 2H, CH2CO), 3.71 (br s, 1H, OH), 5.26 (dd, J¼3.6,
7.2 Hz, 1H, CHOH), 7.52 (t, J¼7.8 Hz, 1H, ArH), 7.70 (d,
J¼7.8 Hz, 1H, ArH), 8.10–8.14 (m, 1H, ArH), 8.24 (m,
1H, ArH). The ee was determined by HPLC with Chiralpak
AS-H column (70/30 hexane/2-propanol), 254 nm, 1.0 mL/
min, tr¼10.92 min (major), tr¼9.98 min (minor).
4.2.8. (2S,10R)-2-(Hydroxy-(p-(trifluoromethyl)phenyl)-
methyl)cyclohexan-1-one (Table 2, entry 6).3w [a]D27
+10.1 (c 1.33, CHCl3), 91% ee. anti-Isomer: 1H NMR
(400 MHz, CDCl3): d 1.24–1.37 (m, 1H, one proton of
CH2), 1.48–1.70 (m, 3H, CH2 and one proton of CH2),
1.77–1.82 (m, 1H, one proton of CH2), 2.09 (ddd, J¼12.8,
6.0, 3.2 Hz, 1H, CH), 2.34 (ddt, J¼13.6, 6.0, 0.8 Hz, 1H,
CH), 2.44–2.50 (m, 1H, CH), 2.54–2.61 (m, 1H, CH), 3.99
(br s, 1H, OH), 4.83 (d, J¼8.8 Hz, 1H, CHOH), 7.42 (d,
J¼8.0 Hz, 2H, ArH), 7.59 (d, J¼8.0 Hz, 2H, ArH). The ee
was determined by HPLC with a Chiralpak AD column
4.2.3. (R)-4-Hydroxy-4-(2,6-dichlorophenyl)-butan-2-
one (Table 1, entry 13).4e [a]D22 ꢁ47.4 (c 0.58, CHCl3)];
93% ee. 1H NMR (300 MHz, CDCl3): d 2.26 (s, 3H,
CH3CO), 2.73–3.44 (m, 2H, CH2CO), 3.22 (br s, 1H, OH),
5.96–6.03 (m, 1H, CHOH), 7.13–7.33 (m, 3H, ArH). The
ee was determined by HPLC with Chiralpak AS-H column
(70/30 hexane/2-propanol), 220 nm, 1.0 mL/min, tr¼
5.3 min (major), tr¼5.8 min (minor).
4.2.4. (2S,10R)-2-(Hydroxy-(p-nitrophenyl)methyl)cyclo-
hexan-1-one (Table 2, entry 1).3q,v,w [a]D22 +18.3 (c 0.58,
CHCl3), 92% ee. anti-Isomer: 1H NMR (300 MHz, CDCl3):
d 1.31–1.45 (m, 1H, one proton of CH2), 1.51–1.67 (m, 3H,
CH2 and one proton of CH2), 1.78–1.87 (m, 1H, one proton
of CH2), 2.06–2.17 (m, 1H, one proton of CH2), 2.36 (td,
J¼13.2, 5.7 Hz, 1H, CH), 2.45–2.65 (m, 2H, CH2), 4.09 (d,
J¼3.0 Hz, 1H, OH), 4.90 (dd, J¼8.4, 3.0 Hz, 1H, CHOH),
7.51 (d, J¼8.7 Hz, 2H, ArH), 8.21 (d, J¼8.7 Hz, 2H, ArH).
The ee was determined by HPLC with Chiralpak AD column
(90/10
hexane/2-propanol),
220 nm,
0.5 mL/min,
tr¼33.0 min (major), tr¼35.3 min (minor).
4.2.9. (2S,10R)-2-(Hydroxy-(p-chlorophenyl)methyl)-
cyclohexan-1-one (Table 2, entry 7).3v,w [a]D25 +13.7
(c 0.33, CHCl3), 93% ee. anti-Isomer: 1H NMR (300 MHz,
CDCl3): d 1.20–1.37 (m, 1H, one proton of CH2), 1.50–
1.70 (m, 3H, CH2 and one proton of CH2), 1.75–1.85 (m,
1H, one proton of CH2), 2.05–2.15 (m, 1H, one proton of
CH2), 2.35 (td, J¼12.9, 5.4 Hz, 1H, CH), 2.44–2.61 (m,
2H, CH2), 3.99 (d, J¼3.0 Hz, 1H, OH), 4.76 (dd, J¼8.7,
2.7 Hz, 1H, CHOH), 7.23 (d, J¼8.4 Hz, 2H, ArH), 7.30 (d,
J¼8.4 Hz, 2H, ArH). The ee was determined by HPLC
with Chiralpak AD column (90/10 hexane/2-propanol),
220 nm, 0.5 mL/min, tr¼31.8 min (major), tr¼26.6 min
(minor).
(80/20
hexane/2-propanol),
254 nm,
0.5 mL/min,
tr¼52.7 min (major), tr¼41.7 min (minor).
4.2.5. (2S,10R)-2-(Hydroxy-(o-nitrophenyl)methyl)cyclo-
hexan-1-one (Table 2, entry 3).3v,w [a]D24 +7.6 (c 0.99,
CHCl3), 90% ee. anti-Isomer: 1H NMR (300 MHz,

11890
A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
4.2.10. (2S,10R)-2-(Hydroxy-(o-chlorophenyl)methyl)-
cyclohexan-1-one (Table 2, entry 8).4f [a]D22 +10.2 (c
1.01, CHCl3), 90% ee. anti-Isomer: H NMR (400 MHz,
3.46 (t, J¼9.9 Hz, 1H, CH), 3.70–3.83 (m, 3H, CH2 and
OH), 4.18–4.23 (m, 1H, CH), 4.96 (dd, J¼3.3, 8.1 Hz, 1H,
CHOH), 7.50 (d, J¼8.7 Hz, 2H, ArH), 8.21 (d, J¼8.7 Hz,
2H, ArH). The ee was determined by HPLC with Chiralpak
AD column (80/20 hexane/2-propanol), 254 nm, 1.0 mL/
min, tr¼25.0 min (major), tr¼21.9 min (minor).
4.2.15. (3S,10R)-3-(Hydroxy-(p-nitrophenyl)methyl)-tet-
rahydrothiopyran-4-one (Table 2, entry 13).4g,9d [a]D30
+3.0 (c 0.7, CHCl3), 94% ee. anti-Isomer: 1H NMR
(400 MHz, CDCl3): d 2.51–2.55 (m, 1H, CH), 2.64–2.70
(m, 1H, CH), 2.74–2.88 (m, 2H, CH2), 2.97–3.05 (m, 3H,
CH2 and CH), 3.68 (br s, 1H, OH), 5.06 (d, J¼8.0 Hz, 1H,
CHOH), 7.55 (d, J¼8.8 Hz, 2H, ArH), 8.23 (d, J¼8.8 Hz,
2H, ArH). The ee was determined by HPLC with Chiralpak
AD column (90/10 hexane/2-propanol), 254 nm, 1 mL/min;
tr¼75.6 min (major), tr¼42.4 min (minor).
4.2.16. (3S,10R)-3-(Hydroxy-(o-nitrophenyl)methyl)-tet-
rahydrothiopyran-4-one (Table 2, entry 14).4g [a]D25 +7.2
(c 0.74, CHCl3), 93% ee. anti-Isomer: 1H NMR
(400 MHz, CDCl3): d 2.61 (dt, J¼13.6, 3.2 Hz, 1H, CH),
2.72–3.06 (m, 5H, 2 CH2 and CH), 3.14–3.20 (m, 1H,
CH), 3.83 (br s, 1H, OH), 5.56 (d, J¼7.2 Hz, 1H, CHOH),
7.46 (t, J¼8.0 Hz, 1H, ArH), 7.67 (t, J¼7.6 Hz, 1H, ArH),
7.77 (d, J¼7.6 Hz, 1H, ArH), 7.89 (d, J¼8.4 Hz, 1H,
ArH). The ee was determined by HPLC with Chiralpak
AD column (90/10 hexane/2-propanol), 254 nm, 1 mL/
min, tr¼41.4 min (major), tr¼33.7 min (minor).
1
CDCl3): d 1.51–2.09 (m, 6H, 3 CH2), 2.28–2.46 (m, 2H,
CH2), 2.63–2.70 (m, 1H, CH), 3.92 (s, 1H, OH), 5.34 (d,
J¼8.0 Hz, 1H, CHOH), 7.19 (t, J¼7.6 Hz, 1H, ArH), 7.28
(d, J¼7.6 Hz, 1H, ArH), 7.31 (d, J¼8.0 Hz, 1H, ArH),
7.53 (d, J¼7.6 Hz, 1H, ArH). The ee was determined by
HPLC with a Chiralcel OD column (95/5 hexane/2-propa-
nol), 220 nm, 0.8 mL/min; tr¼11.5 min (major),
tr¼13.3 min (minor).
4.2.11. (2S,10R)-2-[Hydroxy-(5-nitrofuran-2-yl)methyl]-
cyclohexan-1-one (Table 2, entry 9).18 [a]D24 +14.0
(c 2.15, CHCl3), 79% ee. anti-Isomer: 1H NMR
(400 MHz, CDCl3): d 1.59–1.79 (m, 3H, CH2 and one proton
of CH2), 1.89–1.95 (m, 2H, CH2), 2.14–2.18 (m, 1H, one
proton of CH2), 2.37–2.50 (m, 2H, CH2), 2.95–3.00 (m,
1H, CH), 4.02 (br s, 1H, OH), 4.82 (d, J¼6.5 Hz, 1H,
CHOH), 6.59 (d, J¼3.6 Hz, 1H, ArH), 7.28 (d, J¼3.6 Hz,
1H, ArH); 13C NMR (100.1 MHz, CDCl3): 24.6, 27.7,
30.8, 42.6, 54.3, 68.8, 110.5, 112.4, 151.6, 158.4, 214.2.
The ee was determined by HPLC with Chiralpak AD column
(95/5
hexane/2-propanol),
254 nm,
1.0 mL/min,
tr¼36.5 min (major), tr¼43.3 min (minor).
4.2.12. 2-(Hydroxy-(p-nitrophenyl)methyl)cyclopentan-
1-one (Table 2, entry 10).4e anti-Isomer: 1H NMR
(300 MHz, CDCl3): d 1.50–2.03 (m, 4H, 2 CH2), 2.25–2.48
(m, 3H, CH2 and CH), 4.78 (s, 1H, OH), 4.84 (d, J¼4.6 Hz,
1H, CHOH), 7.54 (d, J¼4.3 Hz, 2H, ArH), 8.21(d,
J¼4.3 Hz, 2H, ArH). syn-isomer: 1H NMR (300 MHz,
CDCl3): d 1.60–2.20 (m, 4H, 2 CH2), 2.30–2.50 (m, 2H,
CH2), 2.65 (d, J¼2.4 Hz, 1H, CH), 5.42 (s, 1H, CHOH),
7.52 (d, J¼4.4 Hz, 2H, ArH), 8.20 (d, J¼4.4 Hz, 2H, ArH).
The ee was determined by HPLC with Chiralpak AS-H
column (70/30 hexane/2-propanol), 254 nm, 1.0 mL/min,
syn-isomer: tr¼20.8 min (major), tr¼7.6 min (minor); anti-
isomer: tr¼17.3 min (major), tr¼13.8 min (minor).
4.2.17. (3S,10R)-3-(Hydroxy-(p-cyanophenyl)methyl)-tet-
rahydrothiopyran-4-one (Table 2, entry 15).4g [a]D24 +8.0
(c 0.78, CHCl3), 90% ee. anti-Isomer: H NMR (400 MHz,
1
CDCl3): d 2.52 (ddd, J¼13.6, 4.8, 2.0 Hz, 1H, CH), 2.63
(dd, J¼13.6, 10.4 Hz, 1H, CH), 2.73–3.03 (m, 5H, 2 CH2
and CH), 3.69 (br s, 1H, OH), 5.02 (d, J¼8.0 Hz, 1H,
CHOH), 7.48 (d, J¼8.0 Hz, 2H, ArH), 7.67 (d, J¼8.4 Hz,
2H, ArH). The ee was determined by HPLC with Chiralcel
OD column (92/8 hexane/2-propanol), 254 nm, 1 mL/min;
tr¼43.6 min (major), tr¼61.1 min (minor).
4.2.18. (3S,10R)-3-(Hydroxy-(p-(trifluoromethyl)phenyl)-
methyl)-tetrahydrothiopyran-4-one (Table 2, entry
16).9d [a]D25 +4.4 (c 0.77, CHCl3), 90% ee. 1H NMR
(400 MHz, CDCl3): d 2.51 (ddd, J¼13.7, 4.9, 2.2 Hz, 1H,
CH), 2.63 (dd, J¼13.7, 10.6 Hz, 1H, CH), 2.77 (ddd,
J¼13.5, 10.2, 5.8 Hz, 1H, CH), 2.84 (dt, J¼13.5, 4.2 Hz,
1H, CH), 2.93–3.04 (m, 3H, CH2 and CH), 3.54 (d,
J¼3.7 Hz, 1H, OH), 5.04 (dd, J¼8.4, 3.7 Hz, 1H, CHOH),
7.48 (d, J¼8.3 Hz, 2H, ArH), 7.63 (d, J¼8.3 Hz, 2H,
ArH). The ee was determined by HPLC with a Chiralpak
OD column (90/10 hexane/2-propanol), 220 nm, 0.7 mL/
min; tr¼21.8 min (major), tr¼34.4 min (minor).
4.2.13. 2-(Hydroxy-(o-nitrophenyl)methyl)cyclopentan-
1-one (Table 2, entry 11).4h anti-Isomer: 1H NMR
(400 MHz, CDCl3): d 1.70–2.03 (m, 4H, 2 CH2), 2.19–
2.38 (m, 2H, CH2), 2.68 (d, J¼7.6 Hz, 1H, CH), 2.90 (br
s, 1H, OH), 5.21 (d, J¼7.2 Hz, 1H, CHOH), 7.44 (t,
J¼8.0 Hz, 1H, ArH), 7.66 (t, J¼8.0 Hz, 1H, ArH), 7.89 (d,
J¼8.0 Hz, 1H, ArH), 8.00 (dd, J¼8.0, 0.8 Hz, 1H, ArH).
1
syn-Isomer: H NMR (400 MHz, CDCl3): d 1.70–1.78 (m,
2H, CH2), 2.03–2.19 (m, 3H, CH2 and CH), 2.37 (dd,
J¼8.0, 1.6 Hz, 1H, CH), 2.60 (br s, 1H, OH), 2.74 (m, 1H,
CH,), 5.92 (d, J¼2.4 Hz, 1H, CHOH), 7.44 (td, J¼8.0,
0.8 Hz, 1H, ArH), 7.66 (t, J¼8.0 Hz, 1H, ArH), 7.89 (d,
J¼8.0 Hz, 1H, ArH), 8.02 (d, J¼8.0 Hz, 1H, ArH). The ee
was determined by HPLC with Chiralpak AS-H column
(95/5 hexane/2-propanol), 254 nm, 1.0 mL/min; syn-isomer:
tr¼35.1 min (major), tr¼25.8 min (minor); anti-isomer:
tr¼43.3 min (major), tr¼36.9 min (minor).
4.2.14. (3S,10R)-3-(Hydroxy-(p-nitrophenyl)methyl)-tet-
rahydropyran-4-one (Table 2, entry 12).4g [a]D26 +1.0
(c 1.86, CHCl3), 70% ee. anti-Isomer: 1H NMR (300 MHz,
CDCl3): d 2.50–2.54 (m, 1H, one proton of CH2), 2.66–
2.69 (m, 1H, one proton of CH2), 2.88–2.90 (m, 1H, CH),
4.2.19. (3S,4S)-3-Methoxy-4-(p-nitrophenyl)-butan-2-
one (Table 3, entry 1).8d,15 [a]D25 ꢁ8.4 (c 0.21, CHCl3),
1
84% ee. anti-Isomer: H NMR (400 MHz, CDCl3): d 2.17
(s, 3H, CH3CO), 3.14 (d, J¼3.7 Hz, 1H, OH), 3.33 (s, 3H,
OCH3), 3.71 (d, J¼6.2 Hz, 1H, CH), 5.03 (dd, J¼6.2,
3.7 Hz, 1H, CHOH), 7.57 (d, J¼8.7 Hz, 2H, ArH), 8.23 (d,
J¼8.7 Hz, 2H, ArH). The ee was determined by HPLC with
a Chiralpak OD column (90/10 hexane/2-propanol), 254 nm,
0.8 mL/min; tr¼15.8 min (major), tr¼18.8 min (minor).

A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
11891
J. Am. Chem. Soc. 2006, 128, 734; (w) Wu, Y.; Zhang, Y.; Yu,
M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417.
4.2.20. (3S,4S)-3-Chloro-4-(p-nitrophenyl)-butan-2-one
1
(Table 3, entry 2).15,16 ee, 85%. anti-Isomer: H NMR
4. (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am.
Chem. Soc. 2003, 125, 16; (b) Bahmanyar, S.; Houk, K. N.;
Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475; (c)
Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.;
Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 5262; (d) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5755; (e) Tang, Z.; Yang, Z.-H.; Chen,
X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am.
Chem. Soc. 2005, 127, 9285; (f) Chen, J.-R.; Lu, H.-H.; Li,
X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org. Lett. 2005, 7,
4543; (g) Chen, J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J.
J. Org. Chem. 2006, 71, 8198; (h) Fu, Y.-Q.; Li, Z.-H.; Ding,
L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron:
Asymmetry 2006, 17, 3351; (i) See Ref. 12.
(400 MHz, CDCl3): d 2.38 (s, 3H, CH3CO), 3.86 (d,
J¼4.2 Hz, 1H, OH), 4.26 (d, J¼8.1 Hz, 1H, CH), 5.12 (dd,
J¼8.1, 4.2 Hz, 1H, CHOH), 7.57 (d, J¼8.7 Hz, 2H, ArH),
8.19 (d, J¼8.7 Hz, 2H, ArH). The ee was determined by
HPLC with Chiralpak AS-H column (85/15 hexane/2-prop-
anol), 254 nm, 1.0 mL/min; tr¼13.5 min (major),
tr¼12.3 min (minor).
Acknowledgements
ꢀ
Ministero Italiano dell’Universita e Ricerca Scientifica e
Tecnologica (MIUR) is gratefully acknowledged for finan-
cial support.
ꢁ
5. (a) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron:
Asymmetry 2006, 17, 729; (b) Guillena, G.; Hita, M. C.;
References and notes
ꢁ
Najera, C. Tetrahedron: Asymmetry 2006, 17, 1027; (c)
Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry
ꢁ
1. (a) Kim, B. M.; Williams, S. F.; Masamune, S. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, p 229; (b) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357; (c) Machajewski, T. D.;
Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352.
2. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395; (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
122, 7386; (c) See Ref 9a; (d) List, B. Acc. Chem. Res. 2004,
37, 548; (e) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580.
2006, 17, 1493; (d) Gryko, D.; Kowalczyk, B.; Zawadzki, L.
Synlett 2006, 7, 1059; (e) Guizzetti, S.; Benaglia, M.;
Pignataro, L.; Puglisi, A. Tetrahedron: Asymmetry 2006, 17,
2754; (f) Guizzetti, S.; Benaglia, M.; Raimondi, L.;
Celentano, G. Org. Lett. 2007, 9, 1247.
6. Russo, A.; Botta, G.; Lattanzi, A. Synlett 2007, 795.
7. While this manuscript was in preparation a contribution on the
employment of NOBIN-prolinamides in aldol reactions was
published: Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li,
B.-G.; Zhang, G.-L. Tetrahedron Lett. 2007, 48, 4281.
€
3. (a) Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529;
(b) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152; (c)
Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305,
1752; (d) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124,
6254; (e) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794; (f)
See Ref. 9c; (g) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G.
Org. Lett. 2005, 7, 5321; (h) Berkessel, A.; Koch, B.; Lex, J.
Adv. Synth. Catal. 2004, 346, 1141; (i) Hartikka, A.;
Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1983; (j)
Lacoste, E.; Landais, Y.; Schenk, K.; Verlhac, J.-B.; Vincent,
J.-M. Tetrahedron Lett. 2004, 45, 8035; (k) Cobb, A. J. A.;
Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
8. (a) Wang, Y.; Wei, S.; Sun, J. Synlett 2006, 3319; (b) Gryko, D.;
Zimnicka, M.; Lipinski, R. J. Org. Chem. 2007, 72, 964; (c)
Luo, S.; Xu, H.; Li, J.; Zhang; Cheng, J.-P. J. Am. Chem. Soc.
ꢁ
2007, 129, 3074; (d) Guillena, G.; Hita, M.; Najera, C.
ARKIVOC 2007, 4, 260.
9. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260; (b) Nyberg, A. I.; Usano, A.;
Pihko, P. M. Synlett 2004, 1891; (c) Torii, H.; Nakadai, M.;
Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983; (d) Pihko, P. M.; Laurikeinen, K. M.; Usano,
A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317; (e)
Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.;
Shoji, M. Chem. Commun. 2007, 957.
10. In solvent screening it was found that higher enantioselectivity
but moderate conversions to the aldol product can be achieved
in ethereal solvents.
11. (a) Valivety, R. H.; Johnston, G. A.; Suckling, C. J.; Halling,
P. J. Biotechnol. Bioeng. 1991, 38, 1137; (b) Halling, P. J.
Enzyme Microb. Technol. 1994, 16, 178; (c) Hsu, W.-T.;
Clark, D. S. Biotechnol. Bioeng. 2001, 73, 231; (d) Klibanov,
A. M. Nature 2001, 409, 241.
ꢁ
Biomol. Chem. 2005, 3, 84; (l) Gryko, D.; Lipinski, R. Adv.
Synth. Catal. 2005, 347, 1948; (m) Vishnumaya, R. M.;
Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097; (n)
Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.;
Wang, X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron
ꢁ
Lett. 2006, 47, 7793; (o) Diner, P.; Amedjkouh, M. Org.
Biomol. Chem. 2006, 4, 2091; (p) Cheng, C.; Sun, J.; Wang,
C.; Zhang, Y.; Wei, S.; Jiang, F.; Wu, Y. Chem. Commun.
2006, 215; (q) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh,
H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958; (r) Gu, L.; Yu, M.; Wu, X.; Zhang, Y.; Zhao, G. Adv.
Synth. Catal. 2006, 348, 2223; (s) Chowdari, N. S.;
12. He, L.; Jiang, J.; Tang, Z.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Tetrahedron: Asymmetry 2007, 18, 265.
13. (a) Ward, D. E.; Sales, M.; Sasmal, P. K. Org. Lett. 2001, 3,
3671; (b) Karisalmi, K.; Rissanen, K.; Koskinen, A. M. P.
Org. Biomol. Chem. 2003, 3193.
ꢁ
Ramachary, D. B.; Cordova, A.; Barbas, C. F., III. Tetrahedron
Lett. 2002, 43, 9591; (t) Casas, J.; Engqvist, M.; Ibrahem, I.;
14. (a) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002,
58, 8167; (b) Lacoste, E.; Vaique, E.; Berlande, M.;
Pianet, I.; Vincent, J.-M.; Landais, Y. Eur. J. Org. Chem.
2007, 167.
15. Maggiotti, V.; Bahamanyar, S.; Reiter, M.; Resmini, M.; Houk,
K. N.; Gouverneur, V. Tetrahedron 2004, 60, 619.
ꢁ
Kaynak, B.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44,
ꢁ
ꢁ
1343; (u) Cordova, A.; Sunden, H.; Xu, Y.; Ibrahem, I.; Zou,
W.; Engqvist, M. Chem.—Eur. J. 2006, 12, 5446; (v) Mase, N.;
Nakai, Y.; Ohara, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III.

11892
A. Russo et al. / Tetrahedron 63 (2007) 11886–11892
16. a-Chloroacetone displayed a low reactivity in the direct aldol
reaction promoted by L-prolinamide derivatives, which had to
be used in up to 50 mol % loading to achieve satisfactory yields
of the products, see: He, L.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.;
Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron: Asymmetry 2006, 62, 346.
17. For an interesting discussion on the role of water in organo-
catalyzed reactions, see: Blackmond, D. G.; Armstrong, A.;
Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798.
18. Lei, M.; Shi, L.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R.
Tetrahedron 2007, 63, 7892.