α-Chloroacetone as a donor in the BINAM-l-prolinamide organocatalyzed aldol reaction: application to the enantioselective synthesis of α,β-epoxy ketones

Article abstract of DOI:10.1016/j.tetasy.2007.05.029

Recoverable (S_a)-BINAM-l-prolinamide in combination with benzoic acid catalyzed the direct aldol reaction between α-chloroacetone and several aldehydes in different solvents, including water. It is possible to obtain mainly one of the isomers w

Full text of DOI:10.1016/j.tetasy.2007.05.029

Tetrahedron: Asymmetry 18 (2007) 1272–1277
a-Chloroacetone as a donor in the BINAM-L-prolinamide
organocatalyzed aldol reaction: application to the enantioselective
synthesis of a,b-epoxy ketones
*
´
´
Gabriela Guillena, Marıa del Carmen Hita and Carmen Najera
Dpto. Quı´mica Orga´nica and Instituto de Sı´ntesis Orga´nica, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 19 March 2007; accepted 29 May 2007
Dedicated to Professor Gerard van Koten on occasion of his 65th birthday
Abstract—Recoverable (Sa)-BINAM-L-prolinamide in combination with benzoic acid catalyzed the direct aldol reaction between a-chloro-
acetone and several aldehydes in different solvents, including water. It is possible to obtain mainly one of the isomers with good regio-,
diastero-, and enantioselectivity by choosing the appropriate solvent and reaction conditions. Thus, a-chloroacetone mainly gives the
anti-aldol isomer in DMF/H2O with up to 97% ee. The crude a-chloro-b-hydroxy ketones obtained are transformed stereospecifically
into the corresponding enantioenriched trans-a,b-epoxy ketones derivatives with up to 97% ee through an SN2 displacement reaction
by treatment with Et3N.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we and others have reported the use of several
BINAM-prolinamides as catalysts in this type of reaction,
providing the expected aldol products under several reac-
tion conditions using alkyl8 and a-chalcogen substituted9
ketones as donors. The best catalysts were (Sa)-BINAM-
L-Pro 1a and its enantiomer (Fig. 1).8a The addition of
benzoic acid as a cocatalyst in the reaction led to a great
acceleration in the reaction, thus permitting the use of less
reactive ketones, such as butanone,8c a-alkoxy ketones9a
and a-(methylsulfanyl)acetone even in water,8f,9a,b allowing
the synthesis of aldols with a high level of selectivity. We
also found that these catalysts can be recovered by simple
extractive work-up.8a,c,9
Apart from the economic and environmental aspects, the
use of small organic molecules1 as catalysts has shown their
attractiveness due to their simplicity. This fact has broad-
ened the application of this synthetic strategy from enan-
tioselective C–C and C–X bond formation2 to a one-pot
multistep processes, achieving chiral molecules with grow-
ing molecular complexity.3 Although organocatalysis is an
old tool used for promoting asymmetric transformations,4
it was not until the pioneering work of Barbas et al., which
showed that L-proline acted as a synthetic mimic of aldo-
lases class I or II in the direct aldol reaction,5 that this field
has undergone its revolution. For the aldol reaction,6 the
use of a simple proline permitted access to chiral syntheti-
cally useful intermediates by a highly atom efficiency pro-
cess.7 The simultaneous control of the regio-, diastereo-
and enantioselectivities when unsymmetrical ketones are
used as donors, remains as one of the challenges of this
type of transformation.
NH
NH
HN
HN
O
O
HN
HN
O
O
NH
NH
1a
Figure 1. BINAM-derived prolinamides.
ent-1a
*
Corresponding author. Tel.: +34 965 90 3728; fax: +34 965 90 3549;
e-mail: cnajera@ua.es
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.029

G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 1272–1277
1273
1. R2CHO
aldol
R2CHO
R1
O
(a)
(b)
Cl
O
Darzens
reaction
Cl
O
(c)
R1
O
O
R2
R1
2. SN2
R2
R1
Epoxidation
Figure 2. Possible routes for the asymmetric organocatalyzed synthesis of a,b-epoxy carbonyl compounds.
Epoxides are very useful intermediates in organic synthe-
sis,10 with methods dealing in their enantioselective synthe-
sis being of enormous interest. a,b-Epoxy carbonyl
compounds have been synthesized enantioselectively by
organocatalytic methods2 by using either: (a) Darzens reac-
tion11 or (b) epoxidation of a,b-unsaturated carbonyl com-
pounds.12 Alternatively, these compounds can be
synthesized by (c) a two-step procedure based on an aldol
reaction followed by an SN2 displacement from the chiral
a-chlorinated aldols (Fig. 2).13
afford the expected a-chloro-b-hydroxy ketones with mod-
est yields (18–57%) and moderate to good regio- (4:1–20:1),
diastereo- (5:1–31:1) and enantioselectivities (86–98% ee).14
Here we report a two step synthesis of a,b-epoxy ketones
by the aldol reaction of a-chloroacetone with aldehydes
using recoverable BINAM-prolinamide 1a as the organo-
catalyst followed by Et3N mediated cyclization.
2. Results and discussion
In the case of the last strategy, the chiral intermediate a-
chloro-b-hydroxy ketones can be readily synthesized by
the direct aldol reaction between a-chloro ketones and
aldehydes, although this strategy remains almost unex-
plored.13,14 The aldol reaction between a-chloroacetone
and aromatic aldehydes has only been performed using
proline (50 mol %) as organocatalyst in ionic liquids giving
chiral a-chloro-b-hydroxy ketones in moderate yields (21–
82%) and diastereomeric ratios (up to 85:15 for the anti:
syn-isomers).13 By treatment of the obtained products, with
Et3N in the ionic liquid, the corresponding trans-a,b-epoxy
ketones were obtained with up to 75% ee.13 Recently, pro-
linamides derived from simple aromatic amines were eval-
uated in this aldol reaction with THF as solvent, to mainly
First, we studied the best reaction conditions in a reaction
between a-chloroacetone and p-nitrobenzaldehyde using
(Sa)-BINAM-L-Pro 1a as catalyst and comparing the
results obtained with those obtained by using L-proline
(Table 1).
Initially, DMF was choosen as a solvent based upon our
previous work on aldol reactions.8a,c,9 The reaction took
place at 0 ꢁC with good yield and moderate regio- (4:1),
diastereo- (anti/syn dr 10:1) and enantioselectivity (88%
ee for anti-2a). However 108 h was required to achieve
complete conversion (Table 1, entry 1). The addition of
water to the reaction mixture, led to an increase in the reac-
tion rate (from 108 to 19 h) to mainly give the anti-2a aldol
Table 1. Optimization of conditions for the reaction of 4-nitrobenzaldehyde with a-chloroacetone catalyzed by 1aa
CHO
O
OH
O
OH
O
OH
O
1a (10 mol%)
PhCO2H (20 mol%)
Cl
syn-2a
Cl
solvent, T
Cl
anti-2a
Cl
NO2
NO2
NO2
NO2
iso-3a
Entry
Cat.
Solvent
T (ꢁC)
t (h)
Yieldb (%)
Isomer ratioc
eed (%)
Regioselectivity (2a/3a)
dr (anti/syn)
anti-2a
syn-2ae
iso-3a
1
2
3
4
5
6
7
8
9
1a
1a
DMF
0
0
108
19
31
20
168
96
168
31
168
94
90
86
96
78
95
82
85
86
4:1
10:1
>99:1
4:1
19:1
4:1
6:1
2:1
3:2
10:1
6:1
>99:1
6:1
16:1
9:2
5:1
88
89
90
85
88
80
75
7
27
58
—
18
5
40
nd
4
67
95
—
94
67
82
nd
82
88
DMF:H2Of
DMF:H2Of
H2O
1a
ꢀ20
1a
0
1ag
1a
THF
THF
THF:H2Of
DMF:H2Of
H2O
25
25
25
0
1ag
L-Proh
L-Proh
2:3
2:1
0
2
3
a The reaction was carried out using 27.6 equiv of ketone per equivalent of aldehyde in the presence of 10 mol % of catalyst and 20 mol % of acid in 0.5 mL
of solvent, otherwise stated.
b Calculated from the crude product by 1H NMR.
c Determined by 1H NMR.
d Determined by HPLC, Chiracel OJ.
e Tentative absolute configuration assignment based on the intermediate E-enamine.
f 1:1.
g The reaction was performed in the absence of acid.
h 20 mol % of catalyst was used.

1274
G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 1272–1277
isomer with a promising 89% ee (Table 1, entry 2). The
reaction temperature was then decreased to ꢀ20 ꢁC, to give
anti-2a as a unique regioisomer with a nearly quantitative
yield and 90% ee (Table 1, entry 3). A high enantioselectiv-
ity was also reached when water was the chosen solvent,
even at 0 ꢁC (85% ee), with the regioselectivity being lower
than those obtained in DMF/H2O (Table 1, compare
entries 2 and 4). As has been reported that THF at rt is a
good solvent for carrying out the reaction between
a-chloroacetone and aldehydes using an L-prolinamide as
catalyst,14 we used these conditions with catalyst 1a in
the absence or presence of 20 mol % of acid (Table 1,
entries 5 and 6). In both cases, the reaction was extremely
slow, with nearly 7 d required for completion in the
absence of acid and 4 d in the presence of acid, the achieved
regio-, diastero- and enantioselectivities being lower than in
DMF/H2O at 0 or ꢀ20 ꢁC (Table 1, entries 5 and 6). When
the reaction was carried out in THF/H2O 1:1 at rt in the
absence of acid, the reaction time increased to 7 d and
the observed regio-, diastereo- and enantioselectivity was
lower that in DMF/H2O (Table 1, entry 7). In order to
establish a fair comparison with L-proline, the reaction
was performed using this catalyst in the presence of benzoic
acid using DMF/H2O or H2O as solvent at 0 ꢁC. In both
cases the obtained results were worse than those achieved
with catalyst 1a (Table 1, compare entries 2 and 4 with 8
and 9, respectively).
using catalyst 1a in the presence of 20 mol % of benzoic
acid and DMF/H2O (1:1) as solvent, the results are sum-
marized in Table 2.
In all cases, the main product observed was the anti-2 iso-
mer. The reaction proceeded with a reasonable rate when
p-substituted aromatic aldehydes were used as electrophiles
with the exception of p-methoxycarbonylbenzaldehyde
(Table 2, entry 8), where 7 d was needed, even at 0 ꢁC,
for the completion of the reaction. In all cases the anti-
aldol product was obtained with high ee’s (83–97%). Con-
versely, the reactions were very slow when o-substituted
aldehydes were used (Table 2, entries 2, 3, 10 and 11), espe-
cially in the case of o-bromobenzaldehyde in which after 14
d, only 27% of the aldehyde was consumed probably due to
steric reason (Table 2, entry 10). Also, the main isomer
anti-2 was achieved with lower enantioselectivity than
those achieved with p-substituted aldehydes (ee up to
74%, Table 2, entries 2, 3, 10 and 11). The use of m-nitro-
benzaldehyde gave the expected anti-2c product with good
diasteroselectivity and high enantioselectivity (93% ee,
Table 2, entries 4 and 5). The use of a less electrophilic
benzaldehyde gave after 5 d, anti-2i as a unique product
but with a moderate enantiomeric excess (53% ee, Table
2, entry 12). When less reactive aldehydes, such as cyclo-
hexanecarboxaldehyde, were used, the reaction did not
take place after 9 d at either ꢀ20 or 0 ꢁC. The reaction also
failed when other a-chloro ketones such as 3-chloro-2-
butanone or 2-chlorocyclohexanone were used as donors
and p-nitrobenzaldehyde as the acceptor.
Once the best reaction conditions were established, a-chlo-
roacetone was allowed to react with different aldehydes
Table 2. Reaction of substituted aldehydes with a-chloroacetone catalyzed by 1aa
CHO
O
OH
O
OH
O
OH
O
1a (10 mol%)
PhCO2H (20 mol%)
Cl
syn-
Cl
DMF/H2O, T
Cl
anti-
Cl
R
R
R
R
2
2
iso-3
Entry
R
T (ꢁC)
t (d)
Yieldb (%)
Isomer ratioc
eed (%)
Product
Regioselectivity (2/3)
dr (anti/syn)
anti-2
syn-2e
1
2
3
4
5
6
7
8
9
4-NO2
2-NO2
2-NO2
3-NO2
3-NO2
4-NC
ꢀ20
ꢀ20
0
1.5
11
6
1.5
1
3
1
7
2
86
75
93
80
91
80
92
93
77
96
27
66
a
b
>99:1
5:1
5:1
>99:1
16:1
>99:1
14:1
>99:1
3:1
>99:1
3:1
5:1
27:1
8:1
32:1
10:1
16:1
13:1
4:1
90f
72g
67g
93g
97g
90g
92g
91h
83j
—
55g
87g
70g
98g
90g
81g
49h
61j
—
ꢀ20
c
0
ꢀ20
0
d
4-NC
4-MeO2C
4-F3C
2-Cl
2-Br
H
0
0
e
f
10
11
12
ꢀ20
9
14
5
g
h
i
4:1
3:1
>99:1
74g
46j
0
2:1
99:1
66j
—
0
53i
a The reaction was carried out using 27.6 equiv of ketone per equivalent of aldehyde in the presence of 10 mol % of catalyst and 20 mol % of benzoic acid in
DMF/H2O (1:1, 0.5 mL).
b Calculated for the crude product based on the aldehyde.
c Determined by 1H NMR.
d Determined by HPLC.
e Tentative absolute configuration assignment based on the intermediate E-enamine.
f Chiracel OJ, hexane/iPrOH: 98/2.
g Chiracel OJ, hexane/iPrOH: 97/3.
h Chiralpak AD, hexane/iPrOH: 95/5.
i Chiralpak AD, hexane/iPrOH: 98/2.
j Chiralpak AS, hexane/iPrOH: 90/10.

G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 1272–1277
1275
In our hands, any attempts to purify the obtained products
2 by flash silica gel, alumina, neutral alumina or florisil led
to the partial racemization of the mixture.15 Only when
neutral flash silica was employed for the purification of
product anti-2c (Table 2, entry 4), did epimerization occur
to give a 2:1 mixture of anti/syn-2c isomers enantioselectiv-
ity for the anti-2c product was kept. In view of these
results, we decided to directly transform the crude
a-chloro-b-hydroxy ketones 2 to the corresponding a,b-
epoxy ketones by an SN2 displacement reaction. Thus,
the crude mixture of the product obtained from the aldol
reaction between a-chloroacetone and different aldehydes
were dissolved in dry dichloromethane and dry Et3N was
added. The reaction mixture was stirred for 2 d at rt and
the obtained trans-epoxides 4 purified by column chroma-
tography, with the results summarized in Table 3.
between a-chloroacetone and several aldehydes in aqueous
DMF as the solvent affording the corresponding anti-a-
chloro-b-hydroxy ketones with better yields and regio-,
diastereo- and enantioselectivies than with other organo-
catalyts, such as L-Pro13 or aromatic amine derived proli-
namides.14 For the synthesis of chiral trans-a,b-epoxy
ketones, dry Et3N in CH2Cl2 at rt were adequate reaction
conditions.
4. Experimental
4.1. General
All reactions were carried out under argon. All others
reagents were commercially available and used without
further purification, with the exception of PhCHO, which
was distilled prior to its use. Only the structural, most
important peaks of the IR spectra (recorded on a Nicolet
For all cases, the achieved enantioselectivities for products
4 were similar to those obtained for anti-2 isomers with the
exception of epoxides 4b and 4i derived from o-nitrobenz-
aldehyde and benzaldehyde, respectively. For those exam-
ples, the enantioselectivities of the epoxides were higher
(93% and 65%, respectively) than those obtained for the
corresponding isomers anti-2b and anti-2i (67% and 53%
ee, respectively) showing that a possible resolution process
has taken place in the second reaction step (Table 3, entries
2 and 7). The absolute configuration of the epoxides could
be assigned as (3R,4S) by comparison of the specific rota-
tion values obtained for compound 4i to that reported in
the literature.13
1
510 P-FT) are listed. H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained on a Bruker AC-300 using
CDCl3 as the solvent and TMS as the internal standard,
unless otherwise stated. Optical rotations were measured
on a Perkin–Elmer 341 polarimeter. HPLC analyses were
performed on a Shimadzu LC-10AD and on a JASCO
AS 2059 PLUS equipped with a chiral column, using mix-
tures of n-hexane/isopropyl alcohol (IPA) as a mobile
phase, at 25 ꢁC. High-resolution mass spectra were
obtained on a Finnigan VG Platform. Analytical TLC
was performed on Schleicher & Schuell F1400/LS silica
gel plates and the spots were visualized under UV light
(k = 254 nm).
Table 3. Formation of chiral a-epoxy ketones by a subsequent aldol
condensation-SN2 displacementa
4.2. Experimental procedure for the synthesis of the epoxides
O
CHO
1a (10 mol%)
,
1.
Cl
O
O
To a solution of aldehyde (0.25 mmol), in dry DMF and
water (0.25 mL of each) under argon were added benzoic
acid (20 mol %, 6.1 mg) and chloroacetone (5.5 mmol,
0.55 mL). To the resulting solution, catalyst 1a was added
(10 mol %, 12.0 mg) in one portion, and the resulting
mixture stirred at the corresponding temperature. After
completion of the reaction, 6 M aqueous solution of
hydrochloric acid (5 mL) and ethyl acetate (5 mL) were
added. The mixture was stirred vigorously for 10 min.
The emulsion was separated (3 · 5 mL satd NaCl) and
the aqueous phase treated with a satd NaOH solution until
pH > 9 after which ethyl acetate was added (3 · 15 mL).
The organic layer was separated, dried over MgSO4 and
evaporated to recover crude catalyst 1a. The organic phase
from the acidic work up was dried (MgSO4) and evapo-
rated to dryness yielding the aldol products. The resulting
aldol was treated with dry triethylamine (1.32 equiv) under
argon in dry dichloromethane (0.5 mL). The resulting mix-
ture was stirred for 2 days. The reaction was quenched with
diethyl ether (5 mL) and an aqueous solution of 1 M
hydrochloric acid (5 mL). The mixture was stirred vigor-
ously for 10 min. The emulsion was separated (3 · 5 mL
satd NaCl) and the organic layer separated, dried over
MgSO4 and evaporated. The residue was purified by flash
chromatography in silica gel with ethyl acetate/hexane mix-
tures to yield pure epoxides.
PhCO2H (20 mol%), DMF/H2O, T
2. Et3N, CH2Cl2, 25 ºC, 2 d
R
R
4
Entry
R
No.
Yieldb (%)
eec,d (%)
1e
2e
3e
4
5f
6
4-NO2
2-NO2
3-NO2
4-NC
4-MeO2C
4-F3C
H
4a
4b
4c
4d
4e
4f
45
44
60
56
61
58
53
83 (75)
96 (67)
97 (97)
93 (92)
87 (91)
85 (83)
65 (53)
7
4i
a The resulting crude mixture isolated from the aldol reaction in Table 2
was diluted in CH2Cl2 and Et3N (1.32 equiv) were added and the
resulting mixture stirred at rt for 2 d unless otherwise stated.
b For the products isolated by flash column chromatography after two step
synthesis based on the starting aldehyde.
c Determined by HPLC.
d In parentheses ee for the intermediate aldol product anti-2.
e 3 days required to perform the SN2 reaction.
f Only 28 h of reaction required for completion.
3. Conclusion
In conclusion, recoverable BINAM-L-prolinamide 1a and
benzoic acid are adequate catalysts for the aldol reaction

1276
G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 1272–1277
4.2.1. trans-3,4-Epoxy-4-(4-nitrophenyl)butan-2-one 4a.
alpak AD column, hexane/iPrOH: 98/2; 1.25 mL/min;
ret. times, 9.0 (major), 12.0 (minor) min.
20
White solid; mp 38 ꢁC (AcOEt/hexane). ½aꢁD = ꢀ15 (c
1.14, CHCl3). Rf 0.43 (AcOEt/hexane 2:3). IR (KBr)
m = 2912, 2857, 2581, 2381, 1713, 1609, 1517, 1350, 1250,
4.2.6. trans-3,4-Epoxy-4-{4-(trifluoromethyl)phenyl}butan-
2-one 4f.13 Mp 61 ꢁC (AcOEt/hexane). HPLC: Chiralpak
AD column, hexane/iPrOH: 98/2; 1.25 mL/min; ret. times,
11.1 (major), 14.0 (minor) min.
1105 cmꢀ1 1H NMR (CDCl3) d (ppm) = 2.22 (s, 3H),
.
3.47 (d, J = 1.87 Hz, 1H), 4.12 (d, J = 1.71 Hz, 1H), 7.47
(d, J = 8.58 Hz, 2H), 8.25 (d, J = 8.74 Hz, 2H). 13C
NMR (CDCl3) d (ppm) = 24.8, 29.7, 56.5, 63.4, 123.6,
123.9, 124.0, 124.8, 126.1, 126.5, 126.6, 196.2. HRMS
(m/z) C10H9NO4: 207.0532. Found: 207.0514. HPLC:
Chiralpak AD column, hexane/iPrOH: 98/2; 1.25 mL/
min; ret. times, 43.9 (major), 53.4 (minor) min.
4.2.7. trans-(3R,4S)-Epoxy-4-phenylbutan-2-one 4i.13 Mp
62 ꢁC (AcOEt/hexane). HPLC: Chiralpak AD column,
hexane/iPrOH: 98/2; 1.25 mL/min; ret. times, 11.1 (major),
13.7 (minor) min.
4.2.2. trans-3,4-Epoxy-4-(2-nitrophenyl)butan-2-one 4b.
¼
Acknowledgements
20
White solid; mp 59 ꢁC (AcOEt/hexane). ½aꢁD
ꢀ40 ðc 1:2; CHCl3Þ. Rf 0.52 (AcOEt/hexane 2:3); IR
(KBr) m = 2918, 2842, 2372, 2317, 1711, 1520, 1334,
´
This work was financially supported by the Direccion Gen-
´
´
eral de Investigacion of the Ministerio de Educacion y
Ciencia of Spain (Grant CTQ2004-00808/BQU), the Gen-
eralitat Valenciana (Grant CTIOIB/2002/320, GRU-
POS03/134 and GV05/157) and the University of Alicante.
1102 cmꢀ1 1H NMR (CDCl3) d (ppm) = 2.29 (s, 3H),
.
3.40 (d, J = 2.07 Hz, 1H), 4.61 (d, J = 1.88 Hz, 1H), 7.61
(m, 3H), 8.23 (d, J = 0.94 Hz, 1H). 13C NMR (CDCl3) d
(ppm) = 25.2, 56.2, 61.9, 124.9, 127.0, 129.4, 132.3, 134.6,
202.7. HRMS (m/z) calculated for C8H8NO3 (M+ꢀCOMe)
164.1416. Found: 164.0341. HPLC: Chiralpak AD column,
hexane/iPrOH: 98/2; 1.25 mL/min; ret. times, 19.7 (major),
36.0 (minor) min.
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Angew. Chem., Int. Ed. 2006, 45, 3909–3912; (q) Palomo, C.;
Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876–7880; (r)
Gaunt, M. J.; Johansonn, C. C. C.; McNally, A.; Vo, N. T.
Drug Discovery Today 2007, 12, 8–27.
4.2.3. trans-3,4-Epoxy-4-(3-nitrophenyl)butan-2-one 4c.
20
White solid; mp 35 ꢁC (AcOEt/hexane). ½aꢁD
¼
ꢀ17 ðc 1:4; CHCl3Þ. Rf 0.66 (AcOEt/hexane 2:3). IR
(KBr) m = 2918, 2853, 2361, 1601, 1361, 1132 cmꢀ1 1H
NMR (CDCl3) (ppm) = 2.22 (s, 3H), 3.50 (d,
.
d
J = 1.88 Hz), 4.13 (d, J = 1.70 Hz, 1H), 7.61 (m, 2H),
8.20 (m, 2H). 13C NMR (CDCl3) d (ppm) = 29.7, 56.5,
63.3, 120.8, 123.9, 129.9, 131.6, 137.5, 203.1. HRMS (m/z)
calculated for C10H9NO4: 207.0532. Found: 207,0528.
HPLC Chiralpak AD column, hexane/iPrOH: 98/2;
1.25 mL/min; ret. times, 25.4 (major), 32.6 (minor) min.
4.2.4. trans-3,4-Epoxy-4-(4-cyanophenyl)butan-2-one 4d.
¼
20
White solid; mp 49 ꢁC (AcOEt/hexane). ½aꢁD
ꢀ50 ðc 0:84; CHCl3Þ. Rf 0.66 (AcOEt/hexane 2:3). IR
(KBr) m = 3033, 2913, 2852, 2367, 2328, 2219, 1711, 1427,
1366, 1241, 1219 cmꢀ1. H NMR (CDCl3) d (ppm) = 2.21
1
(s, 3H), 3.45 (d, J = 1.87 Hz, 1H), 4.61 (d, J = 1.72 Hz,
1H), 7.40 (d, J = 8.27 Hz, 2H), 7.67 (d, J = 8.42 Hz, 2H).
13C NMR (CDCl3) d (ppm) = 24.8, 56.7, 63.3, 112.8,
118.2, 126.3, 132.5, 140.4, 203.1. HRMS (m/z) calculated
for C11H9NO2: 187.0633. Found: 187.0649. HPLC Chir-
alpak AD column, hexane/iPrOH: 98/2; 1.25 mL/min;
ret. times, 32.3 (major), 43.2 (minor) min.
2. (a) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
´
2001–2011; (b) Guillena, G.; Ramon, D. J. Tetrahedron:
Asymmetry 2006, 17, 1465–1492.
3. (a) Rueping, M. Nachr. Chem. 2007, 55, 35–37; (b) Enders,
D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
¨
´
2007, 46, 1570–1581; (c) Guillena, G.; Ramon, D. J.; Yus, M.
4.2.5.
trans-3,4-Epoxy-4-{4-(methoxycarbonyl)phenyl}-
Tetrahedron: Asymmetry 2007, 18, 693–700.
4. Marckwald, W. Ber. Dtsch. Chem. Ges. 1904, 37, 349–
354.
5. For the first proline catalyzed intramolecular reaction see:
List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395–2396.
6. For general reviews on the catalytic enantioselective aldol
reaction, see: (a) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M.
Chem. Eur. J. 1998, 4, 1137–1141; (b) Nelson, S. G.
Tetrahedron: Asymmetry 1998, 9, 357–389; (c) Carreira, E.
butan-2-one 4e. White solid; mp 62 ꢁC (AcOEt/hexane).
20
½aꢁD ¼ ꢀ63 ðc 0:5; CHCl3Þ. Rf 0.52 (AcOEt/hexane 2:3).
IR (KBr) m = 2954, 2928, 2844, 1722, 1436, 1282, 1106,
1018 cmꢀ1 1H NMR (CDCl3) d (ppm) = 2.21 (s, 3H),
.
3.92 (s, 3H), 3.96 (s, 1H), 4.06 (d, J = 1.72 Hz, 1H), 7.35
(d, J = 8.26 Hz, 2H), 8.03 (d, J = 8.27 Hz, 2H). 13C
NMR (CDCl3) d (ppm) = 24.8, 52.3, 57.1, 63.4, 125.6,
129.9, 130.8, 140.1, 166.5, 203.6. HRMS (m/z) calculated
for C12H12O4: 220.0736. Found: 220.0737. HPLC: Chir-

G. Guillena et al. / Tetrahedron: Asymmetry 18 (2007) 1272–1277
1277
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´
9. (a) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron:
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´
Najera, C. ARKIVOC 2007, iv, 260–269; Corrigendum:
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´
8. (a) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron:
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´
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carried out by using silica gel without any epimerization or
racemization problems.