Asymmetric phase transfer Darzens reactions catalyzed by d-glucose- and d-mannose-based chiral crown ethers

Article abstract of DOI:10.1016/j.tetasy.2012.04.006

Liquid-liquid phase asymmetric Darzens condensations were carried out in the presence of d-glucose- and d-mannose-based crown ethers 1 and 2 as the catalyst. The use of d-glucose-based lariat ether 1 as the catalyst gave the best results. The reaction of

Full text of DOI:10.1016/j.tetasy.2012.04.006

Tetrahedron: Asymmetry 23 (2012) 489–496
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric phase transfer Darzens reactions catalyzed by D-glucose-
and D-mannose-based chiral crown ethers
Zsolt Rapi a, Péter Bakó a, , György Keglevich , Áron Szöllosy , László Drahos , Adrienn Botyánszki ,
⇑
a
b
c
a
}
Tamás Holczbauer c
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, 1521 Budapest, Hungary
b Department of Inorganic and Analytical Chemistry, H-1525 Budapest, Hungary
c Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1525 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2012
Accepted 5 April 2012
Liquid–liquid phase asymmetric Darzens condensations were carried out in the presence of D-glucose-
and
as the catalyst gave the best results. The reaction of 4-phenyl-
lone, and 2-chloro-1-indanone with various aromatic aldehydes afforded the corresponding aromatic
,b-epoxyketones in moderate to high enantiomeric excess (ee up to 96%) under mild reaction conditions.
D-mannose-based crown ethers 1 and 2 as the catalyst. The use of
D-glucose-based lariat ether 1
a
-chloroacetophenone, 2-chloro-1-tetra-
a
The substituents of the benzaldehyde used as the reactants had a significant impact on the chemical
yields and enantiomeric excess. The absolute configuration of some epoxyketone products was deter-
mined by single-crystal X-ray analysis.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Although many examples are known with diastereoselective
control in the Darzens reaction, only a few successful cases involv-
The Darzens reaction, which allows the generation of new ste-
reogenic centers with complete diastereocontrol, is one of the most
ing enantiocontrol, accomplished in the presence of chiral catalysts
or reagents have been reported. North et al. used a cobalt(salen)
complex to catalyze the asymmetric Darzens condensation of
powerful methodologies for the synthesis of
a,b-epoxy carbonyl
and related compounds, and therefore has been recognized as
one of the most significant C–C bond forming processes in syn-
thetic organic chemistry. While epoxides are important functional
groups in organic synthesis as targets in their own right, they are
perhaps more important as intermediates that yield bifunctional
compounds after stereoselective ring-opening by a nucleophile.1a
The Darzens condensation may also be performed under phase-
transfer conditions, which has several advantages, such as a simple
reaction procedure, mild conditions, inexpensive and safe reagents,
a-haloamides and aldehydes. The cis-epoxides were obtained in
up to 50% enantiomeric excess, while the trans-epoxides were
formed with an up to 43% enantiomeric excess.4 Aggarwal et al.
have developed a highly enantioselective variation of the Darzens
condensation to give trans-glycidic amides by replacement of the
halide leaving group with a chiral sulfonium salt.5 Arai et al. used
cinchona alkaloid derivatives as chiral phase transfer catalysts in
asymmetric Darzens condensations resulting in enantioselectives
of up to 86% in the reaction of cyclic
up to 79% ee in the reactions of
a
-chloroketone substrates,6
a
-chloroacetophenone,6,7 and up
and solvents.1b,c Optically active
a,b-epoxy carbonyl compounds
can be easily converted into many types of useful chiral com-
pounds such as chiral building blocks and synthetic intermediates
for biologically active compounds (e.g., Diltiazem, Avermectin syn-
thon, etc.). Starting from an enantiopure epoxide, the absolute ste-
reochemistry at the two adjacent stereogenic centers can be
controlled. The chiral epoxyketones can be produced by a variety
of catalytic asymmetric reactions;2 one of the simplest methods
for the preparation of chiral epoxides involves a Darzens condensa-
tion carried out under phase transfer catalytic conditions in the
presence of optically active catalysts.3
to 83% ee in the reactions of chloromethyl phenyl sulfone.7
Recently, Arai et al. reported the use of a synthetic bis-ammonium
salt as an asymmetric phase transfer catalyst in the Darzens con-
densation of N,N-diphenyl
a-haloamides, predominantly giving
the cis-epoxides with up to 64% ee for the cis-epoxide, and up to
70% ee for the trans-epoxide.8 Jew and Jeong synthesized chiral
a,b-epoxysulfones by the phase transfer catalytic Darzens reaction
of chloromethyl phenyl sulfone with various aromatic aldehydes in
the presence of a new cinchona alkaloid derivative as the catalyst,
resulting in high (up to 97% ee) enantioselectivities.9
One of the most attractive methods in catalytic asymmetric
synthesis is the phase transfer catalytic approach in which the
enantioselectivity is generated by a chiral crown catalyst.3
⇑
Corresponding author.
E-mail address: pbako@mail.bme.hu (P. Bakó).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.006

490
Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
OCH3
OCH3
O
O
O
O
O
O
O
O
O
O
N
(CH2)3OH
N
(CH2)3OH
O
O
O
O
Ph
Ph
1
2
Figure 1. Crown ethers incorporating an a-D-glucopyranoside 1 and an a-D-mannopyranoside 2 unit.
Earlier, chiral monoaza-15-crown-5 type macrocycles incorpo-
rating an -glucopyranoside or -mannopyranoside units 1
Table 1
Asymmetric reaction of 4-phenyl-
the presence of catalyst 1 at 20 °C
a
-D
a-D
a
-chloroacetophenone with aromatic aldehydes in
and 2 were synthesized in our laboratory, and proved to be effi-
cient catalysts in a few asymmetric reactions.10 The Darzens con-
Product and yielda (%)
eec (%)
½ ꢁ
a 2D2
b
Entry
Ar
densation between benzaldehyde and
a-chloroacetophenone
took place in up to 72% ee.11 Chiral heteroaromatic epoxyketones
were formed in good (up to 86% ee) enantioselectivities in the
presence of catalyst 1 (Fig. 1).12
1
Ph
5a: 54
5b: 71
5c: 61
5d: 68
5e: 48
5f: 76
5g: 51
5h: 65
5i: 59
5j: 55
5k: 54
5l: 59
5m: 56
ꢀ173
ꢀ5
96 (100)
84 (90)
60
64 (68)
55
40 (43)
45
51
60 (66)
64
70 (77)
66 (72)
74 (86)
2
3
4
5
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
ꢀ110
ꢀ108
ꢀ81
Herein we report the asymmetric Darzens condensation of
4-phenyl-a-chloroacetophenone, 2-chloro-1-tetralone, and 2-
chloro-1-indanone with various aromatic aldehydes (there was
not any asymmetric induction with aliphatic aldehydes). Our pre-
liminary results concerning the enantioselective Darzens reactions
using catalysts 1 and 2 have already been reported.12a
6
7
8
9
10
11
12
13
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-H3C-C6H4
3-H3C-C6H4
4-H3C-C6H4
1-Naphthyl
2-Naphthyl
ꢀ63
ꢀ63
ꢀ119
ꢀ32
ꢀ122
ꢀ130
+75
ꢀ129
2. Results and discussion
a
b
c
Reaction times 1–2 h; Yield based after isolation by preparative TLC.
In CH2Cl2, c 1.
The Darzens reactions were carried out in a liquid–liquid two-
phase system in toluene, employing 30% aq NaOH as the base
and 7 mol % of chiral crown catalysts 1 and 2 at temperatures of
ꢀ10 to 20 °C. Generally, the reactions were complete within a short
period of time (20 min–2 h). The products were isolated by pre-
parative TLC. The trans-epoxyketones were all obtained in diaste-
reomeric excesses (de) of >98%. The high diastereoselectivity
observed in this reaction system is probably due to the generation
of a single Z-enolate species (the intermediate sodium enolate
would necessarily be in the Z-form).1c,6b The asymmetric induction
expressed in the term of enantiomeric excess was determined by
1H NMR analysis in the presence of Eu(hfc)3 as a chiral shift
reagent.
Determined by 1H NMR spectroscopy; the ee given in parentheses is that
obtained after one recrystallization from EtOH.
value increased to 90% (Table 1, entry 2). The degree of asymmetric
induction was affected by the position of the chloroatom in the
phenyl ring: 2-Cl-, 3-Cl-, and 4-Cl-derivatives 5b, 5c, 5d were
formed with ee values of 84%, 60%, and 64%. Comparison of the
ee values of the 4-chloro- 5d and 4-fluoro- 5e derivatives showed
that the electronic effect is also responsible for the asymmetric
induction reflected in the ee values of 64% and 55%, respectively.
In the reaction of 4-phenyl-a-chloroacetophenone 3 with nitro-
benzaldehydes, the epoxyketones 5f–h were formed in a lower
(40–51%) enantioselectivity (Table 1, 6–8 entries). The methyl
derivatives 5i–k were obtained in 60–70% ee. In the case of the ni-
tro-substitution, as in 5f–h, and methyl-substitution, as in 5i–k, we
observed that the further substituent on the benzaldehyde was
placed from the reaction center, the more considerable the extent
of the asymmetric induction. Hence, within the series, the highest
enantiomeric excesses were obtained with para-substitution (Ta-
ble 1, entries 8 and 11). The 1-naphthyl 5l and 2-naphthyl 5m
products were obtained with ee values of 66% and 74%, respec-
tively. It is noteworthy that the 1-naphthyl derivative 5l had a po-
sitive specific rotation (Table 1, entry 12).
First, the reaction of 4-phenyl-a-chloroacetophenone 3 and aro-
matic aldehydes 4a–m was studied (Scheme 1). We wished to
study the effect of the substituents of the phenyl ring of the benz-
aldehyde on the preparative yield and enantiomeric purity. The
experimental data are listed in Table 1.
The trans-epoxyketones 5a–m (with one exception) had
negative specific rotation values and were obtained in yields of
54–76%. The maximum selectivity was detected in the reaction
of compound 3 with benzaldehyde 4a, giving epoxide 5a in 96%
ee (and after recrystallization in an ee of 100%) (Table 1, entry 1).
The use of substituted benzaldehydes 4b–k led to lower ee values
that were dependent on the substitution pattern of the phenyl ring
(40–84%). In the series, the use of 2-chlorobenzaldehyde 4b led to
the best enantiomeric purity (84% ee). After recrystallization, this
The pure levorotatory enantiomer of epoxyketone 5b obtained
from 2-chlorobenzaldehyde was subjected to single crystal X-ray
analysis. According to this, the absolute configuration was (2R,3S)
O
Ph
crown catalyst
O
Cl
toluene
+
ArCHO
Ar
30 % NaOH
Ph
O
3
4a-m
5a-m
Scheme 1.

Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
491
(Fig. 2). It is reasonable to assume that the other epoxyketone
derivatives with a negative specific rotation also had the same
(2R,3S)-absolute configuration.
O
O
crown cat.
toluene
O
Cl
+
ArCHO
*
30 % NaOH
-10 oC
*
Ar
4a-d, 4f-m
7
8a-m
Scheme 3.
8g, and 8h being obtained in 54%, 43%, and 75% ee, respectively
(Table 2, entries 5–7). The ee value of 75% measured in the case
of 4-nitro-epoxyketone represents a maximum regarding the
whole series. It can be seen that with regards to asymmetric induc-
tion, the para-position is optimal, at least in the case of electron-
withdrawing chloro and nitro substituents (entries 4 and 7).
Methyl derivatives 8i–k were formed in 40–65% ee. The best ee
values were in the reactions of m-methylbenzaldehyde (Table 2,
entries 8–10). There was a significant difference between the ee
values of products 8l and 8m obtained in the reaction of 1-naph-
thaldehyde and 2-naphthaldehyde, respectively. In the former
case, the ee was 32%, while in the latter it was 59% (entries 11
and 12, respectively). It is noteworthy that in contrast to all of
the other cases, compound 8l had a positive specific rotation. In
the case of naphthyl derivatives the steric effect may be responsi-
ble for the asymmetric induction.
Figure 2. ORTEP representation of compound 5b at a 50% probability level.
In the Darzens condensation studied, we isolated a by-product
in an optically active form, which was found to be the base initi-
ated self-condensation product of 4-phenyl-a-chloroacetophe-
none. The by-product can be formulated as epoxyketone
6
(Scheme 2). The self-condensation of compound 3 was then stud-
ied in a blank experiment carried out under the previously de-
scribed conditions (toluene, 30% sodium hydroxide) in the
presence of glucose-based crown-ether catalyst 1. The 1H NMR
spectroscopy showed that the ratio of the cis:trans isomers of the
condensed by-product 6 was 2:8. The trans-isomer was separated
by chromatography in which the levorotatory enantiomer was in
10% excess.
Table 2
Asymmetric reaction of 2-chloro-1-tetralone with aromatic aldehydes in the presence
of catalyst 1 at ꢀ10 °C
½ ꢁ
a 2D2
b
Entry
Ar
Product and yielda (%)
eec (%)
The mannose-based crown ether 2 generated lower enantiose-
lectivities and promoted the formation of the enantiomer with a
positive specific rotation. For example, the epoxyketones 5b and
5k were obtained with ee values of 70% and 59%, respectively.
1
2
3
4
5
6
7
8
Ph
8a: 84
8b: 84
8c: 88
8d: 84
8f: 71
8g: 58
8h: 51
8i: 83
8j: 83
8k: 65
8l: 90
8m: 77
ꢀ144
ꢀ15
74
36
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-O2N-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-H3C-C6H4
3-H3C-C6H4
4-H3C-C6H4
1-Naphthyl
2-Naphthyl
ꢀ122
ꢀ137
ꢀ83
44 (68)
59 (69)
54
43 (23)
75
40
65 (69)
55
The reaction of cyclic a-chloroketones with aromatic aldehydes
ꢀ83
was studied under the conditions described above in the presence
of catalysts 1 and 2. Starting materials 7 and 9 were readily pre-
pared from 1-tetralone and 1-indanone, respectively. The reactions
of 2-chloro-1-tetralone 7 with various aromatic aldehydes 4 were
complete after stirring for 20–40 min at ꢀ10 °C in the presence
of catalyst 1 (Scheme 3). The trans-epoxyketones 8a–m were ob-
tained in good yields and with high diastereoselectivites (de of
>98%) and with moderate to good enantioselectivities. With one
exception, all of the products had a negative specific rotation.
The results are listed in Table 2.
ꢀ145
ꢀ32
9
ꢀ142
ꢀ133
+36
10
11
12
32
59
ꢀ225
a
b
c
Based on isolation by preparative TLC.
In CHCl3, c 1.
Determined by 1H NMR spectroscopy, ee given in parentheses is that obtained
after one recrystallization from EtOH.
Repeated recrystallization of products 8d and 8m led to pure
enantiomers whose absolute configurations were determined by
single crystal X-ray crystallography. In both cases the configuration
of the stereogenic centers was found to be (2R,30S) (Figs. 3 and 4).
We next investigated if the ring size of the cyclic chloro-ketone
had an impact on the enantioselectivity. Hence, the Darzens
reaction of 2-chloro-1-indanone 9 with aromatic aldehydes was
studied in the presence of crown ether 1 under the conditions de-
scribed above (Scheme 4). Completion of the reactions required
20–40 min at 0 °C. Products 10a–d and 10f–m were isolated in
In the reaction of cyclic chloroketone 7 with benzaldehyde,
epoxyketone 8a was formed in a yield of 84% and with 74% ee.13
On the basis of the negative specific rotation, the absolute config-
uration of product 8a was assigned as (2R,30S).6b The effect of the
substituents of the benzaldehyde was evaluated next. With one
exception, the substituted derivatives were formed with lower ee
values. The ortho-, meta-, and para-chloro derivatives 8b, 8c, 8d
were obtained in 36%, 44%, and 59% ee, respectively, (Table 2, en-
tries 2–4). The reactions with nitro-benzaldehydes resulted in
higher enantioselectivities, with the corresponding products 8f,
Cl
Ph
O
1
catalyst
O
Cl
toluene
30 % NaOH
O
Ph
Ph
3
6
Scheme 2.

492
Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
Table 3
Asymmetric reaction of 2-chloro-1-indanone with aromatic aldehydes in the
presence of catalyst 1 at 0 °C
Product and yielda (%)
eec (%)
½ ꢁ
a 2D2
b
Entry
Ar
1
2
3
4
5
6
7
8
Ph
10a: 59
10b: 52
10c: 74
10d: 48
10f: 36
10g: 18
10h: 16
10i: 84
10j: 72
10k: 76
10l: 20
10m: 25
ꢀ246
ꢀ31
65 (70)
85
59 (67)
37
20
62 (73)
—
49
63
58 (54)
47
15
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-H3C-C6H4
3-H3C-C6H4
4-H3C-C6H4
1-Naphthyl
2-Naphthyl
ꢀ229
ꢀ140
ꢀ69
ꢀ152
0
Figure 3. ORTEP representation of compound 8d at a 50% probability level.
ꢀ104
ꢀ233
ꢀ240
ꢀ29
9
10
11
12
ꢀ72
a
b
c
Based on isolation by preparative TLC.
In CHCl3, c 1.
Determined by 1H NMR spectroscopy; the ee given in parentheses is that
obtained after one recrystallization from EtOH.
Darzens reactions and obtained with ee values higher than 80%.
Only Arai et al. have reported high enantioselectivities of up to
86% ee for the reaction of cyclic
a-chloro ketones and aldehydes
in the presence of a cinchonine derivative after prolonged (40–
80 h) reaction times.6
Figure 4. ORTEP representation of compound 8m at a 50% probability level.
3. Conclusion
variable yields and displayed negative specific rotations. The data
are summarized in Table 3.
The monosaccharide-based crown ethers used as phase transfer
catalysts act as asymmetric inductors in the Darzens condensation
only with aromatic aldehydes. In the presence of D-mannose-based
It can be seen that a change in the ring size (i.e., replacing 6-ring
compound 7 with 5-ring species 9) had a dramatic impact on the
isolated yields and enantiomeric purities. The reaction of chloro-
ketone 9 and benzaldehyde gave epoxyketone 10a in a yield of
59% with an ee value of 65%.14 The substituted derivatives 10b–
k, with one exception, were formed in lower ee values. Chloro
derivatives 10b, 10c, and 10d were obtained in 85%, 59%, and
37% ee values, respectively (Table 3, entries 2–4). The nitro deriv-
atives 10f–10h were obtained in low yields (18–36%) and in vari-
able ee values (0–62%). Products 10f and 10g were formed in
20% and 62% ee values, respectively, while p-nitro derivative 10h
was obtained practically as a racemate (Table 3, entries 5–7). Using
crown catalyst 1, methyl derivatives 10i–k were obtained in good
yields and with 49–63% ee (Table 3, entries 8–10). Among the
substituted benzaldehydes, the best results were obtained in the
reaction with 2-chlorobenzaldehyde; in this case, product 10b
was formed with an ee of 85%. Product 10l formed from 1-naph-
thaldehyde and compound 10m formed from 2-naphthaldehyde
were obtained with ee values of 47% and 15%, respectively. The
yields were rather low (Table 3, entries 11 and 12).
crown ether 2, the chiral epoxyketones were obtained in 20–30%
lower ee values, than those obtained with glucose-based catalyst
1. For this, crown catalyst 1 was applied to the test reactions. As
compared to the cinchona alkaloid-catalyzed reactions, milder
conditions could be applied, the reaction times were shorter
(20 min–2 h), and the ee values were variable or high; in a few
cases, the ee values were higher compared to those reported in
the literature. We have shown that the substituents on the aro-
matic ring of the benzaldehyde had a significant impact on the
yields and enantiomeric purity. In some cases, the steric factors
controlled the extent of the asymmetric induction, while in other
cases, it was electronic factors. The monosaccharide unit of the cat-
alyst is decisive with respect to the configuration of the epoxyke-
tone formed. The glucose-based catalyst 1 promoted mostly the
formation of the enantiomer with a negative specific rotation
[(2R,3S) and (2R,30S)] while the mannose-based crown 2 enhanced
the predominant formation of the enantiomer with a positive spe-
cific rotation. However, it should be emphasized that the sign of
the specific rotation cannot be reliably used to determine the abso-
lute configuration.
In the reactions shown in Schemes 3 and 4, the mannose-based
crown ether 2 generated lower ee values and the chiral epoxyke-
tones formed, had positive specific rotations. For example in the
presence of catalyst 2, products 8a and 10b were formed with ee
values of 64% and 71%, respectively.
4. Experimental
To the best of our knowledge, there are only a few examples of
,b-epoxy ketones prepared in phase-transfer catalytic asymmetric
4.1. General procedures
a
Melting points were taken on using a Büchi 510 apparatus and
are uncorrected. Melting points of the epoxyketones were deter-
mined after recrystallization from ethanol. Specific rotations were
measured with a Perkin–Elmer 241 polarimeter at 20 °C. 1H and
13C NMR spectra were recorded on a Bruker 300 and a Bruker
DRX-500 or a Varian Inova 500 instrument in CDC13 with TMS as
the internal standard. Analytical and preparative thin layer chro-
matography was performed on silica gel plates (60 GF-254, Merck),
while column chromatography was carried out using 70–230 mesh
O
O
crown cat.
toluene
O
+
ArCHO
*
*
Ar
30 % NaOH
Cl
0 o
C
4a-d, 4f-m
9
10a-d, 10f-m
Scheme 4.

Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
493
silica gel (Merck). Chemicals and the shift reagent Eu(hfc)3 were
purchased from Aldrich Chem. Co. The exact mass measurements
were performed using Q-TOF Premier mass spectrometer (Waters
Corporation, 34 Maple St, Milford, MA, USA) in positive electro-
spray ionization mode.
X-ray analysis: the absolute configuration of the crystals is de-
scribed in most cases by two crystallographic data: the Flack x
parameter15 and the Hooft y parameter.16 These parameters show
the probability of the correct absolute configuration. If the value is
near 0, with a correspondingly small uncertainty, the absolute con-
figuration is correct. If the value is near 1, then one must invert the
structure. If the standard uncertainty is large or the parameter va-
lue is near 0.5 the crystal may be racemic twin or we cannot prove
the real configuration.
4.29 (d, J = 1.5 Hz, 1H), 4.09 (d, J = 1.5 Hz, 1H). HRMS calcd for
21H15ClO2 334.0761, found 334.0756.
C
4.2.4. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(4-chlorophenyl)-
propan-1-one 5d
Yield: 68%; ½a 2D2
¼ ꢀ108 (c 1, CH2Cl2) 64% ee; mp 154–160 °C;
ꢁ
1H NMR (CDCl3, 500 MHz) d 8.09 (d, J = 8.5 Hz, 2H), 7.72 (d,
J = 8 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.42
(d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H),
4.27 (d, J = 1.5 Hz, 1H), 4.10 (d, J = 1.5 Hz, 1H). HRMS calcd for
C21H15ClO2 334.0761, found 334.0762.
4.2.5. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(4-fluorophenyl)-
propan-1-one 5e
Yield: 48%; ½a 2D2
ꢁ
¼ ꢀ81 (c 1, CH2Cl2, 55% ee); 1H NMR (CDCl3,
Other important factors for the determination of the absolute
configuration are, for example, the wavelength of the radiation
used, completeness of the data, and the presence of heavy atoms
in the crystal.
500 MHz) d 8.09 (d, J = 8 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.62 (d,
J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.38
(d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.11 (t, J = 8.5 Hz, 2H),
4.28 (d, J = 1.5 Hz, 1H), 4.10 (d, J = 1.5 Hz, 1H). HRMS calcd for
4.2. General procedure for the Darzens condensation
C21H15FO2 318.1056, found 318.1059.
A
toluene solution (3 mL) of aromatic 2-chloroketone
4.2.6. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(2-nitrophenyl)-
(1.87 mmol), aromatic aldehyde (2.8 mmol), and the crown ether
(0.14 mmol) was cooled to the corresponding temperature and
then treated with 30% NaOH (1 mL). The mixture was then stirred
at this temperature. After complete conversion (1–2 h), a mixture
of toluene (7 mL) and water (3 mL) was added and the mixture
stirred for 10 min. The organic phase was washed with cold 10%
HCl (3 ꢂ 10 mL) and then with water (10 mL), dried (Na2CO3) and
concentrated. The crude product was purified on silica gel by pre-
parative TLC using hexane–EtOAc (10:1) as an eluent. The enanti-
oselectivities were determined by 1H NMR spectroscopy in the
presence of Eu(hfc)3 as a chiral shift reagent.
propan-1-one 5f
Yield: 76%; ½a 2D2
ꢁ
¼ ꢀ63 (c 1, CH2Cl2) 40% ee; mp 156–162 °C; 1H
NMR (CDCl3, 500 MHz) d 8.23 (dd, J = 8.5 Hz, 1 Hz, 1H), 8.11 (d,
J = 8.5 Hz, 2H), 7.78–7.76 (m, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.65–
7.61 (m, 2H), 7.58 (ddd, J = 7.5 Hz, 6.5 Hz, 2 Hz, 1H), 7.48 (t,
J = 7.5 Hz, 2H), 7.41 (tt, J = 7.5 Hz, 1 Hz, 1H), 4.68 (d, J = 1.5 Hz,
1H), 4.25 (d, J = 1.5 Hz, 1H). HRMS calcd for C21H15NO4 345.1001,
found 345.1004.
4.2.7. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(3-nitrophenyl)
propan-1-one 5g
Yield: 51%; ½a 2D2
ꢁ
¼ ꢀ63 (c 1, CH2Cl2) 45% ee; 1H NMR (CDCl3,
500 MHz)
d 8.26 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.11 (d,
4.2.1. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-phenylpropan-1-
J = 8.5 Hz, 2H), 7.76–7.71 (m, 3H), 7.65–7.61 (m, 3H), 7.49 (t,
J = 7.5 Hz, 2H), 7.24 (tt, J = 7.5 Hz, 1 Hz, 1H), 4.34 (d, J = 1.5 Hz,
1H), 4.25 (d, J = 1.5 Hz, 1H). HRMS calcd for C21H15NO4 345.1001,
found 345.0998.
one 5a
Yield: 54%; ½a 2D2
ꢁ
¼ ꢀ173 (c 1, CH2Cl2) 96% ee; mp 68–74 °C; 1H
NMR (CDCl3, 500 MHz) d 8.10 (d, J = 8 Hz, 2H), 7.71 (d, J = 8.5 Hz,
2H), 7.64–7.61 (m, 2H), 7.50–7.45 (m, 1H), 7.44–7.38 (m, 7H),
4.33 (d, J = 2 Hz, 1H), 4,11 (d, J = 2 Hz, 1H). 13C NMR (CDCl3,
75 MHz) d 192.74, 146.66, 139.60, 139.05, 134.20, 129.47, 129.01,
128.96, 128.46, 127.46, 127.28, 126.50, 125.79, 61.15, 59.47. HRMS
calcd for C21H16O2 300.1150, found 300.1152.
4.2.8. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(4-nitrophenyl)-
propan-1-one 5h
Yield: 65%; ½a 2D2
¼ ꢀ119 (c 1, CH2Cl2) 51% ee; mp 140–146 °C;
ꢁ
1H NMR (CDCl3, 300 MHz) d 8.27 (d, J = 8.7 Hz, 2H), 8.09 (d,
J = 8.5 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H),
7.57 (d, J = 8.7 Hz, 2H), 7.52–7.40 (m, 3H), 4.29 (d, J = 1.8 Hz, 1H),
4.24 (d, J = 1.5 Hz, 1H). HRMS calcd for C21H15NO4 345.1001, found
345.1002.
4.2.2. (ꢀ)-(2R,3S)-2,3-Epoxy-1-(biphen-4-yl)-3-(2-chloro-
phenyl)propan-1-one 5b
Yield: 71%; ½a 2D2
ꢁ
¼ ꢀ5 (c 1, CH2Cl2) 84% ee; mp 176–177 °C; 1H
NMR (CDCl3, 300 MHz) d 8.13 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz,
2H), 7.63 (d, J = 7.5 Hz, 2H), 7.52–7.38 (m, 5H), 7.37–7.31 (m, 2H),
4.41 (d, J = 1.5 Hz, 1H), 4.21 (d, J = 1.5 Hz, 1H). HRMS calcd for
4.2.9. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(2-methylphenyl)-
propan-1-one 5i
C
21H15ClO2 334.0761, found 334.0757. Crystal data for 5b: CCDC
Yield: 59%; ½a 2D2
ꢁ
¼ ꢀ32 (c 1, CH2Cl2) 60% ee; mp 88–90 °C; 1H
868833 contains the supplementary crystallographic data for this
structure. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Absolute configuration crystal data: Rigaku
NMR (CDCl3, 500 MHz) d 8.13 (d, J = 8 Hz, 2H), 7.72 (d, J = 8.5 Hz,
2H), 7.63 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.41 (t,
J = 7.5 Hz, 1H), 7.36 (dd, J = 6 Hz, 3 Hz, 1H), 7.29–7.25 (m, 2H),
2.38 (s, 1H), 7.20 (dd, J = 6 Hz, 3 Hz, 1H), 4.25 (d, J = 2 Hz, 1H),
4.23 (d, J = 2 Hz, 1H), 2.38 (s, 3H). HRMS calcd for C22H18O2
314.1307, found 314.1309.
R-AXIS Rapid Diffractometer, Cu
Ka radiation, k = 1.54187 Å,
T = 93(2) K, R1 = 3.10, Rw2 = 7.26, N = 2681, Friedel Pair Coverage =
92%, Flack parameter:15 0.024(16), Hooft parameter:16 0.03(1).
4.2.3. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(3-chlorophenyl)-
4.2.10. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(3-methyl-phenyl)
propan-1-one 5c
propan-1-one 5j
Yield: 61%; ½a 2D2
ꢁ
¼ ꢀ110 (c 1, CH2Cl2) 60% ee; mp 90–92 °C; 1H
Yield: 55%; ½a 2D2
¼ ꢀ122 (c 1, CH2Cl2) 64% ee; mp 122–126 °C;
ꢁ
NMR (CDCl3, 500 MHz) d 8.09 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz,
2H), 7.62 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.42 (t,
J = 7.5 Hz, 1H), 7.39–7.33 (m, 3H), 7.29 (dt, J = 6.5 Hz, 1.5 Hz, 1H),
1H NMR (CDCl3, 500 MHz) d 8.10 (d, J = 8.5 Hz, 2H), 7.71 (d,
J = 8.5 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 8 Hz, 2H), 7.41
(t, J = 7.5 Hz, 1H), 7.30 (t, J = 8 Hz, 1H), 7.22–7.18 (m, 3H), 4.32 (d,

494
Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
J = 1.5 Hz, 1H), 4.07 (d, J = 1.5 Hz, 1H), 2.39 (s, 3H). HRMS calcd for
22H18O2 314.1307, found 314.1306.
J = 13.5 Hz, 4.5 Hz, 1H). HRMS calcd for C17H13ClO2 284.0604,
found 284.0606.
C
4.2.11. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(4-methyl-phenyl)
4.2.18. (ꢀ)-(2R,30S)-30-(4-Chlorophenyl)-3,4-dihydro-1H-spiro-
propan-1-one 5k
(naphthalene-2,20-oxiran)-1-one 8d
Yield: 54%; ½a 2D2
ꢁ
¼ ꢀ130 (c 1, CH2Cl2) 70% ee; mp 144–150 °C;
Yield: 84%; ½a 2D2
ꢁ
¼ ꢀ137 (c 1, CHCl3) 59% ee; mp 138–142 °C; 1H
1H NMR (CDCl3, 500 MHz) d 8.09 (d, J = 8.5 Hz, 2H), 7.70 (d,
J = 8.5 Hz, 2H), 7.62 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 8 Hz, 2H), 7.41
(t, J = 7.5 Hz, 1H), 7.28 (d, J = 8 Hz, 2H), 7.23 (d, J = 8 Hz, 2H), 4.31
(d, J = 1.5 Hz, 1H), 4.07 (d, J = 1.5 Hz, 1H), 2.39 (s, 3H). HRMS calcd
for C22H18O2 314.1307, found 314.1304.
NMR (CDCl3, 500 MHz), d 8.11 (d, J = 7.5 Hz, 1H), 7.53 (td, J = 7.5 Hz,
1 Hz, 1H), 7.40–7.35 (m, 3H), 7.32 (d, J = 8.5 Hz, 2H), 7.23 (d,
J = 7.5 Hz, 1H), 4.34 (s, 1H), 2.90–2.79 (m, 2H), 2.44 (ddd,
J = 13.5 Hz, 8.5 Hz, 5 Hz, 1H), 1.81 (dt, J = 14 Hz, 4.5 Hz, 1H). HRMS
calcd for C17H13ClO2 284.0604, found 284.0603. Crystal data for 8d:
CCDC 867376 contains the supplementary crystallographic data for
this structure. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Absolute configuration crystal data: Rigaku R-
4.2.12. trans-(+)-2,3-Epoxy-1-(biphen-4-yl)-3-(naphth-1-yl)-
propan-1-one 5l
Yield: 59%; ½a 2D2
ꢁ
¼ þ75 (c 1, CH2Cl2) 66% ee; mp 143–146 °C; 1H
NMR (CDCl3, 500 MHz) d 8.16 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz,
1H), 7.93 (d, J = 7 Hz, 1H), 7.88 (d, J = 8 Hz, 1H), 7.72 (d, J = 8 Hz,
2H), 7.65–7.61 (m, 3H), 7.56–7.50 (m, 2H), 7.48 (t, J = 7.5 Hz, 2H),
7.41 (t, J = 7.5 Hz, 1H), 4.76 (d, J = 3 Hz, 1H), 4.34 (d, J = 3 Hz, 1H).
HRMS calcd for C25H18O2 350.1307, found 350.1305.
AXIS Rapid Diffractometer, Mo Ka radiation, k = 0.71075 Å,
T = 93(2) K, R1 = 3.57, Rw2 = 8.92, N = 4640, Friedel Pair Cover-
age = 100%, Flack parameter:15 0.01(4), Hooft parameter:16 0.02(1).
4.2.19. trans-(ꢀ)-30-(2-Nitrophenyl)-3,4-dihydro-1H-spiro-
(naphthalene-2,20-oxiran)-1-one 8f
4.2.13. trans-(ꢀ)-2,3-Epoxy-1-(biphen-4-yl)-3-(naphth-2-yl)-
Yield: 71%; ½a 2D2
ꢁ
¼ ꢀ83 (c 1, CHCl3) 54% ee; mp 144–148 °C; 1H
propan-1-one 5m
NMR (CDCl3, 500 MHz), d 8.25 (d, J = 8 Hz, 1H), 8.16 (d, J = 7.5 Hz,
1H), 7.76 (d, J = 4 Hz, 2H), 7.61–7.56 (m, 1H), 7.53 (td, J = 7.5 Hz,
1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.75 (s,
1H), 2.86–2.81 (m, 2H), 2.42 (ddd, J = 13.5 Hz, 10 Hz, 7.5 Hz, 1H),
Yield: 56%; ½a 2D2
¼ ꢀ129 (c 1, CH2Cl2) 74% ee; mp 178–182 °C;
ꢁ
1H NMR (CDCl3, 500 MHz) d 8.11 (d, J = 8 Hz, 2H), 7.90 (d,
J = 8.5 Hz, 2H), 7.87 (d, J = 4.5 Hz, 1H), 7.86 (d, J = 4.5 Hz, 1H),
7.71 (d, J = 8 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.55–7.50 (m, 2H),
7.49–7.38 (m, 4H), 4.43 (d, J = 1.5 Hz, 1H), 4.28 (d, J = 1.5 Hz, 1H).
HRMS calcd for C25H18O2 350.1307, found 350.1308.
1.63 (dt, J = 13.5 Hz, 4 Hz, 1H). HRMS calcd for
C17H13NO4
295.0845, found 295.0849.
4.2.20. trans-(ꢀ)-30-(3-Nitrophenyl)-3,4-dihydro-1H-spiro
4.2.14. trans-(ꢀ)-2,3-Epoxy-1,3-di(biphen-4-yl)-4-chlorobutan-
(naphthalene-2,20-oxiran)-1-one 8g
1-one 6
Yield: 58%; ½a 2D2
ꢁ
¼ ꢀ83 (c 1, CHCl3) 43% ee; mp 147–150 °C; 1H
Yield: 45% ½a 2D2
ꢁ
¼ ꢀ35 (c 1, CH2Cl2) 10% ee; mp 112–114 °C; 1
H
NMR (CDCl3, 500 MHz), d 8.27–8.25 (m, 1H), 8.24 (d, J = 8 Hz, 1H),
8.12 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 8 Hz, 1H),
7.55 (td, J = 7.5 Hz, 1 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.25 (d,
J = 7 Hz, 1H), 4.48 (s, 1H), 2.90 (dt, J = 16.5 Hz, 4.5 Hz, 1H), 2.82
(ddd, J = 16.5 Hz, 12 Hz, 4.5 Hz, 1H), 2.47 (ddd, J = 13.5 Hz, 12 Hz,
4.5 Hz, 1H), 1.80 (dt, J = 13.5 Hz, 4.5 Hz, 1H). HRMS calcd for
NMR (CDCl3, 300 MHz) d 8.00 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz,
2H), 7.61 (dd, J = 8.1 Hz, 2H), 7.52–7.30 (m, 12H), 4.70 (s, 1H), 4.13
(s, 1H). Anal. Calcd for C28H21ClO2: C, 79.14; H, 4.98; Cl, 8.34.
Found: C, 79.10; H, 5.03; Cl, 8.28.
4.2.15. (ꢀ)-(2R,30S)-30-Phenyl-3,4-dihydro-1H-spiro-(naphtha-
C17H13NO4 295.0845, found 295.0844.
lene-2,20-oxiran)-1-one 8a
Yield:84%; ½a 2D2
ꢁ
¼ ꢀ144 (c 1, CHCl3) 74%; 1H NMR (CDCl3,
4.2.21. trans-(ꢀ)-30-(4-Nitrophenyl)-3,4-dihydro-1H-spiro-
300 MHz), d 8.12 (d, J = 7.5 Hz, 1H), 7.52 (td, J = 7.5 Hz, 1.2 Hz,
1H), 7.41–7.36 (m, 6H), 7.23 (d, J = 7.5 Hz, 1H), 4.36 (s, 1H), 2.83
(dd, J = 8.4 Hz, 4.2 Hz, 2H), 2.45 (dt, J = 13.5 Hz, 8.4 Hz, 1H), 1.86
(dt, J = 13.5 Hz, 4.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz) d 193.58,
143.35, 134.23, 134.14, 132.69, 128.74, 128.36, 128.32, 127.64,
126.99, 126.63, 64.32, 64.09, 27.34, 25.34. HRMS calcd for
(naphthalene-2,20-oxiran)-1-one 8h
Yield: 51%; ½a 2D2
¼ ꢀ145 (c 0.5, CHCl3) 75% ee; mp 192–195 °C;
ꢁ
1H NMR (CDCl3, 500 MHz), d 8.28 (d, J = 8.5 Hz, 2H), 8.12 (d,
J = 7.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.55 (td, J = 7.5 Hz, 1 Hz,
1H), 7.40 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 4.47 (s, 1H),
2.90 (dt, J = 16.5 Hz, 4.5 Hz, 1H), 2.80 (ddd, J = 16.5 Hz, 12 Hz,
4.5 Hz, 1H), 2.47 (ddd, J = 13.5 Hz, 12 Hz, 4.5 Hz, 1H), 1.80 (dt,
J = 13.5 Hz, 4.5 Hz, 1H). HRMS calcd for C17H13NO4 295.0845, found
295.0847.
C17H14O2 250.0994, found 250.0991.
4.2.16. trans-(ꢀ)-30-(2-Chlorophenyl)-3,4-dihydro-1H-spiro-
(naphthalene-2,20-oxiran)-1-one 8b
Yield: 84%; ½a 2D2
ꢁ
¼ ꢀ15 (c 1, CHCl3) 36%; mp 132–134 °C; 1H
4.2.22. trans-(ꢀ)-30-(2-Methylphenyl)-3,4-dihydro-1H-spiro-
NMR (CDCl3, 500 MHz),
d
8.14 (d, J = 8 Hz, 1H), 7.53 (td,
(naphthalene-2,20-oxiran)-1-one 8i
J = 7.5 Hz, 1 Hz, 1H), 7.46–7.42 (m, 1H), 7.41–7.31 (m, 4H), 7.25
(d, J = 8 Hz, 1H), 4.44 (s, 1H), 3.01 (ddd, J = 16.5 Hz, 7.5 Hz, 4 Hz,
1H), 2.86 (dt, J = 16.5 Hz, 4 Hz, 1H), 2.40 (td, J = 13 Hz, 4.5 Hz,
1H), 1.66 (dt, J = 13 Hz, 4 Hz, 1H). HRMS calcd for C17H13ClO2
284.0604, found 284.0600.
Yield: 83%; ½a 2D2
ꢁ
¼ ꢀ32 (c 1, CHCl3) 40% ee; mp 114–116 °C; 1H
NMR (CDCl3, 500 MHz), d 8.14 (d, J = 7.5 Hz, 1H), 7.54 (td, J = 7.5 Hz,
1.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.36 (dd, J = 7.5 Hz, 2.5 Hz, 1H),
7.28–7.22 (m, 3H), 7.20–7.16 (m, 1H), 4.36 (s, 1H), 2.87 (td,
J = 16.5 Hz, 4.5 Hz, 1H), 2.82 (dd, J = 12 Hz, 4.5 Hz, 1H), 2.38 (ddd,
J = 16.5 Hz, 12 Hz, 5 Hz, 1H), 2.25 (s, 3H), 1.74 (dt, J = 13.5 Hz,
4.5 Hz, 1H). HRMS calcd for C18H16O2 264.1150, found 264.1147.
4.2.17. trans-(ꢀ)-30-(3-Chlorophenyl)-3,4-dihydro-1H-spiro-
(naphthalene-2,20-oxiran)-1-one 8c
Yield: 88%; ½a 2D2
ꢁ
¼ ꢀ122 (c 1, CHCl3) 44% ee; mp 94–97 °C; 1H
4.2.23. trans-(ꢀ)-30-(3-Methylphenyl)-3,4-dihydro-1H-spiro-
NMR (CDCl3, 300 MHz),
d
8.11 (d, J = 7.8 Hz, 1H), 7.54 (td,
(naphthalene-2,20-oxiran)-1-one 8j
J = 7.5 Hz, 1.2 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.36–7.32 (m, 2H),
7.28 (t, J = 5.1 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 4.34 (s, 1H), 2.90–
2.81 (m, 2H), 2.44 (ddd, J = 13.8 Hz, 10.8 Hz, 6.3 Hz, 1H), 1.84 (dt,
Yield: 83%; ½a 2D2
ꢁ
¼ ꢀ142 (c 1, CHCl3) 65% ee; mp 96–98 °C; 1H
NMR (CDCl3, 500 MHz),
d 8.12 (d, J = 7.5 Hz, 1H), 7.52 (td,
J = 7.5 Hz, 1 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H),

Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
495
7.22 (d, J = 7.5 Hz, 1H), 7.20–7.15 (m, 3H), 4.33 (s, 1H), 2.84 (dd,
J = 8.5 Hz, 4 Hz, 2H), 2.44 (dt, J = 13.5 Hz, 8.5 Hz, 1H), 2.38 (s, 3H),
7.24–7.21 (m, 1H), 4.45 (s, 1H), 3.26 (d, J = 18 Hz, 1H), 2.93 (d,
J = 18 Hz, 1H). HRMS calcd for
C16H11ClO2 270.0448, found
1.88 (dt, J = 13.5 Hz, 4 Hz, 1H). HRMS calcd for
C
18H16O2
270.0450.
264.1150, found 264.1154.
4.2.30. trans-(ꢀ)-30-(4-Chlorophenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10d
4.2.24. trans-(ꢀ)-30-(4-Methylphenyl)-3,4-dihydro-1H-spiro-
(naphthalene-2,20-oxiran)-1-one 8k
Yield: 48%; ½a 2D2
¼ ꢀ140 (c 1, CHCl3) 37% ee; mp 162–164 °C;
ꢁ
Yield: 65%; ½a 2D2
ꢁ
¼ ꢀ133 (c 1, CHCl3) 55% ee; mp 165–169 °C; 1H
(Lit. mp 168–169 °C)17 1H NMR (CDCl3, 500 MHz) d 7.85 (d,
J = 7.5 Hz, 1H), 7.63 (td, J = 7.5 Hz, 1 Hz, 1H), 7.46–7.39 (m, 2H),
7.36 (d, J = 8 Hz, 2H), 7.27 (d, J = 8 Hz, 2H), 4.46 (s, 1H), 3.24 (d,
J = 18 Hz, 1H), 2.91 (d, J = 18 Hz, 1H). HRMS calcd for C16H11ClO2
270.0448, found 270.0444.
NMR (CDCl3, 500 MHz), d 8.11 (d, J = 8 Hz, 1H), 7.51 (td, J = 7.5 Hz,
1.5 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.22 (d,
J = 8 Hz, 1H), 7.19 (d, J = 7.5 Hz, 2H), 4.33 (s, 1H), 2.83 (dd,
J = 8.5 Hz, 4 Hz, 2H), 2.44 (dt, J = 13.5 Hz, 8.5 Hz, 1H), 2.38 (s, 3H),
1.86 (dt, J = 13.5 Hz, 4 Hz, 1H). HRMS calcd for
264.1150, found 264.1151.
C18H16O2
4.2.31. trans-(ꢀ)-30-(2-Nitrophenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10f
4.2.25. trans-(+)-30-(Naphth-1-yl)-3,4-dihydro-1H-spiro-(naph-
Yield: 36%; ½a 2D2
ꢁ
¼ ꢀ69 (c 1, CHCl3) 20% ee; mp 136–140 °C; 1H
thalene-2,20-oxiran)-1-one 8l
NMR (CDCl3, 300 MHz) d 8.22 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.8 Hz,
1H), 7.79–7.74 (m, 2H), 7.62 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.62–7.54
(m, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 4.91 (s,
1H), 3.10 (d, J = 18 Hz, 1H), 2.72 (d, J = 18 Hz, 1H). HRMS calcd for
Yield: 90%; ½a 2D2
ꢁ
¼ þ36 (c 1, CHCl3) 32% ee; mp 120–121 °C; 1H
NMR (CDCl3, 500 MHz), d 8.21 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8 Hz,
1H), 7.87 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.61 (d,
J = 7 Hz, 1H), 7.56–7.49 (m, 3H), 7.44 (td, J = 8 Hz, 1 Hz, 1H), 7.41
(t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 4.86 (s, 1H), 2.78–2.65
(m, 2H), 2.38 (ddd, J = 13.5 Hz, 12 Hz, 6 Hz, 1H), 1.70 (dt,
J = 13.5 Hz, 4 Hz, 1H). HRMS calcd for C21H16O2 300.1150, found
300.1154.
C16H11NO4 281.0688, found 281.0690.
4.2.32. trans-(ꢀ)-30-(3-Nitrophenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10g
Yield: 18%; ½a 2D2
ꢁ
¼ ꢀ152 (c 1, CHCl3) 62% ee; mp 176–180 °C; 1H
NMR (CDCl3, 500 MHz) d 8.27–8.21 (m, 2H), 7.87 (d, J = 7.5 Hz, 1H),
7.69 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 8 Hz, 1H), 7.61 (t, J = 8 Hz, 1H),
7.46 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 4.58 (s, 1H), 3.31
(d, J = 18 Hz, 1H), 2.88 (d, J = 18 Hz, 1H). HRMS calcd for
4.2.26. (ꢀ)-(2R,30S)-30-(Naphth-2-yl)-3,4-dihydro-1H-spiro-(naph-
thalene-2,20-oxiran)-1-one 8m
Yield: 77%; ½a 2D2
ꢁ
¼ ꢀ225 (c 1, CHCl3) 59% ee; mp 139–140 °C; 1H
NMR (CDCl3, 500 MHz), d 8.15 (dd, J = 8 Hz, 1 Hz, 1H), 7.89–7.84
(m, 4H), 7.55–7.49 (m, 3H), 7.48 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.38
(t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 4.52 (s, 1H), 2.82–2.78
(m, 2H), 2.48 (ddd, J = 13.5 Hz, 10.5 Hz, 8 Hz, 1H), 1.90 (dt,
J = 13.5 Hz, 4.5 Hz, 1H). HRMS calcd for C21H16O2 300.1150, found
300.1148. Crystal data for 8m: CCDC 867377 contains the supple-
mentary crystallographic data for this structure. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Absolute configu-
C16H11NO4 281.0688, found 281.0693.
4.2.33. trans-30-(4-Nitrophenyl)spiro(inden-2,20-oxiran)-1(3H)-
one 10h
Yield: 18%; ½a 2D2
ꢁ
¼ 0 (c 1, CHCl3) racemic; mp 204–206 °C; 1H
NMR (CDCl3, 500 MHz)
d 8.28 (d, J = 8.5 Hz, 2H), 7.87 (d,
J = 7.5 Hz, 1H), 7.66 (td, J = 7.5 Hz, 1 Hz, 1H), 7.53 (d, J = 8.5 Hz,
2H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 4.58 (s, 1H),
3.27 (d, J = 18 Hz, 1H), 2.87 (d, J = 18 Hz, 1H). HRMS calcd for
ration crystal data: Rigaku R-AXIS Rapid Diffractometer, Cu Ka radi-
C16H11NO4 281.0688, found 281.0689.
ation, k = 1.54187 Å, T = 93(2) K, R1 = 6.86, Rw2 = 19.06, N = 2306,
Friedel Pair Coverage = 96%, Flack parameter:15 ꢀ0.1(6), Hooft
parameter:16 0.1(1).
4.2.34. trans-(ꢀ)-30-(2-Methylphenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10i
Yield: 84%; ½a 2D2
ꢁ
¼ ꢀ104 (c 1, CHCl3) 49% ee; mp 112–114 °C; 1H
4.2.27. trans-(ꢀ)-30-Phenylspiro(inden-2,20-oxiran)-1(3H)-one
NMR (CDCl3, 500 MHz) d 7.86 (d, J = 7.5 Hz, 1H), 7.62 (td, J = 7 Hz,
1 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.35–
7.32 (m, 1H), 7.28–7.26 (m, 2H), 7.19–7.15 (m, 1H), 4.54 (s, 1H),
3.12 (d, J = 18 Hz, 1H), 2.76 (d, J = 18 Hz, 1H), 2.19 (s, 3H). HRMS
calcd for C17H14O2 250.0994, found 250.0997.
10a
Yield: 59%; ½a 2D2
¼ ꢀ246 (c 1, CHCl3) 65% ee; mp 152–154 °C
ꢁ
(Lit. 95–96 °C);17 1H NMR (CDCl3, 300 MHz) d 7.85 (d, J = 7.5 Hz,
1H), 7.62 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.46–7.30 (m, 7H), 4.48 (s,
1H), 3.26 (d, J = 18.3 Hz, 1H), 2.94 (d, J = 18.3 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) d 199.53, 151.12, 135.81, 135.60, 134.65, 128.63,
128.52, 127.97, 126.66, 126.46, 124.11, 67.15, 63.06, 29.05. HRMS
calcd for C16H12O2 236.0837, found 236.0833.
4.2.35. trans-(ꢀ)-30-(3-Methylphenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10j
Yield: 72%; ½a 2D2
ꢁ
¼ ꢀ233 (c 1, CHCl3) 63% ee; mp 110–112 °C; 1H
NMR (CDCl3, 500 MHz) d 7.84 (d, J = 7.5 Hz, 1H), 7.62 (td, J = 7.5 Hz,
1 Hz, 1H), 7.45–7.38 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.17 (d,
J = 7.5 Hz, 1H), 7.15–7.11 (m, 2H), 4.45 (s, 1H), 3.25 (d, J = 18 Hz,
1H), 2.95 (d, J = 18 Hz, 1H), 2.38 (s, 3H). HRMS calcd for C17H14O2
250.0994, found 250.0993.
4.2.28. trans-(ꢀ)-30-(2-Chlorophenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10b
Yield: 52%; ½a 2D2
ꢁ
¼ ꢀ31 (c 1, CHCl3) 85% ee; mp 160–164 °C; 1H
NMR (CDCl3, 500 MHz) d 7.87 (d, J = 7.5 Hz, 1H), 7.63 (td, J = 7.5 Hz,
1 Hz, 1H), 7.47–7.29 (m, 6H), 4.68 (s, 1H), 3.11 (d, J = 18 Hz, 1H),
2.80 (d, J = 18 Hz, 1H). HRMS calcd for C16H11ClO2 270.0448, found
270.0443.
4.2.36. trans-(ꢀ)-30-(4-Methylphenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10k
Yield: 76%; ½a 2D2
¼ ꢀ240 (c 1, CHCl3) 58% ee; mp 102–104 °C (lit.
ꢁ
4.2.29. trans-(ꢀ)-30-(3-Chlorophenyl)spiro(inden-2,20-oxiran)-
1(3H)-one 10c
116–118 °C);17 1H NMR (CDCl3, 500 MHz) d 7.84 (d, J = 7.5 Hz, 1H),
7.61 (td, J = 7.5 Hz, 1 Hz, 1H), 7.45–7.37 (m, 2H), 7.22–7.20 (m, 4H),
4.45 (s, 1H), 3.24 (d, J = 18 Hz, 1H), 2.95 (d, J = 18 Hz, 1H), 2.38 (s,
3H). HRMS calcd for C17H14O2 250.0994, found 250.0991.
Yield: 74%; ½a 2D2
ꢁ
¼ ꢀ229 (c 1, CHCl3) 59% ee; mp 120–124 °C; 1H
NMR (CDCl3, 500 MHz) d 7.85 (d, J = 7.5 Hz, 1H), 7.64 (td, J = 7.5 Hz,
1 Hz, 1H), 7.46–7.41 (m, 2H), 7.35–7.33 (m, 2H), 7.33–7.31 (m, 1H),

496
Z. Rapi et al. / Tetrahedron: Asymmetry 23 (2012) 489–496
4.2.37. trans-(ꢀ)-30-(Naphth-1-yl)spiro(inden-2,20-oxiran)-
1(3H)-one 10l
2. (a) Comprehensive Asymmetric Catalysis I–III; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, pp 649–677; (b)
Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47–51.
3. (a) O’ Donnell, M. I. Catalytic Asymmetric Synthesis. In Asymmetric Phase-
Transfer Reactions; Ojima, I., Ed., 2nd ed.; Wiley-VCH: New York, 2000; pp 231–
280; (b) Asymmetric Phase Transfer Catalysis; Marouka, K., Ed.; Wiley-VCH
Verlag GmbH & Co. KgaA: Weinheim, 2008.
4. (a) Achard, T. J. R.; Belokon, Y. N.; Ilyin, M.; Moskalenko, M.; North, M.; Pizzato,
F. Tetrahedron Lett. 2007, 48, 2965; (b) Achard, T. J. R.; Belokon, Y. N.; Hunt, J.;
North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2961.
5. Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara,
D.; Picoul, W.; Robiette, R.; Smith, C.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc.
2006, 128, 2105.
Yield: 20%; ½a 2D2
ꢁ
¼ ꢀ29 (c 1, CHCl3) 47% ee; mp 128–130 °C; 1H
NMR (CDCl3, 500 MHz) d 7.93–7.89 (m, 2H), 7.87 (d, J = 8 Hz, 1H),
7.76 (d, J = 8.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.54 (t, J = 7.5 Hz,
1H), 7.50 (t, J = 7.5 Hz, 1H), 7.46–7.41 (m, 2H), 7.29 (d, J = 7.5 Hz,
1H), 5.05 (s, 1H), 3.12 (d, J = 18.5 Hz, 1H), 2.72 (d, J = 18.5 Hz,
1H). HRMS calcd for C20H14O2 286.0994, found 286.0999.
4.2.38. trans-(ꢀ)-30-(Naphth-2-yl)spiro(inden-2,20-oxiran)-
1(3H)-one 10m
6. (a) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Chem. Commun. 1999, 49; (b) Arai, S.;
Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55, 6375.
7. (a) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1998, 39, 8299; (b) Arai, S.;
Shioiri, T. Tetrahedron 2002, 58, 1407.
Yield: 25%; ½a 2D2
ꢁ
¼ ꢀ72 (c 1, CHCl3) 15% ee; mp 152–154 °C; 1
H
NMR (CDCl3, 500 MHz) d 7.88 (d, J = 8 Hz, 1H), 7.88–7.84 (m, 3H),
7.84–7.82 (m, 1H), 7.61 (td, J = 7.5 Hz, 1 Hz, 1H), 7.55–7.49 (m,
2H), 7.45–7.40 (m, 2H), 7.36 (d, J = 8 Hz, 1H), 4.65 (s, 1H), 3.31
(d, J = 18.5 Hz, 1H), 2.95 (d, J = 18.5 Hz, 1H). HRMS calcd for
8. Arai, S.; Tokumara, K.; Aoyama, T. Tetrahedron Lett. 2004, 45, 1845.
9. Ku, J.-M.; Yoo, M.-S.; Park, H.-g.; Jew, S.-s.; Jeong, B.-S. Tetrahedron 2007, 63,
8099.
}
}
10. (a) Bakó, T.; Bakó, P.; Szöllosy, Á.; Czugler, M.; Keglevich, G.; Toke, L.
Tetrahedron: Asymmetry 2002, 13, 203; (b) Jászay, Z.; Pham, T. S.; Németh, G.;
C20H14O2 286.0994, found 286.0992.
}
Bakó, P.; Petneházy, I.; Toke, L. Synlett 2009, 1429; For a review, see: (c) Bakó,
P.; Keglevich, G.; Rapi, Z. Lett. Org. Chem. 2010, 7, 645.
Acknowledgments
}
}
11. (a) Bakó, P.; Szöllosy, Á.; Bombicz, P.; Toke, L. Synlett 1997, 291; (b) Bakó, P.;
}
Vízvárdi, K.; Bajor, Z.; Toke, L. Chem. Commun. 1998, 1193; (c) Bakó, P.;
}
Vízvárdi, K.; Toppet, S.; Van der Eycken, E.; Hoornaert, G. J.; Toke, L. Tetrahedron
1998, 54, 14975; (d) Bakó, P.; Czinege, E.; Bakó, T.; Czugler, M.; Toke, L.
Tetrahedron: Asymmetry 1999, 10, 4539.
Financial support by the Hungarian Scientific Research Found
(OTKA No. K 75098 and K 81127) is gratefully acknowledged. This
work is connected to the scientific program of the Development of
quality-oriented and harmonized R+D+I strategy and functional
model at BME project. This project is supported by the New Hun-
gary Development Plan (Project ID:TÁMOP-4.2.1/B-09/1/KMR-
2010–0002). One of us (Zs.R.) is grateful for the Gedeon Richter
Plc for a fellowship.
}
}
12. (a) Bakó, P.; Rapi, Z.; Keglevich, G.; Szabó, T.; Sóti, P. L.; Vigh, T.; Grun, A.;
Holczbauer, T. Tetrahedron Lett. 2011, 52, 1473; (b) Rapi, Z.; Szabó, T.;
}
Keglevich, G.; Szöllosy, Á.; Drahos, L.; Bakó, P. Tetrahedron: Asymmetry 2011,
22, 1189.
13. An earlier preparation of the (+)-(2S,10R) isomer of compound 8a by Arai et al.
with Darzens reaction (43 h) with a cinchonine derivative (59% ee).6b
14. An earlier preparation of the (aS,bR)-isomer of 10a via asymmetric epoxidation
of the corresponding ,b-enone: Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J.
a
Am. Chem. Soc. 2004, 126, 6844 (physical data are not given).
15. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
16. Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96–103.
17. Adam, W.; Halasz, J.; Jambor, Z.; Levai, A.; Nemes, C.; Patonay, T.; Tóth, G.
Monatsh. Chem. 1996, 127, 683.
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