Synthesis of D-mannose-based azacrown ethers and their application in enantioselective reactions

Article abstract of DOI:10.1016/j.tetasy.2005.03.025

New chiral monoaza-15-crown-5 compounds anellated to methyl-4,6-O- benzylidene-α-D-mannopyranosides 2a-f have been synthesized. These crown ethers showed significant asymmetric induction as phase-transfer catalysts in the Michael addition of 2-nitropropan

Full text of DOI:10.1016/j.tetasy.2005.03.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1861–1871
Synthesis of D-mannose-based azacrown ethers and
their application in enantioselective reactions
a,
Peter Bako, Attila Mako, Gyo¨rgy Keglevich, Miklos Kubinyi and Krisztina Pal
a
a
b,c
b
*
´
´
´
´
´
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, PO Box 91,
1521 Budapest, Hungary
bDepartment of Physical Chemistry, Budapest University of Technology and Economics, 1521 Budapest, Hungary
cChemical Research Center, Institute of Chemistry, Hungarian Academy of Sciences, PO Box 17, 1525 Budapest, Hungary
Received 9 March 2005; accepted 22 March 2005
Abstract—New chiral monoaza-15-crown-5 compounds anellated to methyl-4,6-O-benzylidene-a-D-mannopyranosides 2a–f have
been synthesized. These crown ethers showed significant asymmetric induction as phase-transfer catalysts in the Michael addition
of 2-nitropropane to chalcone (92% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (45% ee) and in
the epoxidation of chalcones with tert-butyl-hydroperoxide (82% ee). The enantioselectivity was effected by the substituents at
the nitrogen atom of the crown ring. The absolute configurations of epoxyketones 10 were determined by CD spectroscopy.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
report the synthesis of analogous azacrown ethers anel-
lated to a-D-mannopyranoside 2 and their applications
in enantioselective reactions. Our main purpose was to
compare the catalytic effects of sugar based azacrown
ethers with different configurations at C-2.
The development of new methodologies for efficient
asymmetric synthesis is of tremendous importance due
to the increasing demand for optically active com-
pounds.1 One of the techniques of catalytic asymmetric
synthesis currently generating great interest is phase-
transfer catalysis, in which the enantioselectivity is
induced by a chiral crown ether.2 Crown ethers with
carbohydrate moieties form a special group of optically
active crown ethers. Over the past two decades numer-
ous macrocycles made up of one or more monosaccha-
ride units have been synthesized.3 Inexpensive natural
sugars are attractive starting materials in organic syn-
theses. Until now, only a limited number of asymmetric
reactions have, however, been explored, in which the
application of a sugar-based crown catalyst resulted in
a good enantioselectivity.4 Recently Itoh and Shirakami
2. Results and discussion
2.1. Synthesis
The vicinal hydroxy groups of the 4,6-O-benzylidene-a-
D-mannopyranoside 3 were alkylated with bis(2-chloro-
ethyl) ether in the presence of tetrabutylammonium
hydrogen sulfate and 50% aq NaOH in a liquid–liquid
two-phase system to give intermediate 4, which was
purified by chromatography.8 The exchange of chlorine
to iodine in 4 was accomplished by NaI in acetone, at
the boiling point resulting in bis-iodo derivative 5. Com-
pound 5 was then cyclized with various primary amines,
namely with ethanolamine, propanolamine, butanol-
amine and 3-methoxypropylamine in boiling acetoni-
trile, in the presence of dry sodium carbonate yielding
azacrowns 2a, 2b, 2c and 2d, respectively. This protocol
is the extension of our previously described method.6
After purification by column chromatography, the
15-membered macrocycles 2a–d was obtained in yields
between 44% and 53%.
introduced
a variety of a-D-glucose-based chiral
macrocycles that gave high enantioselectivities in a
Michael addition.5 Chiral monoaza-15-crown-5 macro-
cycles incorporating a-methyl-glucopyranoside 1 were
synthesized in our laboratory,6 which proved to be effi-
cient catalysts in a few asymmetric reactions.7 Herein we
*
Corresponding author. Fax: +36
mail.bme.hu
1 463 3648; e-mail: pbako@
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.025

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1862
OCH3
OCH3
O
O
O
O
O
O
O
O
N
R
N
R
O
O
O
O
O
O
1
2
2a R = (CH2)2OH
2b R = (CH2)3OH
2c R = (CH2)4OH
2d R = (CH2)3OCH3
2e R = Ts
2f R = H
OCH3
OR1
OR1
O
iii
2a-d
5 + RNH2
4 + TsNH2
O
O
iv
v
2e
2f
3
3 R1 = H
i
4 R1 = (CH2)2O(CH2)2Cl
5 R1 = (CH2)2O(CH2)2I
ii
Scheme 1. Reagents and conditions: (i) O(CH2CH2Cl)2, 50% aq NaOH, NBu4HSO4, 89%; (ii) NaI, acetone, reflux, 92%; (iii) Na2CO3, CH3CN,
reflux, 44–53%; (iv) K2CO3, DMF, reflux, 52%; (v) 4% Na/Hgx, Na2HPO4, MeOH, reflux, 85%.
The N-tosyl macrocycle 2e needed for the preparation of
the unsubstituted derivative 2f was obtained from the
dichloro intermediate 4 by treatment with 1 equiv of
p-toluene-sulfonamide in the presence of dry potassium
carbonate, in DMF at boiling point. After work-up, 2e
was obtained in 52% yield. The tosyl group of 2e was re-
moved then by 4% sodium amalgam in methanol to give
2f in a yield of 85% (Scheme 1). All intermediates and
new products were characterized by 1H NMR and mass
spectroscopy.
ble-bond of the a,b-unsaturated ketones or aldehydes
have been extensively investigated in recent years.9 Per-
haps, the most frequently studied model reaction is the
Michael addition of methyl phenylacetate to methyl
acrylate carried out in the presence of a sugar-based
crown ether, where enantioselectivities between 53%
and 70% were achieved.10
Asymmetric induction due to glucose-based azacrown
ethers 1 in the Michael addition of 2-nitropropane to
chalcone has already been observed earlier.7,11 Herein,
the effect of mannose-based macrocycles 2a–d and 2f
was studied in the same reaction. The solid–liquid
phase-transfer reaction was carried out in dry toluene,
in the presence of a chiral catalyst (7 mol %) and solid
sodium tertiary butoxide (35 mol %) as base, at room
temperature (Scheme 2). The experimental results are
summarized in Table 1. It can be seen that the substitu-
ent at the nitrogen atom of the catalyst has a significant
influence on the enantiomeric excess.
2.2. Asymmetric induction
Chiral crown ethers 2a–d and 2f were tested in a Michael
addition, a Darzens condensation and in an epoxidation
reaction. In all cases, the products were isolated by pre-
parative TLC after the usual work-up procedure. The
enantiomeric excess (ee) was determined by measuring
1
the specific rotation of the products or by H NMR
spectroscopy using (+)-Eu(hfc)3 as a chiral shift reagent.
2.2.1. Michael addition of 2-nitropropane to chal-
cone. The stereoselective variants of the addition of
enolates or their analogues to the carbon–carbon dou-
The Michael addition carried out in the presence of the
unsubstituted catalyst 2f led to an ee of 61% (entry 1).
Comparing the results obtained by azacrowns 2a–c,
O2N
CH3
CH3
O
O
CH3
NO2
CH3
catalyst 2
Ar1
Ar2
Ar1
Ar2
+
*
H
C
NaOtBu
toluene
6a-l
7a-l
Scheme 2. Michael addition of 2-nitropropane to chalcones, Ar1 and Ar2 listed in Tables 1 and 2.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1863
Table 1. The effect of the side arm in crown catalyst 2 in the addition
of 2-nitropropane to chalcone at room temperature (Scheme 2,
Ar1 = Ar2 = Ph)
(92%, entry 1). Substitution of the b-phenyl ring of 6a
decreased the ee values to a high extent. In the case of
the 4-nitro- and 4-methyl-substituted starting materials
6b and 6c, the products 7b and 7c were obtained with
enantioselectivities of 21% and 30%, respectively (entries
2 and 3). Substitution of the keto-aryl ring (as in starting
materials 6d–f) led to ee values of 44–49% (entries 4–6).
A comparison of the results obtained using chalcones 6f
and 6g suggests that the simultaneous substitution of
both phenyl rings reduces the enantioselectivity further
(ee values of 48% and 40%, respectively). Catalytic
hydrogenation of Michael adducts 7f and 7g led to a
product that was fully identical with 7a. The negative
specific rotations of the products obtained by reduction
suggested that the absolute configuration of 7f and 7g
was identical with that of 7a, that is, S.
Entry Catalyst R substituent Time (h) Yielda (%) eeb (%)
on catalyst 2
1
2
3
4
5
2f
H
50
CH2CH2OH 44
34
32
37
40
37
61 (S)
70 (S)
92 (S)
63 (S)
77 (S)
2a
2b
2c
2d
(CH2)3OH
(CH2)4OH
52
58
(CH2)3OCH3 50
a Based on isolation by preparative TLC.
b Determined by 1H NMR spectroscopy in the presence of Eu(hfc)3 as
chiral shift reagent.
the importance of the length of the side arm can be seen.
The best result of 92% ee was obtained with catalyst 2b,
which incorporates three carbon atoms between the het-
eroatoms (entry 3). Replacement of the hydroxy group
of 2b by a methoxy substituent (as in 2d) led to a de-
crease in the enantioselectivity (77% ee, entry 5). Using
azacrowns with shorter and longer side arms (2a and
2c), ee values of 70% and 63%, respectively, were de-
tected (entries 2 and 4). Then, lariat ether 2b, which gave
the best results among the model compounds 2a–d and
2f studied was tested as a phase-transfer catalyst in the
Michael reactions of substituted chalcones 6a–g and of
the heteroaromatic analogues of chalcones 6h–l. The re-
sults are shown in Table 2. It can be seen that any kind
of substitution in one or both phenyl groups of 6a led to
products 7b–g with much lower enantioselectivities (21–
49%, entries 2–7), when compared to the result of the
reference reaction involving 6a as the starting material
The change of the phenyl ring to a naphthyl group in
chalcone 6a resulted in a dramatically decreased asym-
metric induction: product 7h was formed with an ee
value of only 20% (entry 8). Product 7i with a piperonyl
substituent was obtained with a somewhat higher
enantioselectivity (47%). As the naphthyl and piperonyl
groups are sterically demanding, the decrease in the
enantioselectivity in these cases may be the consequence
of steric effects. In the case of heteroaromatic chalcones
6j–l, products 7j–l were obtained with enantioselectivi-
ties between 51% and 57% (entries 10–12). Relatively
the best result (ee of 57%) was achieved with the pyr-
idyl-substituted model compound (entry 10). The furyl-
and thienyl-products 7k and 7l were obtained with sim-
ilar enantioselectivities, 53% and 51%, respectively. The
absolute configuration of Michael adduct 7k is based on
Table 2. Asymmetric Michael reaction of 2-nitropropane with chalcones and heteroaromatic chalcone analogues mediated by chiral azacrown ethers
2b (Scheme 2)
Ar1
Ar2
Time (h)
Product and yielda (%)
[a]D
eec (%)
b
Entry
Starting material
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
52
51
7a, 37
7b, 28
7c, 38
7d, 42
7e, 27
7f, 42
7g, 54
ꢀ74.8
ꢀ8.5
92 (S)
21
30
4-NO2–Ph
4-CH3–Ph
Ph
Ph
58
70
ꢀ33.1
ꢀ48.2
ꢀ46.3
ꢀ51.7
ꢀ51.6
4-CH3–Ph
4-OCH3–Ph
4-Cl–Ph
4-Cl–Ph
44
49
Ph
Ph
160
40
48 (S)
40 (S)
6g
4-Cl–Ph
67
8
6h
Ph
167
7h, 28
ꢀ67.5
20
O
O
9
6i
6j
Ph
Ph
72
20
7i, 54
7j, 72
ꢀ35.4
ꢀ84.8
47
57
N
10
O
S
11
12
6k
6l
Ph
Ph
48
49
7k, 48
7l, 36
ꢀ33.3
ꢀ56.7
53 (R)
51
a Based on product quantity isolated by preparative TLC.
b In CH2Cl2 at 22 ꢁC.
c Determined by 1H NMR spectroscopy.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1864
the sign of its specific rotation.12 It is noteworthy that
using glucose-based azacrowns 1 products 7 had positive
specific rotation signs,11 whereas the mannose-based
catalysts 2 led to products 7 with negative specific
rotations.
enantioselectivities were also achieved using non-cata-
lytic systems, such as molecular oxygen in the presence
of diethylzinc/chiral amino alcohols.19 The use of chiral
quaternary ammonium salts as phase-transfer catalyst
for this transformation has also been investigated,20 to
date, results have been, however, disappointing.
2.2.2. Darzens condensation. The mannose-based
crown ethers induced a moderate asymmetric induction
in the condensation of phenacyl chloride 8 with benzal-
dehyde 9 (Scheme 3). This reaction was studied by a
number of other groups. The best results were obtained
using N-(4-trifluoromethylbenzyl)cinchoninium bro-
mide (42% ee)13 or a crown ether incorporating a gluco-
pyranoside unit (72% ee)4 as phase-transfer catalysts.
We performed the above reaction in a liquid–liquid
(LL) as well as in a solid–liquid (SL) system and our cat-
alysts were found to be more efficient under LL phase-
In our experiments, the epoxidation of chalcones 6 was
carried out with tert-butyl hydroperoxide (TBHP,
2 equiv) in toluene, in a liquid–liquid two-phase system,
employing 20% aq NaOH (3.5 equiv) as base and
7 mol % of lariat ethers having mannopyranoside unit
2a–d at a temperature of between 0 and 4 ꢁC (Scheme
4). The trans-epoxyketone 10 was obtained in all exper-
iments. Table 3 summarizes the results obtained in the
epoxidation of chalcones in the presence of chiral crown
catalysts. It can be seen that the yields and the enantio-
selectivities are significantly affected by the N-substitu-
ent of the crown ring.
transfer conditions. The reagents and catalyst
2
(7 mol %) were dissolved in toluene and the reaction ini-
tiated by adding 30% sodium hydroxide. After a reac-
tion time of 1–4 h the trans-epoxyketone 10a was
formed (de >98%) in each case and its enantiomer with
positive specific rotation was found to be in excess. This
corresponds to an absolute configuration of (2S,3R).13
The highest enantiomeric excess was achieved in the
presence of crown catalyst 2b; where product 10a was
obtained with an enantioselectivity of 45% after 2 h of
stirring at ꢀ10 ꢁC.
Table 3. Effect of chiral crown catalysts 2a–f on the asymmetric
epoxidation of chalcone 6a by t-BuOOH, at 0–4 ꢁC (Scheme 3)
Entry
Catalyst
Time (h) Yielda ee (%)b
(%)
Compound
R
1
2
3
4
5
2f
H
9
3
8
3
6
25
50
47
61
67
9
72
82 (81)c
51
31
2a
2b
2c
2d
CH2CH2OH
(CH2)3OH
(CH2)4OH
(CH2)3OCH3
2.2.3. Asymmetric epoxidation of chalcones. A signifi-
cant enantioselectivity was generated by the mannose-
based crown ethers 2 in the epoxidation of chalcones
and chalcone analogues under phase-transfer conditions
(Scheme 4).
a Based on the isolation by preparative TLC.
b Determined by specific rotation.
c Determined by 1H NMR spectroscopy.
The enantioselective epoxidation of a,b-unsaturated ke-
tones employing chiral catalysts has received consider-
able attention in recent years.14 A variety of methods
have been developed including the use of polyphasic sys-
tems involving hydrogen peroxide in the presence of
polyamino acids,15 alkylperoxides in conjuction with
lanthanoid–binaphthol complexes,16 tartrate-modified
metal tert-butyl peroxides17 and hydrogen peroxide in
the presence of chiral platinum(II) complexes.18 Good
The lowest enantiomer excess (9%) was observed using
catalyst 2f containing no substituent at the nitrogen
(entry 1). The best result (82% ee) was obtained applying
catalyst 2b with c-hydroxypropyl substituent on the
nitrogen atom (entry 3). In the presence of azacrown
2a with b-hydroxyethyl group, an ee of 72%, while using
the d-hydroxybutyl derivative 2c, an ee of 51% was ob-
served (entries 2 and 4). It can be seen that the length of
the chain connecting the hydroxy group to the nitrogen
O
O
*
30 % NaOH
*
+
CH2Cl
H
toluene
crown cat.
O
8
O
9
10a
Scheme 3. Darzens condensation of phenacyl chloride and benzaldehyde.
O
O
catalyst 2
O
t-BuOOH
*
Ar1
Ar2
Ar1
Ar2
20 % NaOH
toluene
*
10a, c-e, g, h, j, m
6a, c-e, g, h, j, m
Scheme 4. Asymmetric epoxidation of chalcones, Ar1 and Ar2 listed in Table 4.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1865
atom plays an important role in the asymmetric induc-
tion: the chain with three carbon atoms is the optimum
length, as in 2b. It is noteworthy that the methylation of
the hydroxy group in 2b results in a dramatic decrease in
the enantioselectivity, as indicated by the ee value of
31% obtained in the presence of 2d. It has been clearly
demonstrated that the hydrophilic substituents improve
the transport of the catalyst between the two phases (tolu-
ene and water), while the lipophilic –(CH2)3OMe sub-
stituents have the opposite effect. The discrimination
between the prochiral planes of the chalcone is the most
efficient, when catalyst 2b assists the formation of the
transient complex.
displayed positive specific rotations, suggesting the ex-
cess of the same enantiomer configuration in them.
The impact of a naphthyl group as the Ar2 unit in 10h
on the specific rotation will be clarified at a later stage.
The efficiency of the chiral crown ether in this oxidation
can be explained by assuming a mechanism, in which the
t-BuOOꢀ anion accompanied by the crown-complexed
sodium cation attacks the electron-deficient alkene.
The efficiency of the azacrown ether in the asymmetric
induction suggests that the substituent on the nitrogen
atom assists the complexation of the cation of the salt
in the third dimension. The complexing interaction
may be optimal in case of a hydroxypropyl substituent.
The role of the side arm of the lariat ethers in the asym-
metric induction will be the subject of further
investigation.
It is worth noting that the earlier described glucopyr-
anoside-based catalysts 1 promoted the formation of
the (2R,3S) isomer of epoxyketone 10a (with negative
specific rotation).21 In contrast, the lariat ethers incor-
porating a mannose unit 2 used as catalysts favoured
the formation of the opposite antipodes—(2S,3R)—of
the epoxyketones 10a–g and 10j with positive rotations.
In conclusion, both in the Michael addition and in the
epoxidation of chalcone, the asymmetric induction
strongly depends on the nature of the aryl substituents.
The optimum value was observed with the unsubstituted
model compound. It is uncertain whether the steric or
the electronic effects of the substituents have a larger im-
pact on the asymmetric induction. The situation may be
complicated by the possible retro-Michael addition
reaction and by deracemization, both modifying the
outcome of the asymmetric induction.
Finally, we studied the asymmetric epoxidation of
substituted chalcones 6c–e, 6g and 6m, as well as their
naphthyl- and pyridyl-analogues 6h and 6j using the
tert-butylperoxide base in the presence of lariat ether
2b, which produced the best results in the epoxidation
of chalcone (see above). The experimental results are
presented in Table 4. Due to the poor solubility of chal-
cones 6e, 6m and 6j, the epoxidation of these starting
materials had to be carried out at a somewhat elevated
temperature (24 ꢁC). The reference reaction, the epoxi-
dation of chalcone 6a was accomplished both at 0–
4 ꢁC and at 24 ꢁC, yielding the product 10a with enan-
tiomeric excesses of 82% and 60%, respectively (entries
2 and 1). It can be seen that the substitution of the phen-
yl rings resulted in lower enantioselectivities, 50–54%
at room temperature (entries 5 and 6) when compared
to the values of 55–64% obtained at 0–4 ꢁC (entries 3,
4 and 7). Modest enantioselectivities of 42% and 32%
were obtained with the naphthyl- and the pyridyl-substi-
tuted model compounds 6h and 6j (entries 8 and 9). As
can be seen, all the products, with the exception of 10h,
2.3. CD spectra of chalcone epoxides
As has been pointed out in our previous paper,21 the CD
spectra of trans-chalcone epoxide samples give a reliable
indication of which enantiomer—whether it be (2R,3S)
or (2S,3R)—they contain in excess. The identification
of the dominant component is based on the Ôoctant ruleÕ,
which predicts the sign of CD signal belonging to the
n ! p* transition of C@O groups from the arrangement
of the atoms around the carbonyl unit.22
The CD spectra of the chalcone epoxides obtained here-
in from substituted chalcones in the presence of the lar-
iat ether 2b are illustrated in Figure 1, where the spectra
Table 4. Epoxidation of substituted chalcones by t-BuOOH in the presence catalyst 2b (Scheme 4)
Ar1
Ar2
Temperature (ꢁC)
Time (h)
Yielda (%)
[a]D
eec (%)
b
Entry
Starting compd
1
2
3
4
5
6
7
6a
6a
6c
6d
6e
6m
6g
Ph
Ph
Ph
Ph
24
5
8
7
7
3
5
4
10a, 70
10a, 47
10c, 37
10d, 40
10e, 37
10m, 40
10g, 38
+128
+171.4
+81.6
60
82
55
61
54
50
64
0–4
0–4
0–4
24
Ph
4-CH3–Ph
Ph
Ph
4-CH3–Ph
4-OCH3–Ph
4-CH3–Ph
4-Cl–Ph
+120.4
+142.9
+122.8
+124.8
4-CH3–Ph
4-Cl–Ph
24
0–4
8
9
6h
6j
Ph
0–4
24
11
6
10h, 49
10j, 55
ꢀ46.5
42
32
N
Ph
+81
a Based on product quantity isolated by preparative TLC.
b In CH2Cl2 at 22 ꢁC.
c Determined by 1H NMR spectroscopy in the presence of Eu(hfc)3 as the chiral shift reagent.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1866
Figure 2. Octant projection diagram for the (2S,3R)-isomer of
chalcone epoxide 10a. The atomic positions were determined by
quantum chemical geometry optimization.
Figure 1. CD spectra of the enantiomers of unsubstituted trans-
chalcone epoxide (+)-10a and (ꢀ)-10a and of the substituted deriva-
tives 10d, 10m and 10g [5 · 10ꢀ5 M solutions in acetonitrile, ee values
(+)-10a 82%, (ꢀ)-10a 80%, 10d 61%, 10m 50%, 10g 64%].
Likewise the carbonyl bands, the exciton couplets also
show a similar pattern in the spectra of the compounds
studied. In general, these couplets are very sensitive to
the conformation27 and in the spectra of some other
trans-chalcone epoxides this range exhibits completely
different features.28 Consequently, the appearance of
similar positive couplets in the CD spectra of our chal-
cone epoxides confirms that these molecules have very
similar conformations in solvent phase and the employ-
ment of the projection diagram of 10a for the determina-
tion of the absolute configuration of the substituted
derivatives was correct.
of 10a [denoted as (+)-10a], 10d,10m and 10g are dis-
played. For comparison, the spectrum of the antipode
of 10a [denoted as (ꢀ)-10a] is also shown. The positive
CD signals around 320 nm belong to the n ! p* transi-
tions of the C@O units. The positive bands around
260 nm and the negative bands around 240 nm arise
probably from exciton couplings between the p ! p*
transitions of the phenyl and benzoyl moieties.
The steric structures of the two enantiomers of 10a were
determined by quantum chemical calculations: their
molecular geometries were optimized with the aid of
density functional theory (DFT) using the Becke 3-
parameter–Lee–Yang–Parr (B3LYP)] functional23 and
the correlation consistent valence double-zeta (cc-
pVDZ) basis set.24 All calculations were carried out by
the Gaussian 98 suite of quantum chemical programs.25
The octant projection diagrams of the two isomers of
10a were created then using the atomic coordinates
obtained in the calculations.
3. Experimental
3.1. General procedures
Melting points were determined using a Bu¨chi 510 appa-
ratus and are uncorrected. The specific rotation was
measured with the help of a Perkin–Elmer 241 polari-
meter at 22 ꢁC, the IR spectra were recorded on a Perkin–
Elmer 237 spectrophotometer. CD spectra were taken
on a Jasco 810 spectropolarimeter. NMR spectra were
obtained in CDCl3 on a Brucker DRX-500 instrument.
Mass spectra were obtained on a Varian MAT312
instrument. Elemental analyses were carried out using
a Perkin–Elmer 240 automatic analyzer. Analytical
and preparative thin layer chromatography was per-
formed on silica gel plates (60 GF-254, Merck), while
column chromatography was carried out using 70–230
mesh silica gel (Merck). The shift reagent was Eu(hfc)3
(Aldrich Chem. Co.).
The diagram obtained for (2S,3R)-10a is shown in Fig-
ure 2. The octant rule for such an arrangement predicts
a positive Cotton-effect, since the chiral disturbance of
the carbonyl group arises primarily from the atoms
lying in the upper back left octant. Thus, the positive
sign of the n ! p* band in the CD spectrum of 10a
is a clear evidence that the (2S,3R) isomer being dom-
inant in the sample. This is in accordance with the
result of Marsman and Wynberg, who proved by
chemical correlation that the antipode (ꢀ)-10a has a
(2R,3S)-configuration.26 The spectra of the substituted
chalcone epoxides 10c, 10d, 10e, 10m, 10g also exhibit
a positive n ! p* Cotton-effect. Providing that the
substitutions in the 4-positions of the benzene rings
do not lead to substantial conformational changes,
one concludes that the (2S,3R)-isomers are in excess
in all these products.
3.1.1.
Methyl-4,6-O-benzylidene-2,3-bis[(2-chloroeth-
oxy)ethyl]-a-D-mannopyranoside, 4. A solution of com-
pound 3 (12.3 g, 43.8 mmol) and tetrabutylammonium
hydrogensulfate (12.5 g, 36.9 mmol) in bis(2-chloro-
ethyl)ether (93 mL, 650.3 mmol) was vigorously stirred
with 50% NaOH solution (93 mL) at room temperature
for 18 h. A mixture of CH2Cl2 (160 mL) and water
(160 mL) was added to the reaction mixture. The organic
layer was decanted and the aqueous phase washed with

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1867
CH2Cl2. The organic phases were combined and washed
with water, dried over MgSO4, filtered and concentrated
under vacuum. After removal of the solvent and excess of
the bis(2-chloroethyl)ether, the product was purified by
column chromatography on silica gel using CH2Cl2–
3.37 (s, 3H, OCH3), 3.55–3.98 (m, 20H, CH and CH2
groups), 4.11 (t, J = 9.6 Hz, 1H, H-6), 4.24 (q,
J = 10.1 Hz, 1H, H-6), 4.75 (s, 1H, anomer-H), 5.30 (s,
1H, PhCH), 7.48 (d, 2H, ArH), 7.35 (t, 3H, ArH);
FAB-MS: (M++H) 498, (M++Na) 520. Anal. Calcd
for C25H39NO9: C, 60.35; H, 7.90; N, 2.81. Found: C,
60.44; H, 7.68; N, 2.88.
MeOH (100:1 ! 100:7) as the eluant to give 4 (19.3 g,
20
89%) in the form of a gum; ½aꢁ ¼ þ22:9 (c 1, CHCl3);
D
20
D
1
lit.8 ½aꢁ ¼ þ23:2 (c 1.13, CHCl3); H NMR (CDCl3) d
3.36 (s, 3H, OCH3), 3.52–3.88 (m, 19H, CH and CH2
groups), 3.93–3.97 (tt, 1H, H-6), 4.05 (t, 1H, H-4),
4.21–4.24 (dd, 1H, H-6), 4.77 (s, 1H, anomer-H), 5.57
(s, 1H, PhCH), 7.33–7.46 (m, 5H, Ar).
3.1.6. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-N-hydroxybuty1-1,4,7,10-tetraoxa-13-
20
D
azacyclopentadecane, 2c. Yield: 50%; ½aꢁ ¼ þ13:6 (c
1
1, CHCl3); H NMR (CDCl3) d 2.78 (t, 6H, CH2N),
3.37 (s, 3H, OCH3), 3.55–3.98 (m, 22H, CH and CH2
groups), 4.11 (t, J = 9.6 Hz, 1H, H-6), 4.24 (q,
J = 10.1 Hz, 1H, H-6), 4.75 (s, 1H, anomer-H), 5.30 (s,
1H, PhCH), 7.48 (d, 2H, ArH), 7.35 (t, 3H, ArH);
FAB-MS: (M++H) 512, (M++Na) 534. Anal. Calcd
for C26H41NO9: C, 61.04; H, 8.08; N, 2.74. Found: C,
61.15; H, 8.12; N, 2.82.
3.1.2.
Methyl-4,6-O-benzylidene-2,3-bis[(2-iodoeth-
oxy)ethyl]-a-D-mannopyranoside, 5. A mixture of bis-
chloro derivative 4 (18.0 g, 36.4 mmol) and dry NaI
(21.8 g, 145.3 mmol) in dry acetone (360 mL) was stirred
under reflux for 22 h. After cooling, the precipitate was
filtered off and washed with acetone. The combined ace-
tone solutions were evaporated under vacuum. The res-
idue was dissolved in CH2Cl2 (200 mL), washed with
3.1.7. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-N-methoxy-propyl-1,4,7,10-tetraoxa-
water and dried over Na2SO4 to give 5 (22.6 g, 91.5%)
20
D
20
D
as a syrup. ½aꢁ ¼ þ18:0 (c 1, CHCl3); 1H NMR
13-azacyclopentadecane, 2d. Yield: 49%; ½aꢁ ¼ þ19:6
1
(CDCl3) d 3.26 (t, 4H, ICH2), 3.38 (s, 3H, OCH3),
3.66–4.0 (m, 15H, CH and CH2 groups), 3.95–3.97 (tt,
1H, H-6), 4.06 (t, J = 9.6 Hz, 1H, H-4), 4.23–4.26 (dd,
1H, H-6), 4.78 (s, 1H, anomer-H), 5.59 (s, 1H, PhCH),
7.47 (d, 2H, ArH), 7.36 (t, 3H, ArH). Anal. Calcd for
C22H32I2O8: C, 38.96; H, 4.76; I, 37.42; Found: C,
39.05; H, 4.82; I, 37.48.
(c 1, CHCl3), H NMR (CDCl3) d 1.69 (m, 2H, CH2),
2.56 (t, 2H, CH2N), 2.72 (t, 4H, CH2N), 3.24 (s, 3H,
OCH3), 3.31 (s, 3H, OCH3), 3.45–3.95 (m, 18H, CH
and CH2 groups), 4.02 (t, 1H, J = 9.6 Hz, H-4), 4.16
(q, 1H, J = 10.1 Hz, H-6), 4.67 (s, 1H, anomer-H),
5.52 (s, 1H, PhCH), 7.27 (t, 3H, ArH), 7.39 (d, 2H,
ArH); FAB-MS: (M++H) 512, (M++Na) 534. Anal.
Calcd for C26H341NO9: C, 61.04; H, 8.08; N, 2.74.
Found: C, 61.10; H, 8.11; N, 2.78.
3.1.3. General method for preparation of crown ethers
2a–d. Dry Na2CO3 (3.84 g, 36.2 mmol) was suspended
in a solution of the corresponding primary amine
3.1.8. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-N-tosyl-1,4,7,10-tetraoxa-13-azacycl-
opentadecane, 2e. A mixture of bis-chloro compound 4
(2.6 g, 5.0 mmol), toluene-p-sulfonamide (0.86 g,
5.0 mmol) and anhydrous K2CO3 (3.5 g, 25.3 mmol)
was stirred and refluxed in dry DMF (150 mL) for
32 h. When the reaction was complete, the precipitate
was filtered off and washed with chloroform. The com-
bined filtrates and washings were evaporated under re-
duced pressure and the residue was dissolved in
chloroform, washed with water and dried (MgSO4).
After removal of the solvent, column chromatography
of the residue on silica gel using CH2Cl2–MeOH
(4.60 mmol) and bis-iodo compound
5
(3.45 g,
4.60 mmol) in dry acetonitrile (100 mL) under argon.
The stirred reaction mixture was refluxed for 24–48 h
and monitored by TLC. After cooling, the precipitate
was filtered off and washed with acetonitrile. The com-
bined organic solutions were concentrated at reduced
pressure. The residual oil was dissolved in CHCl3,
washed with water, dried over Na2SO4 and the solvent
evaporated under vacuum. The corresponding mono-
aza-crown ether was isolated by column chromatogra-
phy on silica gel using CHCl3–MeOH (100:2 ! 100:7)
as eluant.
(100:2) as eluant gave the N-tosyl macrocycle 2e as a yel-
20
3.1.4. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-N-hydroxy-ethyl-1,4,7,10-tetraoxa-13-
low solid (1.6 g, 52%); mp 52–54 ꢁC; ½aꢁ ¼ þ18:8 (c 1,
D
CHCl3); 1H NMR (CDCl3) d 2.44 (s, 3H, ArCH3),
3.20–3.26 (m, 4H, CH2N), 3.40 (s, 3H, OCH3), 3.51–
4.00 (m, 16H, CH and CH2 groups), 4.12 (t, 1H,
J = 9.6 Hz, H-6), 4.26 (q, 1H, J = 10.1 Hz, H-6), 7.71
(d, 2H, tosyl-ArH), 4.74 (s, 1H, anomer-H), 5.62 (s,
1H, PhCH), 7.32 (t, 3H, ArH), 7.49 (d, 2H, tosyl-
ArH), 7.38 (d, 2H, ArH); FAB-MS: (M++H) 594,
(M++Na) 616. Anal. Calcd for C29H39NO10S: C, 58.67;
H, 6.62; N, 2.36. Found: C, 58.60; H, 6.61; N, 2.38.
20
D
azacyclopentadecane, 2a. Yield: 44%; ½aꢁ ¼ þ16:0 (c
1
1, CHCl3); H NMR (CDCl3) d 2.78 (t, 6H, CH2N),
3.37 (s, 3H, OCH3), 3.55–3.98 (m, 19H, CH and CH2
groups), 4.11 (t, 1H, J = 9.6 Hz, H-6), 4.24 (q,
J = 10.1 Hz, 1H, H-6), 4.75 (s, 1H, anomer-H), 5.30 (s,
1H, PhCH), 7.48 (d, 2H, ArH), 7.35 (t, 3H, ArH);
FAB-MS: (M++H) 484, (M++Na) 506. Anal. Calcd
for C24H37NO9: C, 59.61; H, 7.71; N, 2.90. Found: C,
59.70; H, 7.79; N, 2.97.
3.1.9. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-1,4,7,10-tetraoxa-13-azacyclopentade-
cane, 2f. Compound 2e (1.4 g, 2.27 mmol), anhydrous
disodium hydogenphosphate (1.3 g, 9.10 mmol) and
4% sodium amalgam (11.0 g, 19.1 mmol) were placed
3.1.5. Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-manno-
pyranosido(2,3-h)-N-hydroxy-propyl-1,4,7,10-tetraoxa-
20
D
13-azacyclopentadecane, 2b. Yield: 53%; ½aꢁ ¼ þ15:0
1
(c 1, CHCl3); H NMR (CDCl3) d 2.78 (t, 6H, CH2N),

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1868
in dry methanol (20 mL). The mixture was heated at re-
flux under a nitrogen atmosphere for 20 h, while being
stirred intensely. After cooling to room temperature,
the resulting slurry was decanted into water (80 mL)
and extracted with chloroform (4 · 30 mL). The organic
layers were combined, dried over MgSO4 and evapo-
3.2.4. 1-(4-Tolyl)-4-methyl-4-nitro-3-phenylpentan-1-one,
20
D
7d. Yield: 42%; mp 111–115 ꢁC; ½aꢁ ¼ ꢀ48:2 (c 1,
CH2Cl2); 44% ee. IR (KBr), m 2999, 1680, 1606, 1537,
1453, 1397, 1346, 1232, 818, 723 cmꢀ1 1H NMR
;
(CDCl3) d 1.55 (s, 3H), 1.64 (s, 3H), 2.40 (s, 3H), 3.25
(dd, Jgem = 17.2, 3.7 Hz, 1H), 3.65 (dd, Jgem = 17.2,
10.4 Hz, 1H), 4.15 (dd, 1H), 7.22–7.25 (m, 5H, CHPhH),
7.28 (d, 2H, COPhH-m), 7.78 (d, 2H, COPhH-o);
HRMS: calcd for C19H21NO3 (M+): 311.1521, found
311.1529.
rated under reduced pressure to yield compound 2f
20
(0.89 g, 85%) as a yellow oil. ½aꢁ ¼ þ26:3 (c 1, CHCl3);
D
1H NMR (CDCl3) d 2.55 (m, 1H, NH), 2.76 (t, 2H,
CH2N), 2.85 (t, 2H, CH2N), 3.39 (s, 3H, OCH3), 3.55–
4.08 (m, 16H, CH and CH2 groups), 4.14 (t, 1H,
J = 9.6 Hz, H-6), 4.25 (q, 1H, J = 10.1 Hz, H-6), 4.78
(s, 1H, anomer-H), 5.60 (s, 1H, PhCH), 7.35 (t, 3H,
ArH), 7.47 (d, 2H, ArH); FAB-MS: (M++H) 440,
(M++Na) 462. Anal. Calcd for C22H33NO8: C, 60.12;
H, 7.57; N, 3.19; Found: C, 60.19; H, 7.64; N, 3.12.
3.2.5. 1-(4-Methoxyphenyl)-4-methyl-4-nitro-3-phenyl-
pentan-1-one, 7e. Yield: 27%; mp 102–104 ꢁC;
20
½aꢁ ¼ ꢀ46:3 (c 1, CH2Cl2); 49% ee. IR (KBr), m 2998,
D
1662, 1601, 1535, 1454, 1344, 1267, 1245, 1175, 1027,
1
833, 762, 705 cmꢀ1; H NMR (CDCl3) d 1.55 (s, 3H),
1.63 (s, 3H), 3.23 (dd, Jgem = 16.8, 3.2 Hz, 1H), 3.63
(dd, Jgem = 16.8, 10.4 Hz, 1H), 3.85 (s, 3H), 4.15 (dd,
1H), 6.90 (d, 2H, COPhH-m), 7.22–7.29 (m, 5H,
CHPhH), 7.86 (d, 2H, COPhH-o); HRMS calcd for
C19H21NO4 (M+): 327.1471, found 327.1478.
3.2. General procedure for the Michael addition
of 2-nitropropane to chalcones
The corresponding azacrown ether (0.1 mmol) and so-
dium tert-butoxide (0.05 g, 0.5 mmol) was added to a
solution of chalcone (1.44 mmol) and 2-nitropropane
(0.3 mL, 3.36 mmol) in dry toluene (3 mL). The mixture
was stirred under argon at room temperature. After a
reaction time of 20–168 h, a new portion of toluene
(7 mL) was added and the mixture stirred with water
(10 mL). The organic phase was washed with water
and dried Na2SO4. The crude product obtained after
evaporating the solvent was purified by preparative
TLC (silica gel, hexane–ethyl acetate; 10:1, eluant) to
give pure adducts 7a–l.
3.2.6. 3-(S)-1-(4-Chlorophenyl)-4-methyl-4-nitro-3-phen-
ylpentan-1-one, 7f. Yield: 48% (colourless crystals);
20
D
mp 112–117 ꢁC; ½aꢁ ¼ ꢀ51.7 (c 1, CH2Cl2), 48% ee,
(S); IR (KBr), m 2997, 1689, 1589, 1529, 1452, 1344,
1
1231, 1094, 797, 703 cmꢀ1; H NMR (CDCl3) d 1.46
(s, 3H), 1.55 (s, 3H), 3.16 (dd, Jgem = 17.3, 3.1 Hz,
1H), 3.55 (dd, Jgem = 17.3, 10.4 Hz, 1H), 4.04 (dd, 1H),
7.13–7.21 (m, 5H, CHPhH), 7.32 (d, 2H, COPhH-o),
7.72 (d, 2H, COPhH-m); HRMS calcd for C18H18ClNO3
(M+): 331.0975, found 331.0972.
3.2.1. 3-(S)-4-Methyl-4-nitro-1,3-diphenylpentan-1-one,
3.2.7. 3-(S)-4-Methyl-4-nitro-3-(4-chlorophenyl)-1-(4-chloro-
phenyl)pentan-1-one, 7g. Yield: 54%; mp 109– 110 ꢁC;
20
7a. Yield: 37%, mp: 140–146 ꢁC; ½aꢁ ¼ ꢀ74:8 (c 1,
D
20
½aꢁ ¼ ꢀ51:6 (c 1, CH2Cl2); 40% ee; IR (KBr), m 2996,
CH2Cl2), 92% ee; 1H NMR (CDCl3) d 1.54 (s, 3H),
1.63 (s, 3H), 3.70 (dd, 1H; Jgem = 17.6, 3.1 Hz); 4.09
(dd, 1H, Jgem = 17.6, 10.0 Hz), 4.15 (dd, 1H), 7.18–7.32
(m, 5H, CHPhH), 7.42 (t, 2H, COPhH-m), 7.53 (t, 1H,
COPhH-p), 7.85 (d, 2H, COPhH-o); HRMS calcd for
C18H19NO3 (M+) 297.1365, found 297.1361.
D
1682, 1590, 1533, 1398, 1345, 1231, 1095, 821,
1
770 cmꢀ1; H NMR (CDCl3) d 1.55 (s, 3H), 1.61 (s,
3H), 3.25 (dd, Jgem = 17.2, 3.1 Hz, 1H), 3.58 (dd,
Jgem = 17.2, 10.5 Hz, 1H), 4.09 (dd, 1H), 7.16 (d, 2H,
CHPhH-m), 7.27 (d, 2H, CHPhH-o), 7.41 (d, 2H,
COPhH-m), 7.80 (d, 2H, COPhH-o); HRMS calcd for
C18H17Cl2NO3 (M+): 365.0586, found 365.0590.
3.2.2. 4-Methyl-4-nitro-3-(4-nitrophenyl)-1-phenylpentan-
20
D
1-one, 7b. Yield: 28%; mp: 92–96 ꢁC; ½aꢁ ¼ ꢀ8:5 (c
1, CH2Cl2), 21% ee. IR (KBr), m 2929, 1680, 1532,
3.2.8. 4-Methyl-3-naphthalen-2-yl-4-nitro-1-phenylpen-
20
D
1
1449, 1370, 1335, 1214, 820; 746, 680 cmꢀ1; H NMR
tan-1-one, 7h. Yield: 28%; ½aꢁ ¼ ꢀ67:5 (c 1, CH2Cl2),
(CDCl3) d 1.60 (s, 3H), 1.65 (s, 3H), 3.40 (dd,
Jgem = 17.7, 3.2 Hz, 1H), 3.71 (dd, Jgem = 17.7,
10.6 Hz, 1H), 4.25 (dd, 1H), 7.43 (d, 2H, COPhH-m),
7.46 (d, 2H, CHPhH-o), 7.58 (t, 1H, COPhH-p); 7.87
(d, 2H, COPhH-o), 8.16 (d, 2H, CHPhH-m); HRMS
calcd for C18H18N2O5 (M+) 342.1216, found 342.1212.
20% ee. IR (KBr), m 3000, 1689, 1590, 1531, 1454, 1341,
1
1238, 765, 698 cmꢀ1; H NMR (CDCl3) d 1.47 (s, 3H),
1.66 (s, 3H), 3.45 (dd, Jgem = 17.4, 3.2 Hz, 1H), 3.86
(dd, Jgem = 17.4, 10.2 Hz, 1H), 5.28 (dd, 1H), 7.33–7.38
(m, 5H, naphthalene-CH), 7.50 (t, 2H, COPhH-m),
7.61 (t, 1H, COPhH-p), 7.76 (d, 1H, naphthalene-CH),
7.82 (d, 2H, COPhH-o), 8.47 (d, 1H, naphthalene-
CH); HRMS calcd for C22H21NO3 (M+): 347.1521,
found 347.1530.
3.2.3. 4-Methyl-4-nitro-3-(4-tolyl)-1-phenylpentan-1-one,
20
D
7c. Yield: 38%; mp 109–110 ꢁC; ½aꢁ ¼ ꢀ33:1 (c 1,
CH2Cl2); 30% ee. IR (KBr), m 2921, 1686, 1532, 1449,
1372, 1334, 1216; 814, 748, 686 cmꢀ1; 1H NMR (CDCl3)
d 1.55 (s, 3H), 1.63 (s, 3H), 2.29 (s, 3H), 3.25 (dd,
Jgem = 17.3, 3.3 Hz, 1H), 3.66 (dd, Jgem = 17.3,
10.6 Hz, 1H), 4.12 (dd, 1H), 7.09 (d, 2H, CHPhH-m),
7.13 (d, 2H, CHPhH-o), 7.43 (t, 2H, COPhH-m), 7.55
(t, 1H, COPhH-p), 7.87 (d, 2H, COPhH-o); HRMS
calcd for C19H21NO3 (M+) 311.1521, found 311.1526.
3.2.9. 3-Benzo[1,3]dioxol-5-y1-4-methyl-4-nitro-1-phenyl-
20
D
pentan-1-one, 7i. Yield: 54%; mp 92 ꢁC; ½aꢁ ¼ ꢀ35:4
(c 1, CH2Cl2), 47% ee. IR (KBr), m 3441, 1687, 1597,
1580, 1534, 1489, 1448, 1345, 1253, 1039, 748,
1
689 cmꢀ1; H NMR (CDCl3) d 1.47 (s, 3H), 1.55 (s,
3H), 3.14 (dd, Jgem = 17.1, 3:2 Hz, 1H), 3.53 (dd,
Jgem = 17.1, 10.6 Hz, 1H), 3.98 (dd, 1H), 5.83 (s, 2H),

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1869
20
D
6.58–6.63 (m, 3H, CHPhH), 7.35 (t, 2H, CO PhH-m),
7.47 (t, 114, COPhH-p), 7.79 (d, 2H, COPhH-o); HRMS
calcd for C19H19NO5 (M+): 341.1263, found 341.1268.
Yield: 56%, mp: 64–66 ꢁC; ½aꢁ ¼ þ97 (c l, CH2Cl2),
45% ee for (2S,3R)-enantiomer. 1H NMR (CDCl3) d
4.09 (d, J = 1.9 Hz, 1H, PhCH), 4.30 (d, J = 1.9 Hz,
1H, COCH), 7.38–7.44 (m, 5H, Ph), 7.50 (t, 2H,
COPhH-m), 7.63 (t, 1H, COPhH-p), 8.02 (d, 2H,
COPhH-o); HRMS calcd for C15H12O2 (M+):
224.0837, found 224.0830.
3.2.10. 4-Methyl-4-nitro-1-phenyl-3-pyridin-2-yl-pentan-
20
D
1-one, 7j. Yield: 72%; ½aꢁ ¼ ꢀ84:8 (c 1, CH2Cl2),
57% ee. IR (KBr), m 3448, 1680, 1594, 1535, 1447,
1
1400, 1374, 1341, 1238, 1001, 846, 760, 694 cmꢀ1; H
NMR (CDCl3) 5 1.55 (s, 3H), 1.77 (s, 3H), 3.11 (dd,
Jgem = 17.3, 2.0 Hz, 1H), 4.24 (dd, Jgem = 17.3,
10.7 Hz, 1H), 4.35 (dd, 1H), 7.15 (t, 1H, pyridine-CH),
7.38 (d, 1H, pyridine-CH), 7.44 (t, 2H, COPhH-m),
7.55 (t, 1H, pyridine-CH), 7.64 (t, 1H, COPhH-p),
7.91 (d, 2H, COPhH-o), 8.48 (d, 1H, pyridine-CH);
HRMS calcd for C17H18N2O (M+): 298.1317, found
298.1322.
3.4. General procedure for the epoxidation of chalcones
A solution of chalcone (1.44 mmol) and the appropriate
catalyst (0.1 mmol) in toluene (3 mL) containing sodium
hydroxide (1 mL 20% aq) was treated with 50% tert-but-
yl hydroperoxide in decane (0.5 mL, 2.88 mmol) and
the mixture stirred at 0–4 ꢁC. After a reaction time of
1–10 h, a new portion of toluene (7 mL) was added
and the mixture was stirred with water (10 mL). The
organic phase was washed with 10% aq hydrochloridic
acid (10 mL) twice and then with (10 mL) water. The
organic phase was dried (Na2CO3). The crude product
obtained after evaporating the solvent was purified by
preparative TLC (silica gel, hexane–ethylacetate, 10:1,
eluant) to give adduct 10a–j in a pure form.
3.2.11. (R)-3-Furan-2-yl-4-methyl-4-nitro-1-phenylpentan-
20
D
1-one, 7k. Yield: 48%; mp 79–80 ꢁC; ½aꢁ ¼ ꢀ33:3 (c 1,
CH2Cl2), 53% ee. IR (KBr), m 3447, 1681, 1596, 1539,
1450, 1397, 1380, 1346, 1231, 1149, 1016, 766, 750,
1
691 cmꢀ1; H NMR (CDCl3) d 1.57 (s, 3H), 1.67 (s,
3H), 3.05 (dd, Jgem = 17.0, 2.9 Hz, 1H), 3.69 (dd,
Jgem = 17.0, 10.8 Hz, 1H), 4.34 (dd, 1H), 6.19 (d, 1H,
furane-CH), 6.27 (t, 1H, furane-CH), 7.29 (d, 1H, fur-
ane-CH),7.44 (t, 2H, COPhH-m), 7.55 (t, 1H, COPhH-
p), 7.89 (d, 2H, COPhH-o); HRMS calcd forC16H17NO4
(M+): 287.1158, found 287.1162.
3.4.1. (2S,3R)-2,3-Epoxy-1,3-diphenyl-3-propan-1-one,
20
D
1, CH2Cl2), 82% ee; H NMR spectra see before.
10a. Yield: 47%, mp: 65–67 ꢁC; ½aꢁ ¼ þ171:4 (c
1
3.4.2. (2S,3R)-2,3-Epoxy-1-phenyl-3-(4-tolyl)-propan-1-
one, l0c. Yield: 37% (white crystals); mp 76 ꢁC (lit.29
3.2.12. 4-Methyl-4-nitro-1-phenyl-3-thiophen-2-yl-pentan-
20
D
20
77–78 ꢁC); ½aꢁ ¼ þ81:6 (c 1, CH2Cl2); 55% ee. 1H
1-one, 7l. Yield: 36%; mp 107–109 ꢁC; ½aꢁ ¼ ꢀ56:7 (c
D
1, CH2Cl2), 51% ee. IR (KBr), m 3447, 1680,1596, 1528;
NMR (CDCl3) d 2.37. (s, 3H, CH3), 4.04 (d,
1447, 1399, 1380, 1348, 1233, 848, 743, 710, 684 cmꢀ1
;
J = 1.3 Hz, 1H), 4.28 (d, J = 1.6 Hz, 1H), 7.21 (d, 2H,
CHPhH-o), 7.26 (d, 2H, CHPhH-m), 7.48 (t, 2H,
COPhH-m), 7.61 (t, 1H, COPhH-p), 8.00 (d, 2H,
COPhH-o); HRMS calcd for C16H14O2 (M+):
238.0998, found 238.0994.
1H NMR (CDCl3) d 1.60 (s, 3H), 1.71 (s, 3H), 3.18
(dd, Jgem = 17.1, 2.8 Hz, 1H), 3.63 (dd, Jgem = 17.1,
10.6 Hz, 1H), 4.54 (dd, 1H), 6.92 (m, 2H, thiophene-
CH), 7.16 (d, 1H, thiophene-CH), 7.44 (t, 2H,
COPhH-m), 7.55 (t, 1H, COPhH-p), 7.87 (d, 2H,
COPhH-o); HRMS calcd for C16H17NO3S (M+):
303.0929, found 303.0930.
3.4.3. (2S,3R)-2,3-Epoxy-1-(4-tolyl)-3-phenylpropan-1-
one, l0d. Yield: 40% (white crystals); mp 58–60 ꢁC
20
(lit.30 59–60 ꢁC); ½aꢁ ¼ þ120:4 (c 1, CH2Cl2); 61% ee;
D
3.2.13. Catalytic hydrogenation of compound 7f and
7g. A solution of chloro-compound 7f or 7g (0.3 g,
0.9 mmol), sodium acetate (0.1 g, 1.22 mmol) and 10%
Pd/C (100 mg) in methanol (5 mL) was stirred under
an atmosphere of H2 (1 atm), at room temperature for
14 h. The reaction mixture was filtered and concen-
1H NMR (CDCl3) d 2.42 (s, 3H, CH3), 4.07 (d,
J = 1.2 Hz, 1H), 4.27 (d, J = 1.7 Hz, 1H), 7.28 (d, 2H,
COPhH-m), 7.39 (m, 5H, CHPhH), 7.91 (d, 2H,
COPhH-o); HRMS calcd for C16H14O2 (M+):
238.0998, found 238.0995.
trated. The residue was purified by crystallization to
3.4.4. (2S,3R)-2,3-Epoxy-1-(4-methoxyphenyl)-3-phenyl-
propan-1-one, l0e. Yield: 37% (white crystals); mp 69–
20
D
give 7a as a solid (0.24 g, 80%); ½aꢁ ¼ ꢀ45:2 (c 1, CH2-
20
Cl2); 56% ee; mp 146–148 ꢁC {½aꢁ ¼ ꢀ80:8 (c 1,
20
D
1
73 ꢁC; ½aꢁ ¼ þ142:9 (c 1, CH2Cl2); 54% ee; H NMR
D
CH2Cl2) for pure (ꢀ)-(S) enantiomer}.4 The data are
(CDCl3) d 3.87 (s, 3H, CH3), 4.07 (d, J = 1.3 Hz, 1H),
4.25 (d, J = 1.7 Hz, 1H), 6.95 (d,2H, COPhH-m), 7.39
(m, 5H, CHPhH), 8.01 (d, 2H, COPhH-o); HRMS calcd
for C16H14O3 (M+): 254.0943, found 254.0948.
identical with those of 7a.
3.3. General procedure for Darzens condensation
A toluene solution (3 mL) of 1.3 mmol of phenacyl chlo-
ride was treated with 1.9 mmol of benzaldehyde and
0.1 mmol of catalyst in 1.0 mL of 30% NaOH solution.
The mixture was stirred under an argon atmosphere.
After completing the reaction, 7 mL of toluene was
added, the organic phase washed with water, dried over
MgSO4 and the solvent evaporated. Product 10a was
isolated by preparative TLC using CH2Cl2 as eluant.
3.4.5. (2S,3R)-2,3-Epoxy-1-(4-tolyl)-3-(4-tolyl)-propan-1-
one, 10m. Yield: 40% (white crystals); mp 97–100
20
D
ꢁC; ½aꢁ ¼ þ122:8 (c 1, CH2Cl2); 50% ee; 1H
NMR (CDCl3) d ppm: 2.37 (s, 3H, CH3), 2.42 (s, 3H,
CH3), 4.03 (d, J = 1.4 Hz, 1H), 4.27 (d, J = 1.8 Hz,
1H), 7.20 (d, 2H, CHPhH-o), 7.26 (m, 4H, PhCH),
7.91 (d, 2H, COPhH-o); HRMS calcd for C17H16O2
(M+) 252.1150, found 252.1145.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1870
10. (a) Alonso-Lopez, M.; Jimenez-Barbero, J.; Martin-
Lomas, M.; Penades, S. Tetrahedron 1988, 44, 1535; (b)
Van Maarschalkerwaart, D. A. H.; Willard, N. P.; Pandit,
U. K. Tetrahedron 1992, 48, 8825; (c) Kanakamma, P. P.;
Mani, N. S.; Maitra, U.; Nair, V. J. Chem. Soc., Perkin
Trans. 1 1995, 2339.
3.4.6. (2S,3R)-2,3-Epoxy-1-(4-chlorophenyl)-3-(4-chloro-
phenyl)-propan-1-one, l0g. Yield: 38% (yellow crys-
20
D
tals); mp 112–118 ꢁC; ½aꢁ ¼ þ124:6 (c 1, CH2Cl2);
1
64% ee; H NMR (CDCl3) d ppm: 4.09 (d, J = 1.3 Hz,
1H), 4.24 (d, J = 1.6 Hz, 1H), 7.40 (d, 2H, CHPhH-o),
7.44 (d, 2H, CHPhH-m), 7.47 (d, 2H, COPhH-o), 7.98
(d, 2H, COPhH-m); HRMS calcd for C15H10Cl2O2
(M+): 292.0058, found 292.0057.
}
11. (a) Bako, P.; Kiss, T.; Toke, L. Tetrahedron Lett. 1997, 38,
7259; (b) Bako, P.; Bajor, Z.; Toke, L. J. Chem. Soc.,
´
}
´
´
Perkin Trans. 1 1999, 3651; (c) Bako, P.; Novak, T.;
Ludanyi, K.; Pete, B.; Toke, L.; Keglevich, Gy. Tetrahe-
´
´
}
3.4.7. (2S,3R)-2,3-Epoxy-1-phenyl-3-(1-naphthyl)-propan-
dron: Asymmetry 1999, 10, 2373.
´
Gy.; Toke, L. Synlett 2001, 424.
13. Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron
1999, 55, 6375.
14. (a) Fruh, T. A. Agro. Food Ind. Hi-Tech. 1996, 7, 30; (b)
Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med.
Chem. 1999, 7, 2145.
15. (a) Banfi, S.; Colonna, S.; Molinari, H.; Julia, S.; Guixer,
J. Tetrahedron 1984, 40, 5207; (b) Adger, B. M.; Barkley,
J. V.; Bergeron, S.; Cappi, M. W.; Flowerdew, B. E.;
Jackson, M. P.; McCague, R.; Nugent, T. C.; Roberts, S.
M. J. Chem., Soc., Perkin Trans. 1 1997, 3501; For recent
review, see: (c) Pu, L. Tetrahedron: Asymmetry 1998, 9,
1457; (d) Porter, M. J.; Skidmore, J. J. Chem. Commun.
2000, 1215.
16. (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int.
Ed. 1997, 36, 1237; (b) Yamada, K.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Org. Chem. 1998, 63, 3666; (c) Watanabe,
S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. J.
Org. Chem. 1998, 63, 8090.
20
´
12. Novak, T.; Tatai, J.; Bako, P.; Czugler, M.; Keglevich,
}
1-one, l0h. Yield: 49%; ½aꢁ ¼ ꢀ46:5 (c 1, CH2Cl2),
D
42% ee; 1H NMR (CDCl3) d 4.24 (d, J = 0.6 Hz,
1H), 4.66 (d, J = 0.5 Hz, 1H), 7.41–7.48 (m, 5H,
naphthalene-CH), 7.57 (t, 2H, COPhH-m), 7.81 (d,
1H, naphthalene-CH), 7.86 (t, 1H, COPhH-p), 7.93 (d,
1H, naphthalene-CH), 8.01 (d, 2H, COPhH-o);
HRMS calcd for C19H14O2 (M+): 274.0994, found
274.0998.
3.4.8. (2S,3R)-2,3-Epoxy-1-phenyl-3-(1-pyridyl)-propan-
20
1-one, l0j. Yield: 55%; ½aꢁ ¼ þ81:0 (c 1, CH2Cl2),
D
32% ee. 1H NMR (CDCl3) d 4.23 (d, J = 0.2 Hz,
1H), 4.60 (d, J = 0,4 Hz, 1H), 7.32 (t, 1H, pyridine-
CH), 7.42 (d, 1H, pyridine-CH), 7.51 (t, 2H, COPhH-
m), 7.63 (t, 1H, pyridine-CH), 7.77 (t, I H, COPhH-p),
8.06 (d, 2H, COPhH-o), 8.65 (d, 1H, pyridine-CH);
HRMS calcd for C14H11NO2 (M+): 225.0790, found
225.0794.
17. Elston, C. L.; Jackson, R. W. F.; MacDonald, S. J. F.;
Murray, P. J. Angew. Chem., Int. Ed. 1997, 36, 410.
18. Baccin, C.; Gusso, A.; Pinna, F.; Strukul, G. Organomet-
allics 1995, 14, 1161.
19. (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1725; (b) Enders, D.; Kramps, L.; Zhu, J.
Tetrahedron: Asymmetry 1998, 9, 39597.
20. (a) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55,
6289; (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1,
1287; (c) Arai, S.; Oku, M.; Miura, M.; Shioiri, T. Synlett
1998, 1201.
Acknowledgements
This work was supported by grants T 42514 and T
42546 from Hungarian Research Foundation. The
´
authors are grateful to M. Kallay for the quantum
chemical calculations.
References
´
21. Bako, T.; Bako, P.; Keglevich, G. Y.; Bombicz, P.;
Kubinyi, M.; Pal, K.; Bodor, S.; Mako, A.; Toke, L.
´
´
}
´
1. (a) OÕ Donnell, M. I. Catalytic Asymmetric Synthesis. In
Asymmetric Phase-Transfer Reactions; Ojima, I., Ed., 2nd
ed.; VCH: New York, 2000, p 727; (b) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999, p 241.
2. Cram, D. J.; Sogah, G. D. Y. J. Am. Chem. Soc. 1985, 107,
8301.
3. (a) Stoddart, J. F. Top. Stereochem. 1987, 17, 207; (b)
Miethchen, R.; Fehring, V. Synthesis 1998, 94, and
references cited therein.
Tetrahedron: Asymmetry 2004, 15, 1589.
22. Lightner, D. A. In Circular Dichroism, Principles and
Applications; Berova, N., Nakanashi, K., Woody, R. W.,
Eds.; Wiley: New York, 2000, p 261.
23. (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785; (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
24. Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007.
25. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.;
Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.;
Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.3; Gaussian, Inc.: Pittsburgh, PA, 1998.
26. Marsman, B.; Wynberg, H. J. Org. Chem. 1979, 44,
2312.
}
´
´
4. Bako, P.; Czinege, E.; Bako, T.; Czugler, M.; Toke, L.
Tetrahedron: Asymmetry 1999, 10, 4539, and references
cited therein.
5. Itoh, T.; Shirakami, S. Heterocycles 2001, 55, 37.
}
6. Bako, P.; Toke, L. J. Inclusion Phenom. 1995, 23, 195.
7. (a) Bako, P.; Vızvardi, K.; Toppet, S.; Van de Eycken, E.;
´
´
´ ´
}
Hoornaert, G. J.; Toke, L. Tetrahedron 1998, 54, 14975;
´
(b) Bako, T.; Bako, P.; Szo¨llosy, A.; Czugler, M.;
}
Keglevich, Gy.; Toke, L. Tetrahedron: Asymmetry 2002,
´
´
}
13, 203.
8. Di Cesare, P.; Gross, B. Synth. Commun. 1979, 4581.
9. (a) Noyori, R. Asymmetric Catalysis In Organic Synthesis;
John Wiley and Sons: New York, 1994, p 241; (b) Park, Y.
S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1997,
199, 10537; (c) Krause, N.; Hoffmann-Roder, A. Synthesis
2001, 171.

´
P. Bako et al. / Tetrahedron: Asymmetry 16 (2005) 1861–1871
1871
27. Berova, N.; Nakanishi, K.. In Circular Dichroism, Prin-
ciples and Applications; Berova, N., Nakanashi, K.,
Woody, R. W., Eds.; Wiley: New York, 2000, p 337.
28. Augustyn, J. A. N.; Bezuidenhoudt, B. C. B.; Ferreira, D.
Tetrahedron 1990, 46, 2651.
29. House, H. O.; Ryerso, G. D. J. Am. Chem. Soc. 1961, 83,
979.
30. Baures, W. P.; Eggleston, D. S.; Flisak, J. R.; Gombatz,
K.; Lantos, I.; Mendelson, W.; Remfech, J. J. Tetrahedron
Lett. 1990, 31, 6501.