Theoretical study of the asymmetric phase-transfer mediated epoxidation of chalcone catalyzed by chiral crown ethers derived from monosaccharides

Article abstract of DOI:10.1016/j.molstruc.2008.05.057

The synthesis of a novel, optically active crown ether derived from α-d-altropyranoside is described. A significantly different asymmetric induction was generated by the α-d-glucopyranoside-, α-d-mannopyranoside- and α-d-altropyranoside-based chiral crown catalysts in the epoxidation of trans-chalcone with tert-butyl hydroperoxide under phase-transfer catalytic conditions. It was shown that absolute configuration of the crown-ring fused carbon atoms of the monosaccharides has a great impact on the enantioselectivity. The asymmetric induction could be well explained by considering the possible mechanistic pathway. Molecular modeling (MCMM) and subsequent DFT calculations - in accordance with the experimental results - indicate that the use of glucopyranoside-based catalyst 1 and that of mannopyranoside-based crown ether 2 results in the preferred formation of the opposite antipodes (2R,3S and 2S,3R, respectively) of the corresponding epoxyketone. At the same time, practically no asymmetric induction was proved if altropyranoside-based crown 3 is applied as the catalyst. The computational results are in qualitative agreement with the experimental data.

Full text of DOI:10.1016/j.molstruc.2008.05.057

Journal of Molecular Structure 892 (2008) 336–342
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Theoretical study of the asymmetric phase-transfer mediated epoxidation
of chalcone catalyzed by chiral crown ethers derived from monosaccharides
a
c
Attila Makó a, Dóra K. Menyhárd b, Péter Bakó a, , György Keglevich , László Toke
*
}
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, P.O. Box 91, 1521 Budapest, Hungary
b Department of General and Analytical Chemistry, Budapest University of Technology and Economics, 1521 Budapest, Hungary
c Research Group of Organic Chemical Technology of the Hungarian Academy of Sciences, 1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a novel, optically active crown ether derived from
a
-
D
-altropyranoside is described. A
-glucopyranoside-, -mannopy-
-D-altropyranoside-based chiral crown catalysts in the epoxidation of trans-chalcone with
Received 13 March 2008
Received in revised form 27 May 2008
Accepted 30 May 2008
significantly different asymmetric induction was generated by the
ranoside- and
a
-
D
a-D
a
tert-butyl hydroperoxide under phase-transfer catalytic conditions. It was shown that absolute configu-
ration of the crown-ring fused carbon atoms of the monosaccharides has a great impact on the enantiose-
lectivity. The asymmetric induction could be well explained by considering the possible mechanistic
pathway. Molecular modeling (MCMM) and subsequent DFT calculations – in accordance with the exper-
imental results – indicate that the use of glucopyranoside-based catalyst 1 and that of mannopyranoside-
based crown ether 2 results in the preferred formation of the opposite antipodes (2R,3S and 2S,3R, respec-
tively) of the corresponding epoxyketone. At the same time, practically no asymmetric induction was
proved if altropyranoside-based crown 3 is applied as the catalyst. The computational results are in qual-
itative agreement with the experimental data.
Available online 18 June 2008
Keywords:
Enantioselective synthesis
Asymmetric epoxidation
Chiral crown ether
Theoretical calculations
Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction
nary ammonium salt for the asymmetric epoxidation of various en-
one substrates [12]. The group of Jew and Park demonstrated that
The development of efficient methods for the asymmetric epox-
idation of ,b-enones is an important goal in organic synthesis
the combined use of a surfactant and a dimeric cinchona alkaloid-
derived phase-transfer catalyst enables the highly efficient and
enantioselective epoxidation of chalcone derivatives using aque-
ous hydrogen peroxide as oxidant [13].
We have recently described the asymmetric epoxidation of a
variety of chalcone derivatives using tert-butyl hydroperoxide
under phase-transfer catalytic conditions in the presence of
a
since optically active epoxyketones are among the most versatile
building blocks of several natural products and other biologically
active compounds [1]. Many asymmetric synthesis methods have
been developed to meet this purpose in the past years [2]. A variety
of the catalytic asymmetric epoxidation of electron-deficient ole-
fins, particularly
a,b-unsaturated ketones, have been published
methyl-a-
D
-glucopyranoside-anellated azacrown 1 and methyl-
a-
including the use of hydrogen peroxide in the presence of various
polyamino acids [3], cinchona alkaloids [4], chiral platinum(II)
complexes [5], alkylperoxides in conjunction with lanthanoid–
binaphthol complexes [6]. The use of chiral quaternary ammonium
salts as phase-transfer catalysts for this transformation has also
been investigated [7]. Lygo et al. performed the oxidation of chal-
cones with sodium hypochlorite in the presence of modified cin-
chona alkaloids [8], Corey reported the use of same catalysts
with potassium hypochlorite [9]. Among various organocatalysts
D
-mannopyranoside-anellated azacrown 2
catalysts (Fig. 1)
[14,15]. We wished to obtain further information on the impact of
the stereostructure of the monosaccharide moiety on the enantiose-
lectivity. For this, a new derivative, methyl-a-D-altropyranoside-
based lariat ether 3, was synthesized and tested as a chiral catalyst
in the epoxidation of chalcone.
2. Experimental
for enantioselective oxidation of trans-chalcone, L-proline and its
derivatives proved to be most attractive [10,11]. Maruoka’s group
designed a new, dual-function, and highly efficient chiral quater-
2.1. General procedures
Melting points were taken on using a Büchi 510 apparatus and
are uncorrected. The specific rotation was measured with the help
of a Perkin-Elmer 241 polarimeter at 20 °C. NMR spectra were
obtained on a Brucker 300 and a Brucker DRX-500 instrument in
* Corresponding author. Fax: +36 1 463 3648.
E-mail address: pbako@mail.bme.hu (P. Bakó).
0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.05.057

A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
337
OCH3
OCH3
OCH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R
S
S
S
S
R
N
R
N
R
N
R
O
O
O
O
O
O
2
3
1
Fig. 1. Methyl a-D-glucopyranoside- (1), methyl a-D-mannopyranoside- (2) and methyl a-D-altropyranoside-based (3) chiral crown ethers, R'CH2CH2CH2OH.
CDC13 with TMS as the internal standard. Mass spectra were regis-
trated from m-nitrobenzyl alcohol (NOBA) matrix on a Varian
MAT312 instrument. Analytical and preparative thin layer chroma-
tography was performed on silica gel plates (60 GF-254, Merck),
while column chromatography was carried out using 70–230 mesh
silica gel (Merck). Chemicals and the shift reagent Eu (hfc)3 were
purchased from Aldrich Chem. Co.
Methyl-4,6-O-benzylidene-2,3-dideoxy-a-D-altropyranosi-
do(2,3-h)-N-hydroxypropyl-1,4,7,10-tetraoxa-l3-azacyclopentade-
cane, 3. Anhydrous Na2CO3 (13.4 g, 126.4 mmol) was suspended in
a solution of the corresponding primary amine (1.44 g, 1.46 mL,
19.2 mmol) and bis-iodo compound 6 (13 g, 19.2 mmol) in dry ace-
tonitrile (260 mL) under argon. The reaction mixture was refluxed
on stirring 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 in vacuo. The residual
oil was dissolved in CHCl3, washed with water and dried (Na2SO4).
The crude monoaza-crown ether 3 (brown syrup) obtained on
evaporation was isolated by column chromatography (silica gel,
CHCl3–MeOH (100:1 ? 100:10) as the eluant). Yield: 6.5 g,
2.2. Synthesis
Methyl-4,6-O-benzylidene-2,3-bis[(2-chloroethoxy)ethyl]-a-D-
altropyranoside, 5. A solution of compound 4 (25.0 g, 88.6 mmol)
and tetrabutylammonium hydrogensulfate (23.0 g, 67.8 mmol) in
bis(2-chloroethyl)ether (170 mL, 1.45 mol) was vigorously stirred
with 50% NaOH solution (170 mL) at room temperature for 18 h.
CH2Cl2 (600 mL) and water (600 mL) were added to the reaction
mixture. The organic layer was decanted and the aqueous phase
was washed with CH2Cl2 (4 ꢀ 150 mL). The combined organic
phases were washed with water and dried (MgSO4). After re-
moval of the solvent and the excess of the bis(2-chloroeth-
yl)ether, the product was purified by column chromatography
(silica gel, CH2Cl2–MeOH (100:1 ? 100:10) as the eluant), to give
(69%); ½a 2D0
ꢁ
+ 31.5 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) d ppm:
1.67 (qn, 2H, NCH2CH2CH2), 2.58–2.67 (m, 4H, 2 NCH2), 2.82 (m,
2H, 1 NCH2), 3.40 (s, 3H, OCH3), 3.53 (t, 1H, OCH2), 3.56 (t, 2H,
OCH2), 3.58 (t, 1H, OCH2), 3.61 (t, 1H, OCH2), 3.64 (t, 2H, OCH2),
3.66 (t, 1H, OCH2), 3.70 (t, 1H, OCH2), 3.76 (t, J = 10.2 Hz, 1H, H-
6), 3.77 (t, 2H, CH2OH), 3.87 (t, 1H, OCH2), 3.90 (t, J = 5.7 Hz, 1H,
H-4), 3.92 (dd, J = 3.2 and 9.6 Hz, 1H, H-2), 3.95 (t, 2H, OCH2),
4.23 (dd, J = 5.2 and 9.9 Hz, 1H, H-5), 4.28 (dd, J = 4.4 and
9.9 Hz, 1H, H-6), 4.32 (t, J = 2.6 Hz, 1H H-3), 4.62 (s, 1H, H-1),
4.96 (bs, 1H, OH), 5.55 (s, 1H, PhCH), 7.34 (t, 2H, PhH-m), 7.35
(t, 1H, PhH-p), 7.48 (d, 2H, PhH-o); 13C NMR (75 MHz, CDCl3)
d ppm: 27.99 (NCH2CH2CH2), 53.81 (NCH2 of the macrocycle),
53.98 (NCH2 of the macrocycle), 54.70 (NCH2 of the macrocycle),
55.56 (OCH3), 58.00 (C-5), 63.37 (NCH2CH2CH2), 68.54, 68.73,
69.23 (OCH2 of the macrocycle), 70.03 (C-6), 71.35, 71.44,
72.56 (OCH2 of the macrocycle), 75.30 (C-3), 77.38 (C-4), 78.91
(C-2), 99.91 (C-1), 101.90 (PhCH), 126.07 (2 PhC-o), 128.02 (2
PhC-m), 128.73 (PhC-p), 137.82 (PhC-ipso); FAB-MS: 498
[M + H]+, 520 [M + Na]+. HRMS: m/z calcd for C25H39NO9 [M]+:
497.2625, found: 497.2629.
yellow syrup 5. (34.0 g, 78%); ½a D20
ꢁ
+ 50.2 (c 1, CHCl3); 1H NMR
(300 MHz, CDCl3) d ppm: 3.39 (s, 3H, OCH3), 3.56 (t, 2H, 2 pod-
and arm-H), 3.63 (t, 2H, 2 podand arm-H), 3.65 (t, 2H, 2 podand
arm-H), 3.67 (t, 1H, 1 podand arm-H), 3.69 (t, 2H, 2 podand arm-
H), 3.72–3.78 (m, 7H, H-6 and 6 podand arm-H), 3.82 (dd, J = 3.8
and 6.2 Hz, 1H, H-2), 3.87–3.98 (m, 3H, H-3, H-4 and 1 podand
arm-H), 4.23 (dd, J = 5.3 and 9.4 Hz, 1H, H-5), 4.29 (dd, J = 5.3
and 9.9 Hz, 1H, H-6), 4.66 (s, 1H, H-1), 5.55 (s, 1H, PhCH), 7.34
(t, 2H, PhH-m), 7.36 (t, 1H, PhH-p), 7.48 (d, 2H, PhH-o); FAB-
MS: 495 [M + 1]+, 497 [M + 1]+, 517 [M + Na]+ 519 [M + Na]+.
HRMS: m/z calcd for C22H32Cl2O8 [M]+: 494.1474, found:
494.1482.
Methyl-4,6-O-benzylidene-2,3-bis[(2-iodoethoxy)ethyl]-
a-
D-
2.3. General procedure for the epoxidation of chalcones
altropyranoside, 6. A mixture of bis-chloro derivative 5 (34.0 g,
68.7 mmol) and NaI (41.0 g, 273.3 mmol) in dry acetone (680 mL)
was stirred under reflux for 22 h. After cooling, the precipitate
was filtered off and washed with acetone. The combined acetone
solutions were evaporated in vacuum. The residue was dissolved
in CH2Cl2 (340 mL), washed with water and dried (Na2SO4). Evap-
oration of the solvent afforded the product 6 as yellow syrup (39 g,
A mixture of chalcone (1.44 mmol) and the appropriate catalyst
(0.1 mmol) in toluene (3 mL) and 20% aq. NaOH (1 mL) was treated
with 5.5 M tert-butyl hydroperoxide in decane (0.5 mL,
2.88 mmol). The mixture was stirred at 4 °C for 8 h. New portion
of toluene (7 mL) and water (10 mL) was added and the mixture
was stirred for several times. The organic phase was washed with
10% aqueous hydrochloric acid (2 ꢀ 10 mL) and then with water
(10 mL). The organic phase was dried (Na2CO3). The crude product
obtained after evaporating the solvent was purified by preparative
TLC (silica gel, hexane-ethyl acetate, 10:1 as the eluant) to give ad-
78%), which used without further purification. ½a D20
ꢁ
+ 40.2 (c 1,
CHCl3); 1H NMR (300 MHz, CDCl3) d ppm: 3.21 (t, 2H, CH2I), 3.27
(t, 2H, CH2I), 3.40 (s, 3H, OCH3), 3.64 (t, 2H, podand arm-H), 3.65
(t, 2H, podand arm-H), 3.67 (t, 1H, podand arm-H), 3.72–3.84 (m,
8H, H-2, H-6 and 6 podand arm-H), 3.88–3.99 (m, 3H, H-3, H-4
and 1 podand arm-H), 4.24 (dd, J = 5.3 and 9.5 Hz, 1H, H-5), 4.30
(dd, J = 5.3 and 9.6 Hz, 1H, H-6), 4.66 (s, 1H, H-1), 5.55 (s, 1H,
PhCH), 7.35 (t, 2H, PhH-m), 7.37 (t, 1H, PhH-p), 7.47 (d, 2H, PhH-
o); FAB-MS: 679 [M + 1]+, 701 [M + Na]+. HRMS: m/z calcd for
C22H32I2O8 [M]+: 678.0187; found: 678. 0194.
duct in a pure form. In the case of catalyst 1 is the yield 82%; ½a D20
ꢁ
ꢂ196 (c l, CH2Cl2), 94% ee for (2R,3S) enantiomer [14]; M.p.: 64–
66 °C; 1H NMR (300 MHz, CDCl3): d = 8.02 (d, 2H, COPhH-o), 7.63
(t, 1H, COPhH-p), 7.50 (t, 2H, COPhH-m), 7.38–7.44 (m, 5H), 4.30
(d, J = 1.9 Hz, 1H, CH), 4.09 (d, J = 1.9 Hz, 1H, CH). HRMS: m/z calcd
for C15H12O2 [M]+: 224.0837; found: 224.0830.

338
A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
2.4. Molecular modeling
The vicinal hydroxy groups of the altropyranoside derivative 4
were alkylated with bis(2-chloroethyl)ether in the presence of tet-
rabutylammonium hydrogensulfate and 50% aq. NaOH in a liquid–
liquid two-phase system to give bis-chloro-intermediate 5 after
purification by chromatography (Scheme 1). The exchange of chlo-
rine to iodine in 5 was accomplished by NaI in acetone, at the boil-
ing point resulting in the formation of bis-iodo derivative 6.
Compound 6 was then cyclized with aminopropanol in boiling ace-
tonitrile, in the presence of dry sodium carbonate yielding aza-
crown ether 3. (In our earlier studies, the lariat ethers with
hydroxypropyl substituent on the N-atom proved to be the most
efficient enantioselective catalysts in certain model reactions)
[14]. This protocol is the extension of our previously described
method [21]. After purification by column chromatography, the
15-membered chiral macrocycle 3 was obtained in a yield of 69%
(Scheme 1). The formation of unidentified byproducts decreased
the efficiency. All intermediates and the new product were charac-
terized by 1H–13C NMR and mass spectroscopy.
Molecular modeling and subsequent DFT calculations were car-
ried out to study the azacrown systems. MCMM (Monte-Carlo Mul-
tiple Minimum) search [16] – as implemented in macro model [17]
– involved the random variation (within the range of 0–180°) of a
randomly selected subset of all torsional angles (a minimum of 2
and a maximum of 32), combined with the variable molecules
selection (MOLS) method for translations and rotations of the com-
plexing ion and transition state model of chalcone with respect to
the crown. The combined MCMM/MOLS procedure allowed ran-
dom translation (0–3 Å) and rotation (0–180°) during a Monte-Car-
lo step. Calculations typically consisted of 30,000–100,000 steps.
The perturbed structures were minimized using the LBFGS (Low-
memory Broyden–Fletcher–Goldfarb–Shanno) algorithm. The
resulting minimum energy complex structures were sorted by en-
ergy, unique structures within a 50 kJ/mol energy window above
the global minimum were stored.
Calculations were carried out using the OPLSAA force field. Sol-
vent - effects were modeled by the GB/SA algorithm (using chloro-
form as solvent) [18]. Atomic charges were calculated by the ESP
method [19] from B3LYP/6-31G**, SCRF solvated wave functions
of the non-interacting partners of the complex (the independent
crown system and the model of the transition state of chalcone)
using Jaguar (Jaguar, Version 4.1, Schrödinger, Inc., Portland, OR.).
In using such a charge set, our goal was to avoid introducing bias
through a priori supposed charge transfer unintentionally occur-
ring when deriving charges from the charge distribution of a hypo-
thetical complexed state. Final conformation and energy ordering
of the complex structures were obtained by DFT gas phase optimi-
zation (B3LYP/6-31G**) and Poisson–Boltzmann solvation (in ben-
zene) of the low-energy conformers of the force field calculations
(typically 5–10 low-energy conformers were re-optimized with
the DFT method). Host rms values were calculated to describe like-
ness of the structures using all non-hydrogen atoms of the crown
molecules, except those of the phenyl substituent, which was rep-
resented only by a centroid (to avoid artifacts arising from the
practically barrier-less flip of this ring). Heteroatoms were said to
be coordinating the cation if they reached within 2.8 Å of it.
Lariat ether 3 was used as the catalyst in the epoxidation of
trans-chalcone 7 under similar conditions applied in the test reac-
tions with crown ethers 1 and 2. The epoxidation of chalcone 7 was
carried out with tert-butyl hydroperoxide (TBHP, 2 equiv.) at 5 °C,
in toluene, in a liquid–liquid two-phase system, employing 20%
aqueous NaOH (3.5 equiv.) as the base and 7 mol% of the altropy-
ranoside-based lariat ether 3 (Scheme 2). The crown ether incorpo-
rating an altropyranoside unit (3) acted as a phase-transfer
catalyst, its asymmetric induction was, however, negligible as the
(ꢂ)-(2R,3S) trans-epoxyketone 8 was formed in only 3% ee. Practi-
cally, 8 was obtained in a racemic form. This observation is note-
worthy, as in earlier experiments the use of glucopyranoside-
based crown 1 (R'(CH2)3OH) led to the (ꢂ)-(2R,3S) formation of
epoxyketone 8 in 92% ee. [14]; at the same time, the use of manno-
pyranoside-based lariat ether 2 (R'(CH2)3OH) resulted in the for-
mation of the other, (+)-(2S,3R) antipode of 8 in 82% ee. [15]. These
results are summarized in Table 1.
It is wroth of mentioning that the crown ethers under discus-
sion are of similar structure, only the configuration at C-2 and
C-3 is different: in the
a-D-glucopyranoside, a-D-mannopyranoside
and -altropyranoside-units, the C-centers mentioned can be
a-D
O
O
H
3. Results
O
catalyst
t-BuOOH
∗
∗
3.1. Synthesis
H
toluene
aq. 20 % NaOH
The starting material was methyl-4,6-O-benzylidene-
pyranoside 4 which has been synthesised from methyl-4,6-O-ben-
a-D-altro-
8
7
zylidene-
a-
D-glucopyranoside in three steps [20].
Scheme 2.
OCH3
OR1
OCH3
O
O
O
O
O
I
I
H2N(CH2)3OH
O
OR1
3
O
O
O
O
6
4 R1 = H
i
5 R1 = (CH2)2O(CH2)2Cl
6 R1 = (CH2)2O(CH2)2I
ii
Scheme 1.

A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
339
atom. . .Na+ distance will be of 2.5 Å. The mannopyranoside-based
crown–Na+ complex is bent, the carbohydrate segment forms an
approximately 60° angle with the crown plane. Here the lariat
arm also reaches to the cation, bending over the crown. The Olar-
iat. . .Na+ and the average crown-heteroatom. . .Na+ distances are
quite similar to those seen in the glucopyranoside system. On the
Table 1
Effect of chiral crown catalysts 1–3 on the asymmetric epoxidation of chalcone by
tert-BuOOH, at 5 °C
a 2D0
ꢁ
Ee (%)c
Abs. configuration of 8
b
Crown catalyst
Yield (%)a
½
1
2
3
82
67
51
ꢂ196
94
82
3
2R,3S
2S,3R
2R,3S
+171
ꢂ5.0
other hand, among the low-energy conformers of a-D-altropyrano-
side-crown–Na+, two different arrangements can be found, both
are distinctly different form those of gluco- and mannopyranoside.
In one of the conformers, the Olariat. . .Na+ and the average crown-
heteroatom. . .Na+ distances are both 2.5 Å, however, the altropy-
ranoside ring is in a twisted boat conformation. This is not wholly
unexpected, since altropyranoside both in the solid [22] and solu-
tion phase [23], in itself, or as a member of the macromolecule [24]
has been seen to easily undergo such rearrangement. The topogra-
phy of the other low-energy conformer, where the chair conforma-
tion is retained, is very much like a cradle. The O-methyl group of
the sugar unit and the lariat arm form the handles of the cradle
with the Na+ cation complexed by them, well removed from the
crown-ring heteroatoms. The average crown-heteroatom. . .Na+
distance is 3.7 Å, with only two crown oxygen atoms participating
in the coordination of Na+. However, both the lariat ether oxygen
atom and the oxygen of the methoxy group coordinated by the cat-
ion with distances of 2.5 Å and 2.4 Å, respectively.
a
Based on isolation by preparative TLC.
In CH2Cl2.
b
c
Determined by 1H NMR spectroscopy in the presence of chiral shift reagent.
described as 2R,3S, 2S,3S and 2S,3R, respectively (Fig. 1). The
impact of the catalysts on the chiral induction was still quite differ-
ent. To explain these phenomena, we decided to study the role of
the lariat ethers applied in the epoxidation. First, a theoretical
hypothesis was elaborated, then molecular modeling and DFT
calculations were carried out.
4. Calculations
To better understand the structural reason of chiral catalysis,
calculations were carried out for each crown host complexing the
sodium cation together with the guest anion, modeling the epoxi-
dation reaction of chalcone with tert-butyl hydroperoxide. Enanti-
oselectivity was approximated by the relative stability of the
product of the putative first step of the epoxidation reaction, in
which the tert-BuOOꢂ anion accompanied by the crown-com-
plexed sodium cation attacks the electron-deficient alkene at C-3
(3-tert-butylperoxy derivative) – giving a possible transition state
of the mechanism. The precursor structures of both chiral products
were complexed with each crown host and after an extensive con-
formational analysis the obtained minimum energy representative
of the states was compared, keeping in mind that besids the rela-
tive thermodynamic stability of the antipodes, several other factors
also influence the enantioselectivity in these complex systems
(Table 2, Fig. 2).
We found that the pyranoside-based crown systems in the com-
plex with Na+ adopt a characteristic conformation that is only
moderately altered by complexation of the ligand molecule. In
complex with Na+, the glucopyranoside crown system is elongated
with the glucopyranoside segment lying within the plane defined
by the crown, while the lariat ether substituent bends over the
crown, on the opposite side from the O-methyl group. The confor-
mation in which the lariat ether reaches the Na+ cation from the
side occupied also by the O-methyl group, results in an excess of
1.3 kJ/mol. The lariat ether oxygen takes part in the coordination
of Na+, in fact, the cation is shifted by approximately 1 Å out of
the crown plane to make a strong contact with it (Na+. . .Olariat dis-
tance: 2.3 Å). With the shift, the resultant average crown-hetero-
Since the study of enantioselectivity was our goal, precursor
structures corresponding to both possible chiral products (both R
and S 3-(tert-butylperoxy) derivatives of chalcone) were built and
complexed with the crown molecules in the presence of Na+. In
these terner complex structures (of host, cation and peroxidated
guest molecule), besides the lariat ether, the chalcone carbonyl
group also associates to the positive charge of the Na+ ion (Fig. 2).
In case of the glucopyranoside-based host, the peroxo-bound
chalcone molecule, as well as the lariat ether chain, were found
on the more spacious side of the crown, as expected, opposite that
of the O-methyl group. We found that the total energy of the com-
plex formed with 3R-(tert-butylperoxy)-chalcone (3R complex,
Fig. 2a), precursor of the expected (2R,3S)-epoxyketone product
[14], is 12.5 kJ/mol more favourable than that of 3S-(tert-butylper-
oxy)-chalcone (3S complex, Fig. 2b). In both structures, both the
chalcone carbonyl and the lariat ether oxygen are bound to the
Na+ cation. Also, in both structures, the lariat ether oxygen forms
a strong and specific H-bond with the distant oxygen of the peroxo
moiety. Since the host conformation is nearly identical in the two
structures (with a 0.15 Å rms deviation), the source of energy dif-
ference lies in the effectiveness of the previously described interac-
tions. Although in the 3S complex the chalcone carbonyl reaches
closer to the cation (2.45 Å and 2.62 Å, in the 3S and 3R complex,
respectively), the corresponding upward shift of Na+ disfavours
all of its other interactions. In the 3R complex, the average
crown-heteroatom. . .Na+ distance and the coordination distance
Table 2
Comprehensive data of selected geometrical features of the calculated transition state analogue structures and of ee
Complex
Relative energy (kJ/mol)
Distances (Å)
Ee (%)
Average Crown-heteroatom – Na+
Lariat-ether – Na+
Chalcone carbonyl oxygen –Na+
Olariat. . .Operoxo
O1a
O2b
Glucose 3R
Glucose 3S
Mannose 3R
Mannose 3S
Altrose 3R
Altrose 3S
0
2.51
2.55
2.59
2.55
3.59
2.68
2.31
2.39
2.35
2.33
2.31
2.33
2.62
2.45
2.45
2.73
2.25
2.42
3.36
3.65
3.46
3.32
3.28
3.36
2.84
2.85
2.80
2.85
2.86
2.85
94 (2R,3S)
82 (2S,3R)
3 (2R,3S)
12.5
19.0
14.6
44.5
45.0
a
O adjacent to chalcone.
O adjacent to tert-butyl group.
b

340
A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
Fig. 2. Lowest energy conformations obtained for the six different azacrown-cation-3-(tert-butyl-peroxy)-chalcone terner complexes. The structures were superimposed, so
the carbohydrate parts of the respective molecules were overlaid – and are shown in the same setting.
of the lariat oxygen are more favourable (2.51 Å and 2.31 Å in the
3R, while 2.55 Å and 2.39 Å in the 3S complex, respectively). The
most striking difference between the two structures is that while
in the 3R complex nearly both peroxo-oxygens are close enough
to the oxygen of the side arm for an H-bond interaction (2.84 Å
and 3.36 Å), in the 3S complex only one (2.85 Å and 3.65 Å).
In case of the mannopyranoside crown system, the situation is
quite similar, with a considerably smaller energy difference and a
reversed preference. The host conformation of the 3R and 3S com-
plexes is quite similar again with an rms of 0.27 Å, while here the
3S complex, precursor of the (2S,3R)-epoxyketone product, proved
to be more stable by 4.4 kJ/mol (Fig. 2c and d). The complexes are
less tightly bound than those of glucopyranose, but the same ten-
dencies can be recognized. In the favoured 3S complex, the average
crown-heteroatom. . .Na+ distance and the coordination distance of
the side arm oxygen is shorter than that in the 3R complex (2.55 Å
and 2.33 Å in the 3S, while 2.59 Å and 2.35 Å in the 3R complex,
respectively), while the carbonyl oxygen of chalcone-derivative is
closer to the cation in the 3R complex (2.73 Å and 2.45 Å in the
3S and 3R complex, respectively). Ligation of the peroxo-oxygens
of chalcone-intermediate anion by the lariat ether is, again, asym-
metric – the oxygen adjacent to the tert-butyl group is held by a
strong H-bond in both structures (of 2.85 Å and 2.80 Å Olariat. . .
Operoxo distance in the 3S and 3R complex, respectively), while
the other peroxo-oxygen in the 3S complex is within H-bonding
distance (3.32 Å) and in the 3R complex it is not (3.46 Å).
The altropyranoside-based crown system formed two structur-
ally distinct complexes with the two different chalcone
derivatives, with an rms of 2.14 Å for the crown atoms – corre-
sponding to the two low-energy conformers of the Na+ complex
(Fig. 2e and f), In the 3S complex, the cation is coordinated by
all the five crown-heteroatoms (with an average distance of
2.68 Å), the oxygen of the side arm (at 2.33 Å) and the carbonyl
of the chalcone derivative (at 2.42 Å) – however, the altropyra-
nose ring is in a twisted boat conformation. The 3R complex, on
the other hand, retains the chair conformation of the altropyra-
nose ring, which results in the cradle-like arrangement described
above. Only two crown oxygens participate in Na+ coordination
resulting in a quite high, average crown-heteroatom–cation dis-
tance of 3.59 Å. However both the methoxy oxygen and the lariat
ether form strong bonds with Na+ (at distances of 2.38 Å and
2.31 Å, respectively). H-bonding to the peroxo-segment of the
chalcone-anion by the lariat ether side arm is achieved in both
structures with quite similar effectiveness – strong H-bond was
formed with the oxygen adjacent to the tert-butyl group (with
distances of 2.85 Å and 2.86 Å, in the 3S and 3R complexes,
respectively), while the other peroxo-oxygen can be found at dis-
tances alike (at 3.36 Å and 3.28 Å, in the 3S and 3R complexes,
respectively). It was quite interesting to see that despite all the
structural dissimilarities, the energy of the 3S and 3R complexes
of altropyranose is very close to each other, the 3R complex being
only 0.5 kJ/mol more favourable than that of the 3S.

A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
341
The relative energies of the three different crown systems were
found to be of the expected ordering too. The 3R complex of the
glucopyranoside crown system is 14.6 kJ/mol more favourable
then the 3S complex of mannopyranose and by a formidable
44.5 kJ/mol more favourable than the 3R complex of altropyranose.
to a similar chain of thoughts, the anion accompanying the com-
plex formed from the -mannopyranoside-based crown ether 2
a
-D
may attack the chalcone from the Si face to result in the formation
of 3S intermediate to give the 2S,3R antipode after ring closure
(Scheme 3B). To justify the above speculation, we wished to prove
that applying the glucopyranoside-based catalyst, the ‘‘3R interme-
diate” is the more stable, while in the case of the use of mannopy-
ranoside-based catalyst, the ‘‘3S intermediate” is the more
favourable. Furthermore, we wished to get an answer, as to why
the crown ether incorporating an altropyranoside moiety is unable
to generate a significant asymmetric induction in the studied mod-
el reaction.
Over the past years, it has been demonstrated that the spectral
and geometrical features of crown systems, as well as their cation-
and enantioselectivity, can be well described by the B3LYP DFT
method [25,26]. Here we were also successful in reproducing
experimental findings. Results are in accordance with the glucopy-
ranoside-based crown being the most enantioselective catalyst of
the epoxidation reaction of chalcone with tert-butyl-hydroperox-
ide favouring the formation of the expected (2R,3S)-epoxyketone,
the mannopyranose-based crown being less effective and favour-
ing the formation of (3R,2S) product, while the altropyanose-based
crown not being an enantioselective catalyst. The presence of a pi-
vot N-atom along the oxygens of arylazacrown ethers, especially in
the presence of mono-cations, has been shown to result in great
flexibility [26]. We also found that the three different azacrowns
showed great pliability among them, however, each (gluco-, man-
no- or altropyranoside-based) characteristic host conformation
was already reached when complexing the cation, the chalcone
molecule associated to this pre-formed arrangement without caus-
ing major rearrangement of it. We found that the other key deter-
minant of conformation in these systems is the presence of the
5. Discussion
The mechanism proposed for the catalytic asymmetric epoxida-
tion of chalcone 7 involving a crown ether–NaOOBut complex is
shown in Scheme 3. In the first step, the lariat ether transfers the
sodium cation accompanied by the hydroxy anion into the organic
phase, where the (crown–Na+)–tert-BuOOꢂ complex is formed that
is an optically active oxidant. This is followed by the conjugate
nucleophilic addition of the tert-butylperoxide anion at the end
of the
a,b-electron, poor double bond of the chalcone to afford a
chiral enolate intermediate. This intermediate then loses a tert-
BuOꢂ unit and undergoes cyclization as an intramolecular stabil-
ization step to furnish the epoxyketone (Scheme 3), which, in turn,
dissociates from the sphere of the crown–Na+ complex. Assuming
that the conjugate addition of the peroxy-anion on the
>C'CHAC'O moiety is the rate- and stereoselectivity-determin-
ing step, the approach of the reaction center by the nucleophile
determines the configuration of the new stereogenic center. The
predominant way will lead to the antipode formed in excess. Our
experiments showed that the configuration of C-2 and C-3 of the
monosaccharide unit of the lariat ether is decisive regarding the fi-
nal outcome. It was assumed that the
a-D-glucopyranoside-based
crown ether 1 may form such a complex with sodium tert-butyl-
peroxide that gives the 3R intermediate by attacking the chalcone
from the Re side. The 2R,3S antipode is the final result of the ring
closure according to the C.I.P. convention (Scheme 3A). According
O
O
Si
Re
O
O
O
O
OMe
O
OMe
O
Na
O
O
O
O
Na
O
O
O
O
N
O
N
O
O
O
O
O
2
1
O
O
O
O
O
O
H
O
H
O
O
O
3S intermediates
3R intermediates
H
O
H
O
O
O
NaOBut-crown
S
NaOBut-crown
R
R
S
H
H
(-)-2R,3S enantiomer
(+)-2S,3R enantiomer
A
B
Scheme 3. Proposed mechanism for the epoxidation of chalcone catalyzed by
a-
D-glucopyranoside-based (A) and a-D-mannopyranoside-based (B) chiral crown ethers.

342
A. Makó et al. / Journal of Molecular Structure 892 (2008) 336–342
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In this paper we have presented experimental results demon-
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azacrown ethers the configuration of the sugar unit annealed to
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Acknowledgements
The authors are grateful for the OTKA support of this research
(Grant No. T 42514), Dóra K. Menyhárd is a Bolyai research fellow
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