Asymmetric C-C bond forming reactions with chiral crown catalysts derived from D-glucose and D-galactose

Article abstract of DOI:10.1016/S0957-4166(99)00485-1

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O- benzylidene-α-D-glucopyranoside 2a, 2e, 2g-i and to methyl-4,6-O- benzylidene-α-D-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric ind

Full text of DOI:10.1016/S0957-4166(99)00485-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4539–4551
Asymmetric C–C bond forming reactions with chiral crown
catalysts derived from D-glucose and D-galactose
Péter Bakó,a Erzsébet Czinege,a Tibor Bakó,a Mátyás Czugler b and László To˝ke c,∗
aDepartment of Organic Chemical Technology, Technical University of Budapest, H-1521 Budapest, PO Box 91, Hungary
bCentral Research Institute of Chemistry for Hungarian Academy of Sciences, H-1525 Budapest, Hungary
cResearch Group of the Hungarian Academy of Sciences at the Department of Organic Chemical Technology,
Technical University of Budapest, H-1521 Budapest, PO Box 91, Hungary
Received 20 October 1999; accepted 2 November 1999
Abstract
New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-D-glucopyranoside 2a,
2e, 2g–i and to methyl-4,6-O-benzylidene-α-D-galactopyranoside 3a, 3e, 3i have been synthesized. These
crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-
nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee)
and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-
epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14
have also been determined by X-ray diffraction. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Phase-transfer catalysis has been recognized as a practical methodology for organic synthesis due to
its operational simplicity, mild reaction conditions, safety considerations, and environmental concerns.
In addition, the development of novel phase-transfer catalyzed asymmetric reactions is of considerable
industrial interest. One of the most up-to-date and interesting techniques of catalytic asymmetric
synthesis is a phase-transfer reaction in which the enantioselectivity is generated by a chiral crown-
ether catalyst.1 A special group of optically active crown ethers are compounds whose carbohydrate
moieties function as carriers of chirality. In the past two decades numerous macrocycles built up of
one or more monosaccaride units have been synthesized.2 Cheap natural sugars are attractive starting
materials for organic syntheses. However, so far, only a limited number of asymmetric reactions have
been demonstrated in which a sugar-based crown-ether catalyst produced a good enantiomeric excess.1
∗
Corresponding author. E-mail: toke.oct@chem.bme.hu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00485-1
tetasy 3121

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A synthesis of a new monoaza-15-crown-5 type macrocycle, containing D-glucopyranoside- and D-
galactopyranoside units, respectively, has been recently reported.3 Until now we have carefully examined
two important reaction types, the Michael addition to an electrophilic double bond and the Darzens
condensation, in which these crown ethers proved to be effective catalysts.4 It was shown that the
flexibility of the chiral macrocycle, the type of carbohydrate building blocks, the type of the substituents
in the carbohydrate unit and at the nitrogen atom of the macrocycle play the most important roles in the
generation of asymmetric induction. Furthermore, the so-called lariat ethers, in which the N-substituent
contains an electron donating heteroatom (O, P) in the proper place, have also been studied.5
In the present paper, the synthesis of the crown ethers, the study of relationships between the catalysts’
structure and their effect in the above mentioned reactions is disclosed with a more detailed experimental.
Also included are experiments on the self-condensation of the phenacyl chloride reagent giving Darzens
type products in a diastereoselective and enantioselective process.
2. Results and discussion
2.1. Synthesis
The new 15-crown-5 type compounds incorporating methyl-4,6-O-benzylidene-α-D-glucopyranoside
and galactopyranoside as well as a nitrogen atom in the macrocycle, 2 and 3, respectively, were
synthesized using the same route as described by us previously.3 The glucopyranoside based bis-iodo
compound 1a was cyclized with various primary amines, such as n-butylamine, 2-phenylethylamine, 3-
hydroxypropylamine, 4-hydroxybutylamine and 2-methoxyethylamine (Scheme 1). The method requires
dry sodium carbonate in acetonitrile solvent (reflux, 24–48 h). In dilute solutions (1–3%) polycon-
densation side reactions are suppressed and the desired intramolecular cyclization reaction takes place
preferentially. After the usual work-up procedure and chromatographic purification, macrocycles 2a–i
were obtained in 44–64% yields. By the same method 3a, 3e monoaza-crown ethers and 3i lariat
ether were synthesized in 49–75% yields, starting from galactose-based bis-iodo compound 1b and the
corresponding primary amines. The structures of the ligands were confirmed via the analysis of their
respective 1H NMR, 13C NMR spectra and by CIMS and FABMS. The [M+H]+ fragment was present in
all cases in the CIMS and FABMS spectra, the most intense in the CIMS spectra being m/z 452 fragment
characteristic of the [crown-N-CH2]+ ion (see Experimental).
Scheme 1. Cyclization with amines. Glucose-based 2 and galactose-based crown ether 3. Reagents and conditions: (i) CH3CN,
reflux, 28–36 h, RNH2, R=butyl 2a, 3a, 2-phenylethyl 2e, 3e, 3-hydroxypropyl 2g, 4-hydroxybutyl 2h, 2-methoxyethyl 2i, 3i

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
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2.2. Asymmetric induction in Michael additions
The Michael addition of carbon nucleophiles to conjugated enones is one of the most powerful
methods for carbon–carbon bond formation. Due to its relevance in the synthesis of biologically active
compounds, much effort has been centered on carrying out this reaction in a stereoselective way.6a The
stereoselective variants of the addition of enolates or their analogues to the carbon–carbon double bond
of the α,β-unsaturated ketones or aldehydes have been extensively investigated in recent years.6b,c To the
best of our knowledge, only one reaction is known in which significant asymmetric induction has been
achieved with sugar-based crown-ether catalysts, and that is the Michael addition of methylphenylacetate
to methylacrylate.7 Now we describe our results with another Michael reaction, in which the new catalysts
are also effective: the Michael addition of 2-nitropropane 5 to the chalcone 4 that was performed with
60–82% enantiomeric excess in a solid–liquid phase-transfer system4 (Scheme 2). The addition was
carried out in dry toluene, in the presence of a chiral catalyst (5 mol%) and solid sodium tertiary butoxide
as base (35 mol%) at room temperature. After the usual work-up procedure, the adduct 6 was isolated
by preparative TLC; the enantiomeric excess (ee%), was monitored by measuring the optical rotation
of the product 6 and comparing the specifications with literature data for the preferred pure enantiomer
1
and by H NMR spectroscopy using (+)-Eu(hfc)3 as a chiral shift reagent. For comparison purposes,
our earlier results4a,b with 2b–d and 2f are also incorporated in Table 1. The results show that the type
of the monosaccharide and the substituent at the nitrogen atom of the catalyst have the most significant
influence on both the chemical yield and the enantiomeric excess.
Table 1
Addition of 2-nitropropane to chalcone catalyzed by chiral crown ethersa

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Scheme 2. Michael addition of 2-nitropropane to chalcone. Reagents and conditions: (i) catalyst 2 or 3, NaOBut, toluene, 20°C
Among the glucopyranose derivatives 2a–i it was the crown 2c (phenyl group at the nitrogen) which
gave the worst result (21% chemical yield, 10% ee). The catalytic effect was better with N-cyclohexyl
and N-benzyl derivatives (2b, 47% ee; 2d, 46% ee), and further increased with N-butyl (2a, 58% ee),
and N-phenylethyl derivatives (2e, 61% ee). When the side arm cooperation in the complexation could
operate (lariat ethers) again an increase in the ee value was detected: in the case of the N-2-hydroxyethyl
derivative 2f it was 62%, with the N-3-hydroxypropyl crown 2g the ee value was 85%. However, further
increase in the chain length did not increase the ee% value (2h has 85% ee). Interestingly we observed that
the 2i methylether derivative induced a higher enantioselectivity (87% ee) than its analogue containing
a free hydroxyl group (61% ee). It can be seen that the chain length of the substituents is of crucial
importance. In the case of the galactopyranose derivatives 3a, 3e, and 3i the ee% observed were lower
than those for the corresponding 2a, 2e, and 2i (Table 1) in spite of the fact that the stability constants of
the galactose containing crown ethers with sodium ion were found to be higher than those for the glucose
derivatives.3
2.3. Darzens condensation
The Darzens reaction, which allows the generation of new stereocenters with complete diastereocon-
trol, is one of the most powerful methodologies for the synthesis of α,β-epoxy carbonyl and related
compounds, and therefore has been recognized as one of most significant C–C bond forming processes
in synthetic organic chemistry. Although many trials have been performed aimed at developing an
asymmetric variant of the section in recent decades, many of them require a stoichiometric amount of
a chiral source8 and only a few examples which proceed catalytically are known.9 The special attention
paid to the Darzens reactions is justified by their pharmaceutical significance, e.g.: diltiazem is a widely
prescribed cardiovascular drug.10
As already described in our preliminary report,4a the previously discussed chiral crown ethers proved
to be effective asymmetric catalysts in the condensation of phenacyl chloride 7 with benzaldehyde 8a
(Scheme 3). This reaction was studied by many researchers, and in the presence of one of the most
frequently used chiral phase-transfer catalysts benzyl quininium chloride 8% ee was achieved,9a while
N-(4-trifluoromethylbenzyl)cinchoninium bromide resulted in 42% ee.9d
We performed the above reaction in both a liquid–liquid (LL) and solid–liquid (SL) system. Since
our catalysts were more effective in LL phase-transfer conditions, this technique was studied thoroughly.
Solvent, base, reaction time and temperature were varied until optimal reaction conditions were establish-
ed. Reagents and the catalyst (5 mol%) were dissolved in toluene and reaction was initiated by adding
30% sodium hydroxide (volume ratio: 3:1, reaction time: 1–4 h). Following the usual work-up procedure,
the pure epoxy ketone was separated by preparative TLC. The diastereomeric ratio of the product was
1
determined by H NMR spectroscopy, enantiomeric excess (ee%) by rotatory power measurements or
by 1H NMR in the presence of a chiral shift reagent. In each case the trans-epoxy ketone 9 was formed
(de >98%) and its levorotatory enantiomer was found to be in excess. This corresponds to an absolute
configuration of 2R,3S.11 The most important results and reaction conditions are shown in Table 2. From

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
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Scheme 3. Darzens condensation of phenacylchloride with benzaldehyde. Reagents and conditions: (i) crown-ether catalyst,
30% NaOH, toluene
Table 2
Asymmetric Darzens condensation of phenacyl chloride with benzaldehyde in the presence of chiral
crown ethersa
Table 2 it is obvious that, concerning asymmetric induction, the worst catalysts are 2c (N-phenyl, 4%
ee) and 2d (N-benzyl, 13% ee). The compounds 2a and 2e possessing butyl and 2-phenylethyl side
arms, respectively, were somewhat better catalysts (21% ee and 31% ee, respectively). The effect of the
terminal hydroxyl groups was advantageous: 42% ee was achieved with 2-hydroxyethyl containing 2f,
and 62% ee with 3-hydroxypropyl substituted 2g. However, further increases in chain length did not
result in higher ees: in the presence of catalyst 2h containing 4-hydroxybutyl substituent, the ee value
of the epoxy ketone 9 dropped to 26%, there is an optimum in the chain length of the N-substituent.

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The hydrophilic terminal group was found to have an important role in the toluene–water phase-transfer
system: the free OH-group at the end of the substituent significantly decreased the catalytic effect, e.g.
2i methylether derivative resulted in only 19% ee. Furthermore, from Table 2 it is obvious (entries 5–7
and 8–9) that a drop in the temperature increased the enantioselectivity: e.g. at room temperature with
crown ether 2f 42% ee was achieved, compared to 64% ee at −20°C. Maximum enantioselectivity (71%
ee) was achieved with catalyst 2g (having a 3-hydroxypropyl side arm) at −20°C. At temperatures lower
than −20°C the reaction mixture solidified. An experiment carried out in a SL system (Table 2, entry 12),
in the presence of NaOBut base, 2f (possessing a 2-hydroxyethyl side arm) gave 39% ee.
We were also studying the Darzens condensation of phenacyl chloride with various substituted
benzaldehydes under the same reaction conditions as previously described. Results of the reactions
performed with catalyst 2g at ambient temperature are summarized in Table 3. Reactions below room
temperature could not be performed due to solubility problems. In the reaction with o-nitro-benzaldehyde
(entry 1) the best chemical yield (71%) was obtained along with the lowest enantioselectivity (29%
ee). One possible explanation is that the presence of an electron attracting group near the reaction
center is advantageous regarding the chemical reaction itself, but its steric position is disadvantageous
regarding the formation of a stereogenic carbon atom. Furthermore, it was observed that in the case
of benzaldehydes with para electron attracting substituents the corresponding epoxy ketones12 were
obtained with approximately the same enantiomeric excess (p-NO2 11 61% ee and p-Cl 12 59% ee)
as in the case of the unsubstituted benzaldehyde (62% ee). A methoxy group in the para position
drastically decreased both the chemical yield (31%) and the enantioselectivity (12% ee). After repeated
crystallization we managed to obtain pure levorotatory enantiomers of trans-p-NO2 substituted 11 and
trans-p-Cl substituted 12 epoxy ketones, and their specific rotatory power was determined. Their absolute
configuration has not been studied so far, and is only assumed to be 2R,3S.13 We have succeeded in
obtaining a single crystal from the pure levorotatory enantiomer of trans-p-Cl substituted 12 epoxy
ketone, and the subsequent X-ray studies (Fig. 1) confirmed its absolute configuration as 2R,3S.
Table 3
Asymmetric Darzens condensation of phenacyl chloride with substituted benzaldehyde in the presence
of catalyst 2ga
Scheme 4 describes a possible reaction path for the mechanism. Under the influence of the crown
ether the sodium enolate gets solubilized in toluene thereby ensuring the chiral environment for the next
step, in which the Si face of the enolate attacks the Re face of the aldehyde. The stereochemistry of the
reaction is probably decided in this first, possibly slowest step, in which an intermediate with the 2S,3S

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
4545
Fig. 1. Molecular structure of 12 with atomic labeling used in the X-ray analysis
configuration is formed. Following this, the configuration at C-2 is inverted to R by an SiN process, thus
giving the end-product with 2R,3S stereochemistry.
Scheme 4. Presumed reaction mechanism of the enantioselective Darzens condensation
2.4. Self-condensation of phenacyl chloride
During analysis of the by-products of the Darzens condensation, we have isolated an optically active
by-product, which was found to be the base initiated self-condensation product of phenacyl chloride:
4-chloro-2,3-epoxy-1,3-diphenyl-butan-1-one (Scheme 5). This product has already been reported as a
mixture of the racemic diastereomers.14,15 The self-condensation of phenacyl chloride was then studied
under the previously described conditions (toluene, 30% sodium hydroxide) in the presence of 2g
1
sugar-based crown-ether catalyst. By H NMR spectroscopy we have shown that the ratio of cis:trans
isomers was 23:77 in the condensation product, and these isomers were chromatographically separated.
It was found that in the trans isomer the levorotatory enantiomer was in excess (64% ee). By repeated
crystallization we have managed to isolate the pure levorotatory enantiomer, and obtained a single crystal.
Crystal structure determinations of 12 and 14 showed that the stereogenic asymmetric carbons in both
compounds (Figs. 1 and 2) have the respective 2R,3S configuration. The structures have normal bonding
geometry. Intermolecular distances in the crystalline environment have only two peculiarities. One is that

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P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
in 12 there is a short H···H contact (dH1···H15=2.06 Å). The other is that both structures exhibit signs of
the chloro effect.16 The chloro substituted aromatic group in 12 probably causes the characteristic short a
axis (∼4.4 Å), while the chloromethyl moiety in 14 gives rise to numerous Cl···X (X_H, C, O) contacts,
some of which are appreciably shorter than the sum of their van der Waals radii.
Scheme 5. Self-condensation of phenacyl chloride. Reagents and conditions: (i) crown-ether catalyst 2g, 30% NaOH, toluene
Fig. 2. Molecular structure of 14 with atomic labeling used in the X-ray analysis
Our research activity is being continued in field of the self-condensation of phenacyl chloride: the
effect of other chiral catalysts in this reaction is being studied.
3. Experimental
3.1. General procedures
Melting points were determined with Büchi 510 apparatus and are uncorrected. Specific rotation was
measured on a Perkin–Elmer 241 polarimeter at 20°C, and IR spectra were recorded on a Perkin–Elmer
237 spectrophotometer. NMR spectra were recorded on a Bruker WM 250 instrument in CDCl3. The

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
4547
mass spectra were obtained on a Jeol JMS-01 SG-2 instrument. Chemical ionization was applied as
the ionization technique. Elemental analysis was performed on a Perkin–Elmer 240 automatic analyzer.
Analytical and preparative thin layer chromatography was performed on silica gel (60 GF-254, Merck),
column chromatography was carried out using 70–230 mesh silica gel (Merck).
3.2. General method for preparation of crown ethers
Dry Na2CO3 (3.84 g, 36.2 mmol) was suspended in a solution of 4.60 mmol of the corresponding
primary amine and 3.45 g (4.6 mmol) of bis-iodo compound 1 in 110 mL of dry acetonitrile under argon.
The stirred reaction mixture was refluxed for 24–48 h and monitored by TLC until the disappearance of
the bis-iodo compound. After cooling, the precipitate was filtered and washed with acetonitrile. The
combined acetonitrile solution was concentrated at reduced pressure. The residue oil was dissolved
in CHCl3, washed with water and dried over Na2SO4 and the solvent evaporated under vacuum. The
corresponding monoaza-crown ether was isolated by column chromatography.
3.2.1. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido[2,3-h]-N-butyl-1,4,7,10-tetraoxa-
13-azacyclopentadecane 2a
The column chromatography was carried out with eluent dichloromethane:methanol (100:5) on silica
gel. Yield 64% (yellow oil); [α]20 +32 (c 1, CHCl3); IR (neat) 2926, 2869, 1600, 1491, 1368, 1228, 1093,
D
1031, 749, 693 cm−1; 1H NMR (CDCl3) δ 0.91 (t, J=7.3 Hz, 3H, CH3), 1.28–1.76 (m, 4H, CH3CH2CH2),
2.65–2.88 (m, 6H, 3NCH2), 3.40 (s, 3H, OCH3), 3.48–4.07 (m, 16H, CH and CH2 groups), 4.33 (dd,
J=10.5 Hz, 1H, H-6), 4.77 (d, J=3.6 Hz, 1H, anomeric-H), 5.48 (s, 1H, PhCH), 7.18–7.53 (m, 5H,
Ph); 13C NMR (CDCl3) δ 14.0, 20.6, 29.6, (CH3CH2CH2), 54.0, 54.5 (CH2NCH2), 55.0 (OCH3), 56.5
(NCH2), 66.1 (C-5), 68.7 (C-6), 69.2, 69.3, 70.3, 70.4, 72.4, 72.5 (6OCH2 of the macrocycle), 81.0, 81.5
(C-3, C-4), 81.7 (C-2), 96.9 (C-1), 100.9 (PhCH), 125.9 (PhC-o), 128.2 (PhC-m), 129.0 (PhC-p), 137.3
(PhC-ipso); FABMS m/z 496 (M+H). Anal. calcd for C26H41NO8: C, 63.03; H, 8.28; N, 2.83%. Found:
C, 62.98; H, 8.25; N, 2.81%.
3.2.2. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido[2,3-h]-N-(2-phenyl)ethyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane 2e
The purification was carried out by column chromatograpy with eluent chloroform:methanol (10:1)
20
on silica gel. Yield 48% (yellow crystals); mp 73–75°C (ether); [α] +32.4 (c 1, CHCl3); IR (KBr)
D
1
2913, 2866, 1600, 1492, 1368, 1230, 1127, 1092, 751, 694 cm−1; H NMR (CDCl3) δ 2.76–2.88 (m,
8H, 3NCH2 and CH2Ph), 3.43 (s, 3H, OCH3), 3.48–3.86 (m, 17H, CH and CH2 groups), 4.23 (dd, J=10.5
Hz, 1H, H-6), 4.76 (d, J=3.6 Hz, 1H, anomeric-H), 5.47 (s, 1H, PhCH), 7.12–7.53 (m, 10H, 2Ph); 13C
NMR (CDCl3) δ 34.0 (NCH2CH2Ph), 54.1, 54.3 (CH2NCH2), 58.7 (NCH2CH2Ph), 66.1 (C-5), 68.7
(C-6), 69.2, 69.3, 70.3, 70.4, 72.4, 72.5 (6OCH2 of the macrocycle), 81.0, 81.5 (C-3, C-4), 81.7 (C-2),
96.9 (C-1), 100.9 (PhCH), 125.9 (PhC-o), 126.0 (PhC-o), 128.2 (PhC-m), 128.3 (PhC-m), 129.0 (PhC-p),
129.6 (PhC-p), 137.3 (PhC-ipso), 140.5 (PhC-ipso); ClMS m/z (rel. int.) 544 (M+H, 29), 512 (72), 452
(100). Anal. calcd for C30H41O8N: C, 66.29; H, 7.55; N, 2.58; Found: C, 66.31; H, 7.52; N, 2.57%.
3.2.3. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido[2,3-h]-N-3-hydroxypropyl-1,4,7,
10-tetraoxa-13-azacyclopentadecane 2g
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
D
(100:5→100:10) on silica gel. Yield: 58% (yellow crystals); mp 58–60°C; [α] +52.4 (c 1, CHCl3); IR
(neat) 3120–3600, 2920, 2875, 1600, 1491, 1236, 1093, 756, 692 cm−1; 1H NMR (CDCl3) δ 1.67–1.98

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P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
(m, 2H, NCH2CH2CH2), 2.25–2.43 (m, 2H, CH2), 2.73–3.01 (m, 6H, 3NCH2), 3.43 (s, 3H, OCH3),
3.52–3.90 (m, 13H, CH and CH2 groups), 4.01–4.10 (m, 4H, 2OCH2), 4.26 (dd, J=10.5 Hz, 1H, H-6),
4.83 (d, J=3.6 Hz, 1H, anomeric-H), 5.0 (s, 1H, OH), 5.50 (s, 1H, PhCH), 7.27–7.43 (m, 5H, Ph); 13C
NMR (CDCl3) δ 28.4 (NCH2CH2CH2), 54.3 (CH2NCH2), 56.4 (NCH2CH2CH2), 64.0 (NCH2CH2CH2),
66.1 (C-5), 68.7 (C-6), 68.8, 68.9, 70.2, 70.3, 72.3, 72.5 (6OCH2 of the macrocycle), 80.9, 81.4 (C-3,
C-4), 81.7 (C-2), 101.2 (PhCH), 102.1 (C-1), 125.9 (PhC-o), 128.2 (PhC-m), 129.0 (PhC-p), 137.3 (PhC-
ipso); FABMS m/z 498 (M+H, 100). Anal. calcd for C25H39O9N: C, 60.36; H, 7.85; N, 2.82%. Found:
C, 60.30; H, 7.79; N, 2.80%.
3.2.4. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido[2,3-h]-N-4-hydroxybutyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane 2h
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
(100:1→100:5) on silica gel. Yield: 51% (yellow oil); [α] +38.4 (c 1, CH2Cl2); IR (neat) 3120–3600,
D
1
2920, 2875, 1600, 1491, 1236, 1093, 756, 692 cm−1; H NMR (CDCl3) δ 1.54–1.70 (m, 4H, 2CH2),
2.47–2.91 (m, 6H, 3NCH2), 3.37 (s, 3H, OCH3), 3.46–3.93 (m, 20H, CH and CH2 groups), 4.24 (dd,
J=10.5 Hz, 1H, H-6), 4.80 (d, J=3.6 Hz, 1H, anomeric-H), 5.48 (s, 1H, PhCH), 7.23–7.46 (m, 5H, Ph);
FABMS m/z 512 (M+H). Anal. calcd for C26H41O9N: C, 61.05; H, 8.02; N, 2.73%. Found: C, 61.15; H,
8.10; N, 2.70%.
3.2.5. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido[2,3-h]-N-2-methoxyethyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane 2i
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
D
(10:2) on silica gel. Yield: 44% (yellow crystals); mp 78–79°C (ether); [α] +41.6 (c 1.2, CHCl3); IR
(KBr) 2920, 2876, 1600, 1496, 1388, 1239, 1093, 749, 695 cm−1; 1H NMR (CDCl3) δ 2.71–2.92 (m, 6H,
3NCH2), 3.31 (s, 3H, OCH3), 3.40 (s, 3H, OCH3), 3.46–3.90 (m, 19H, CH and CH2 groups), 4.23 (dd,
1H, J=10.5 Hz, H-6), 4.82 (d, J=3.6 Hz, 1H, anomeric-H), 5.50 (s, 1H, PhCH), 7.23–7.46 (m, 5H, Ph);
CIMS m/z (rel. int.) 498 (M+H, 15), 452 (100); FABMS m/z 498 (M+H). Anal. calcd for C25H39O9N: C,
60.36; H, 7.85; N, 2.82%. Found: C, 60.28; H, 7.80; N, 2.78%.
3.2.6. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-galactopyranosido[2,3-h]-N-butyl-1,4,7,10-
tetraoxa-13-aza-cyclopentadecane 3a
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
D
(100:1→100:5) on silica gel. Yield: 61% (yellow oil); [α] +91.8 (c 1, CHCl3); IR (KBr) 2926, 2869,
1600, 1491, 1368, 1228, 1093, 1031, 749, 693 cm−1; 1H NMR (CDCl3) δ 0.90 (t, J=7.3 Hz, 3H, CH3),
1.27–1.74 (m, 4H, CH2), 2.65–2.88 (m, 6H, 3NCH2), 3.40 (s, 3H, OCH3), 3.48–4.14 (m, 18H, CH and
CH2 groups), 4.36 (dd, J=2.8 Hz, 1H, H-6), 4.86 (d, J=2.6 Hz, 1H, anomeric-H), 5.52 (s, 1H, PhCH),
7.18–7.52 (m, 5H, Ph); 13C NMR (CDCl3) δ 14.0, 20.6, 29.6 (CH3CH2CH2), 54.0, 54.5 (CH2NCH2),
55.0 (OCH3), 56.5 (NCH2), 66.1 (C-5), 68.6 (C-6), 69.2, 69.3, 70.3, 70.4, 72.4, 72.5 (6OCH2 of the
macrocycle), 81.1, 81.6 (C-3, C-4), 81.6 (C-2), 100.0 (C-1), 100.9 (PhCH), 125.9 (PhC-o), 128.2 (PhC-
m), 129.0 (PhC-p), 137.2 (PhC-ipso); FABMS m/z 496 (M+H). Anal. calcd for C26H41NO8: C, 63.03; H,
8.28; N, 2.83%. Found: C, 63.07; H, 8.25; N, 2.80%.
3.2.7. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-galactopyranosido-[2,3-h]-N-(2-phenyl)ethyl-1,4,7,
10-tetraoxa-13-azacyclopentadecane 3e
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
D
(100:5→100:10) on silica gel. Yield: 49% (yellow syrup) [α] +103 (c 1, CHCl3); IR (KBr) 2913,

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
4549
1
2866, 1600, 1492, 1368, 1230, 1127, 1092, 751, 694 cm−1; H NMR (CDCl3) δ 2.73–2.87 (m, 8H,
3NCH2 and CH2Ph), 3.40 (s, 3H, OCH3), 3.53–4.16 (m, 17H, CH and CH2 groups), 4.26 (dd, J=2.8 Hz,
1H, H-6), 4.92 (d, J=2.6 Hz, 1H, anomeric-H), 5.46 (s, 1H, PhCH), 7.18–7.51 (m, 10H, 2Ph); EI-MS m/z
544 (M+H, 17), 512 (80), 452 (100). Anal. calcd for C30H41O8N: C, 66.30; H, 7.55; N, 2.58%. Found:
C, 66.35; H, 7.51; N, 2.53%.
3.2.8. Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-galactopyranosido[2,3-h]-N-2-methoxyethyl-1,4,7,
10-tetraoxa-13-azacyclopentadecane 3i
The purification was carried out by column chromatography with eluent dichloromethane:methanol
20
D
(100:1→100:10) on silica gel. Yield: 75% (yellow oil); [α] +85.1 (c 1, CHCl3); IR (neat) 2920, 2876,
1600, 1496, 1388, 1239, 1093, 749, 695 cm−1; 1H NMR (CDCl3) δ 2.71–2.92 (m, 6H, 3NCH2), 3.32 (s,
3H, OCH3), 3.40 (s, 3H, OCH3), 3.51–3.93 (m, 19H, CH and CH2 groups), 4.21 (dd, J=2.8 Hz, 1H, H-6),
4.92 (d, J=2.6 Hz, 1H, anomeric H), 5.50 (s, 1H, PhCH), 7.19–7.52 (m, 5H, Ph); CIMS m/z 498 (M+H,
9), 452 (100). Anal. calcd for C25H39O9N: C, 60.36; H, 7.85; N, 2.82%. Found: C, 60.29; H, 7.80; N,
2.85%.
3.3. General procedure for the Michael addition of 2-nitropropane to chalcone in the presence of
azacrown
The corresponding azacrown (0.1 mmol) and sodium tert-butoxide (0.05 g, 0.5 mmol) were added
to the solution of chalcone (0.3 g, 1.44 mmol) and 2-nitropropane (0.3 mL, 3.36 mmol) in dry toluene
(3 mL). The mixture was stirred under argon atmosphere at room temperature. After a reaction time
of 48 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 (7 mL) and dried (Na2SO4). The crude product obtained after
evaporating the solvent was purified by preparative TLC (silica gel, hexane:ethyl acetate, 10:1, eluant)
20
to give pure adduct. Mp 146–148°C; [α] +80.8 (c 1.5, CH2Cl2) for the pure (+)-(S)-enantiomer.4b 1
H
D
NMR (CDCl3) δ 1.54 (s, 3H, CH3), 1.63 (s, 3H, CH3), 3.27 (dd, 1H, J1=17.2, J2=3.2, COCH), 3.67
(dd, 1H, J1=17.2, J2=10.4, COCH), 4.15 (dd, 1H, J1=10.4, J2=3.2, CH2CH), 7.18–7.32 (m, 5H, CHPh),
7.42–7.85 (m, 5H, C(O)Ph).
3.4. General procedure for Darzens condensation
A toluene solution (3 mL) of 1.3 mmol of phenyl chloride 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 argon
atmosphere. After completing the reaction 7 mL of toluene were added, the organic phase washed
with water, dried over MgSO4 and solvent evaporated. The product was isolated by preparative TLC
20
using CH2Cl2 as eluent. Results are collected in Table 2. [α]
−214 (c 1, CH2Cl2) for pure 2R,3S
578
enantiomer.13 1H NMR (CDCl3) δ 4.08 (d, 1H, J=1.9 Hz, CH), 4.29 (d, 1H, J=1.9 Hz, CH), 7.35–7.45
(m, 5H, CHPhH), 7.49 (t, 2H, COPhH-m), 7.62 (t, 1H, COPhH-p), 8.01 (d, 2H, COPhH-o). The 1H NMR
spectra of substituted (−)-(2R,3S)-epoxy-1,3-diphenyl-1-propanone 11 and 12 were essentially identical
with those reported in the literature.13
3.4.1. trans-(−)-2,3-Epoxy-3-(2-nitrophenyl)-1-phenyl-1-propanone 10
20
Yield: 72% (colorless crystals); mp 69–70°C; [α] −48.7 (c 1, CH2Cl2); 29% ee. 1H NMR CDCl3
D
δ 4.23 (d, J=1.75 Hz, 1H), 4.63 (d, J=1.65 Hz, 1H), 7.27–8.22 (m, 9H, 2Ph); 13C NMR (CDCl3) δ 57.7
(C-O), 59.6 (C-O), 124.9 (Ph, CH), 127.4 (Ph, CH), 128.5 (Ph, CH), 128.9 (Ph, CH), 129.5 (Ph, CH),

4550
P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
132.6 (Ph, CH), 134.1 (Ph, CH), 134.7 (Ph, CH), 135.4 (Ph, CH), 192.6 (C_O); FABMS m/z 270 (M+H).
Anal. calcd for C15H11NO4: C, 66.91; H, 4.08; N, 5.20%. Found: C, 66.90; H, 4.05; N, 5.18%.
3.4.2. trans-(−)-2,3-Epoxy-3-(4-nitrophenyl)-1-phenyl-1-propanone 11
20
Yield: 63%; [α] −161 (c 1, CH2Cl2); 61% ee. Two crystallizations from ethanol and hexane gave
D
20
20
the pure enantiomer, [α] −272 (c 1, CH2Cl2); (lit.12 [α] −274, c 2, CH2Cl2); mp 138–140°C (lit.12
D
557
140–142°C).
3.4.3. (−)-(2R,3S)-Epoxy-3-(4-Chlorophenyl)-1-phenyl-1-propanone 12
20
Yield: 54%; [α] −127 (c 0.33, CH2Cl2); 59% ee. Three crystallizations from ethanol and hexane
D
20
20
gave the pure enantiomer, [α] −224 (c 1, CH2Cl2); (lit.12 [α] −253, c 2.0, CH2Cl2); mp 64–66°C
D
577
(lit.13 68°C).
3.4.4. trans-(−)-2,3-Epoxy-3-(4-methoxyphenyl)-1-phenyl-1-propanone 13
20
20
Yield: 31%; mp 58–60°C (lit.12 60–63°C); [α] −16 (c 1, CH2Cl2); 12% ee (lit.12 [α] −305, c
D
577
1
2.0, CH2Cl2, 90% ee); H NMR (CDCl3) δ 3.83 (s, 3H, OCH3), 4.08 (d, 1H, J=1.9 Hz, CH), 4.63 (d,
1H, J=1.9 Hz, CH), 7.38–8.01 (m, 9H, Ph). Anal. calcd for C16H14O3: C, 75.58; H, 5.55%. Found: C,
75.61; H, 5.54%.
3.5. Self-condensation of phenacylchloride
A 6 mL toluene solution of 0.8 g (5.2 mmol) of phenacyl chloride and 0.1 g (0.2 mmol) of catalyst
2g was treated with 2.0 mL of 30% NaOH solution. The mixture was stirred at room temperature for
1 h. After completing the reaction 14 mL of toluene were added, the organic phase washed with water,
dried over MgSO4 and solvent evaporated. The product was purified by column chromatography (silica
20
gel, CH2Cl2) to give 0.6 g (85%) of 14. Mp 123–130°C; [α] −60.6 (c 1, CH2Cl2). Diastereomeric
D
1
ratio cis:trans=23:77 (by H NMR); separation by preparative TLC (silica gel, CH2Cl2) to give the
20
D
pure trans-form of 14 (0.4 g); mp 122–124°C; [α] −74 (c 1, CH2Cl2); 64% ee. Two crystallizations
from hexane afforded the pure enantiomer, (−)-(2R,3S)-epoxy-1,3-diphenyl-4-chlorobutan-1-one. Mp
20
D
124–126°C; [α] −116 (c 1, CH2Cl2); 1H NMR δ 3.88 (d, J=12 Hz, 1H), 4.02 (d, J=15 Hz, 1H), 4.38
(s, 1H), 7.22–8.02 (m, 10H, Ph). 13C NMR δ 44.1 (C-Cl), 65.4 (C-O), 66.1 (C-O), 126.3 (Ph, CH), 128.4
(Ph, CH), 128.6 (Ph, CH), 128.8 (Ph, CH), 129 (Ph, CH), 129.1 (Ph, CH), 134.4 (Ph, CH), 136.0 (Ph,
CH), 193.6 (C_O). Anal. calcd for C16H13ClO2: C, 70.40; H, 4.77; Cl, 13.0%. Found: C, 70.42; H, 4.76;
Cl, 12.96%.
3.6. X-Ray crystal structure determinations16–19
Diffraction data were collected for both 12 and 14 at room temperature using Mo-Kα radiation.
Initial structure models, obtained routinely by direct methods (SHELXS93), were smoothly refined
to the final scattering model by using full-matrix least-squares and anisotropic displacement variables
for non-H atoms. All hydrogen atoms both in 12 and 14 were positioned using geometric constrains
and included within the final refinement cycles with so-derived contributions using SHELXL97. Perti-
nent crystallographic data for 12: monoclinic P21 (no. 4), a=4.379(1), b=10.740(2), c=13.465(2) [Å],
β=92.53(1) [°], V=632.6(2) [Å3], Z=2, D(calc)=1.358 [g/cm3], data: NTot=2433, NUniq=1952, R(int)=0.039,
NObs [I>2.0σ(I)]=988, refinement: Nref=1952, Npar=163, R=0.0550, Rw=0.1478, S=0.82; for 14: mono-
clinic P21 (no. 4), a=6.990(1), b=5.053(1), c=18.544(2) [Å], β=91.74(1) [°], V=654.7(2) [Å3], Z=2,

P. Bakó et al. / Tetrahedron: Asymmetry 10 (1999) 4539–4551
4551
D(calc)=1.383 [g/cm3], data: NTot=4632, NUniq=3793, R(int)=0.021, NObs [I>2.0σ(I)]=2215, refinement:
Nref=3793, Npar=172, R=0.0476, Rw=0.1178, S=0.91. Absolute configurations for both 12 and 14 were
assigned on the basis of the refined Flack parameters (x=−0.02(14) for 12 and x=−0.03(8) for 14).
Acknowledgements
This work was supported by the Hungarian Academy of Sciences and the National Science Foundation
(OTKA T029253, T026478 and in part T025910).
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