Side-arm effect of a methyl ?±-D-glucopyranoside based lariat ether catalysts in asymmetric syntheses

Article abstract of DOI:10.1002/hc.21214

Methyl ?±-D-glucopyranoside based monoaza-15-crown-5 type lariat ethers with different heteroatom-containing side arm attached to the nitrogen of the macrocyclic ring have been synthesized. These compounds were used as chiral phase transfer catalysts in a few asymmetric reactions, such as Michael additions, Darzens condensation, and epoxidation of chalcone. The side arms of the macrocycles had a significant impact on the chemical yields and the enantioselectivity. The effect of the lariat ethers with side arms having heteroatom (O, N, and S) was compared with the effect of the analogues having substituents without a heteroatom. The terminal allyl group also generated a significant enantioselectivity (79% enantiomeric excess) in one of the Michael additions. The application of crown ethers with substituents (CH₂)₃OH or (CH₂)₃OCH₃ leads to the best enantioselectivities 85% and 99%, respectively.

Full text of DOI:10.1002/hc.21214

Heteroatom Chemistry
Volume 00, Number 00, 2014
Side-Arm Effect of a Methyl
α-D-Glucopyranoside Based Lariat Ether
Catalysts in Asymmetric Syntheses
Zsolt Rapi,1 Pe´ter Bako´,1 La´szlo´ Drahos,2 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521, Budapest, Hungary
2Chemical Research Institute for Chemistry, Hungarian Academy of Sciences, H-1525, Budapest,
Hungary
Received 17 December 2013; revised 16 June 2014
INTRODUCTION
ABSTRACT: Methyl α-D-glucopyranoside based
monoaza-15-crown-5 type lariat ethers with different
heteroatom-containing side arm attached to the ni-
trogen of the macrocyclic ring have been synthesized.
These compounds were used as chiral phase trans-
fer catalysts in a few asymmetric reactions, such as
Michael additions, Darzens condensation, and epoxi-
dation of chalcone. The side arms of the macrocycles
had a significant impact on the chemical yields and
the enantioselectivity. The effect of the lariat ethers
with side arms having heteroatom (O, N, and S)
was compared with the effect of the analogues hav-
ing substituents without a heteroatom. The termi-
nal allyl group also generated a significant enantios-
electivity (79% enantiomeric excess) in one of the
Michael additions. The application of crown ethers
with substituents (CH2)3OH or (CH2)3OCH3 leads to
the best enantioselectivities 85% and 99%, respec-
The number of members of the crown ether family
of lariat type has increased since the time of the early
pioneering studies by Gokel and co-workers. The at-
tachment of a side arm with potential cation coor-
dination sites to crown ethers results in complexing
agents called lariat ethers that have unique binding
properties toward the variety of cation guests [1, 2].
Crown ethers with linear or branched heteroatom-
containing podand arms, depending on the con-
nection point, are either nitrogen-pivot or carbon-
pivot lariat ethers, which exhibit increased guest
specificity. The side arms together with macrocyclic
core structure provide a framework suitable for cap-
turing cations in the form of chelated structures
(Fig. 1).
For some lariat ethers, the presence of a flexible
side arm with an electron donor site is known to en-
hance the binding ability of the ligand by the partici-
pation of its additional donor group in the complexa-
tion, providing three-dimensional cavities [1–4]. The
side arms often comprise ethylene glycol or glyc-
erol type fragments. When two of the glycerol’s
adjacent hydroxyl groups are incorporated into a
heteromacrocycle, the ring possesses a pendant hy-
droxymethyl group (CH2OH) [5].
ꢀC
tively.
2014 Wiley Periodicals, Inc. Heteroatom
Chem. 00:1–9, 2014; View this article online at wi-
leyonlinelibrary.com. DOI 10.1002/hc.21214
A few efforts in this area have focused on the
development of new types of lariat crown ethers and
they were tested as different complexing agents [6].
One important group of the lariat ethers include
Correspondence to: Pe´ter Bako´; e-mail: pbako@mail.bme.hu.
Contract grant sponsor: New Sze´chenyi Development Plan
´
(TAMOP-4.2.1/B-09/1/KMR-2010–0002).
ꢀC
2014 Wiley Periodicals, Inc.
1

2
Rapi et al.
ether on the yield and the enantioselectivity in a few
asymmetric reactions.
RESULTS AND DISCUSSION
Synthesis of Glucose-Based Lariat Ethers
FIGURE 1 Complexation of cation by a lariat ether.
We synthesized a few methyl α-D-glucopyranoside
based monoaza-15-crown-5 type lariat ethers with
side arms containing different heteroatoms, allyl or
phenyl group. The method of the synthesis was ear-
lier elaborated [12,17].
Synthetic approaches for the preparation of lar-
iat crown ether have been traditionally performed by
cyclization reactions that require low concentrations
of reactants to minimize competing polymerization
processes. The chiral macrocycles were purified by
column chromatography.
Methyl α-D-glucopyranoside based bisiodo po-
dand 1 was the key intermediate [12] in the prepa-
ration of the monoaza-15-crown-5 type lariat ethers
with different side arms. Compound 1 was reacted
with various primary amines in the presence of
sodium carbonate in a diluted solution of acetoni-
trile at reflux for 32–40 h (Scheme 1).
The amines used in the ring closure reaction
were allylamine (3), 3-phenylpropylamine (4), 3-
amino-1,2-propanediol (5), 3-methoxypropylamine
(6) N,N-dimethyltrimethylene-diamine (7), N-
phenyl-Nꢁ-aminopropyl-thiocarbamide (8), and
3-(pyridin-2-yl)propylamine (9) (Fig. 2).
Amines 3–7 are available as commercial
reagents. Starting amine derivative 8 was prepared
by the reaction of 1,3-diaminopropane (10) and
phenyl-isothiocianate (11) (Scheme 2) [13].
3-(Pyridin-2-yl)propylamine (9) was prepared
in two steps: 3-(pyridin-2-yl)propan-1-ol (12) was
reacted with phthalimide in the presence of
diisopropyl-azodicarboxilate (in the Mitsunobu re-
action) to afford intermediate 13. The treatment
with hydrazine hydrate led to amine 9 that was
obtained in a yield of 47% after chromatography
(Scheme 3) [14].
chiral macrocycles, which may be utilized for the
determination of the enantiomeric composition of
chiral amino compounds and for the separation
of racemic ammonium salts. The chiral nature of
crown ethers, the rigidity of the microenvironment
of their cavity, and the nature of the side arm play
an important role in enantiomeric recognition [7].
There are only a few examples for the use of chi-
ral lariat ethers as enantioselective catalysts [8]. Ear-
lier, chiral lariat ethers based on different monosac-
charides were synthesized by us that were applied
as phase transfer catalysts in asymmetric reactions
[9]. Phase transfer catalysis has long been recog-
nized as a versatile methodology for organic syn-
thesis in both academic and industrial laboratories,
based on its simple experimental operation, mild re-
action conditions applying aqueous media, inexpen-
sive and environmentally benign reagents and sol-
vents, and the possibility of conducting large-scale
preparations [10]. In particular, from the 1990s,
asymmetric phase transfer catalysis based on the
use of structurally well-defined chiral catalysts has
become a topic of great scientific interest, and re-
cent efforts have resulted in notable achievements,
making it feasible to perform a variety of bond-
formation reactions under mild phase transfer cat-
alyzed conditions. Chiral phase transfer catalysis
has become an attractive area in the “green” chem-
ical discipline, and many types of chiral catalysts
have been developed and applied over the past few
decades [11].
A few of the monosaccharide-based chiral lariat
ethers have been found to be efficient phase trans-
fer catalysts in certain types of asymmetric reac-
tions. A review has been recently published by us in
this topic [9]. Valuable information has been accu-
mulated on the structure–enantioselectivity relation-
ship. Regarding the crown, a glucopyranoside-based
monoaza-15-crown-5 type structure seems to be ad-
vantageous. Beside this, the catalytic effect strongly
depends on the nature of the side arm of the crown
ether.
The lariat ether with
a
((methoxy)ethy
loxy)propyl side arm (2l) was prepared by the
modification of the hydroxypropyl derivative 2f by
alkylation with 2-methoxyethyl-p-toluensulfonate
(14) [15]. The resulting lariat ether contains a side
arm with two oxygen atoms that is suitable to be
involved in more interactions (Scheme 4).
The other α-D-glucose based lariat ethers (2a–b,
2f, and 2j) were synthesized as described earlier [16].
The catalytic effect of these species (2a–b, 2f, and
2j) was also investigated. The results are shown in
Tables 1 and 2.
In this article, we wished to study the influence
of the side arms of a D-glucopyranoside-based lariat
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Side-Arm Effect of a Methyl α-D-Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses
3
SCHEME 1. Synthesis of monoaza-15-crown-5 type lariat ethers with different side arms.
FIGURE 2 Amines used in the ring closure reaction.
SCHEME 2. Synthesis of N-phenyl-Nꢁ-aminopropyl-thiocarbamide (8).
SCHEME 3. Synthesis of 3-(pyridin-2-yl)propylamine (9).
densation, and epoxidation of chalcone. The mech-
anisms of these reactions are well known in the
homogenous phase. The mechanism is completed
with one step in a two-phase reaction using a chi-
ral PT catalyst. In the first step, the lariat ether
Enantioselective Reactions
The D-glucose-based lariat ethers were used as chi-
ral phase transfer catalysts in a few asymmetric re-
actions, such as Michael additions, Darzens con-
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Rapi et al.
SCHEME 4. Synthesis of lariat ether 2l.
TABLE 1 Effect of Lariat Ethers (2a–l) in Michael Addition Reactions
Addition of 2-Nitropropane;
Adduct 17
Addition of Diethyl Acetamido-
malonate; Adduct 20
Lariat Ether Catalyst
R
Yield (%)a
ee (%)b
Yield (%)a
ee (%)c
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
Bu
Allyl
(CH2)3Ph
CH2CH(OH)CH2OH
(CH2)3OH
(CH2)3OCH3
(CH2)3N(CH3)2
(CH2)3NHC(S)NHPh
(CH2)2Pyr
73
41
32
38
35
53
52
57
10
35
24
24
61
58
79
26
60
85
87
71
0
38
50
38
49
69
70
58
30
63
47
92
38
53
42
25
50
75
99
38
78
34
72
56
0
2j
2k
2l
52
8
23
(CH2)3Pyr
(CH2)3O(CH2)2OCH3
aBased on isolation by preparative TLC.
bEnantioselectivities were determined by 1H NMR spectroscopy; the (+)-(R)-antipode of the Michael adduct 17 was formed.
cDetermined by chiral HPLC analysis; the (–)-(S) enantiomer of 20 was formed.
TABLE 2 Effect of Lariat Ethers (2a-l) on Darzens Condensation and Epoxidation of Chalcone
Darzens Condensation;
Epoxidation;
Epoxyketone 23
Epoxyketone 23
Lariat Ether Catalyst
R
Yield (%)a
ee (%)b
Yield (%)a
ee (%)b
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
Bu
Allyl
(CH2)3Ph
CH2CH(OH)CH2OH
(CH2)3OH
(CH2)3OCH3
(CH2)3N(CH3)2
(CH2)3NHC(S)NHPh
(CH2)2Pyr
74
29
45
54
30
69
74
67
63
59
82
76
21
12
21
31
25
72
21
14
35
30
32
8
38
28
63
71
75
82
61
33
13
7
36c
76
94
23
-
No reaction
86
80
46
86
24
8
0
2j
2k
2l
(CH2)3Pyr
(CH2)3O(CH2)2OCH3
0
aBased on isolation by preparative TLC.
bEnantioselectivities were determined by 1H NMR spectroscopy.
cEnantiomer of (+)-(2S,3R) was in excess.
transfers the sodium cation accompanied by the an-
ion into the organic phase, where the (crown-Na+)-
activated nucleophile–anion complex is formed that
is an optically active supramolecular associate (e.g.,
crown/Na+/tert-BuOO− anion) [16a]. This chiral as-
sociate is the attacking agent, its structure deter-
mines the chiral environment, and consequently the
degree of the asymmetric induction. Thus, the chi-
ral structure of the crown ether has a crucial role in
the asymmetric reaction. The process is influenced
by the steric and electronic effects of the side arms
on the lariat ether. We tried to find a correlation
Heteroatom Chemistry DOI 10.1002/hc

Side-Arm Effect of a Methyl α-D-Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses
5
sodium cation [19]. The side arms with heteroatoms,
as in 2e–l, had different effects. The catalysts with
the longest chain (2i and 2l) induced the smallest
extent of ee (23% and 0% ee; and 0% and 34% ee).
If the side arm is too long, it is not suitable to
participate in forming a donor bond. The effect of
catalysts with shorter chains was more favorable. In
the case of the 2,3-dihydroxypropyl group (as in lar-
iat ether 2e), the Michael adducts 17 and 20 were
obtained in 60% and 75% ee, respectively. The cat-
alyst with hydroxypropyl substituent (2f) was one
of the best crown, as revealed high ee values (85%
and 99%) in both model reactions. It is notewor-
thy that the methoxy analogue (2g) resulted in a
high ee (87%) only in reaction with 2-nitropropane
(16). The dimethylaminopropyl side arm (as in 2h)
was quite efficient (leading to 71% and 78% ee), but
its effect remained below that of the hydroxyl ana-
logue (2f). The experiments with catalysts contain-
ing pyridylalkyl side arms revealed the importance
of the distance between the crown N atom and the
heteroatom at the end of the side arms. The model
compound with a two carbon atom chain (as in 2j)
resulted in ee values of 52% and 72%, whereas with
a three-carbon atom chain (as in 2k), the ee values
were only 8% and 56%. The different effect of the
catalysts in the two Michael additions is the conse-
quence of the fact that the first step is different for
the two-phase transfer catalytic reactions. In the ad-
dition of 2-nitropropane (16), NaOBut is solubilized
in toluene by lariat ether, then the chiral complex
dissolved abstracts the proton.
The role of solid Na2CO3 in the solid–liquid
phase transfer catalytic reactions may be interpreted
according to Makosza and co-workers [20]. The
crown catalysts are unable to transfer the carbonate
anions (CO32−) into the bulk of the organic phase,
thus the solid–liquid phase transfer phenomena are
probably not involved here. It is more plausible that
the first step, namely, the proton abstraction, takes
place on the surface of the solid carbonate. The an-
ions so formed then migrate into the organic phase
as ion pairs with the crown ether complexed sodium
cations.
Epoxyketone 23 was prepared by two kinds of a
liquid–liquid phase reaction, in which the D-glucose-
based lariat ethers were efficient. The Darzens con-
densation taking place between phenacyl chloride
(21) and benzaldehyde (22) was performed in a
toluene solution using 30% aqueous NaOH at 22°C
and took place in a stereoselective manner in the
presence of chiral catalysts (Scheme 7) [21]. The
products were isolated by preparative TLC. The
trans-epoxyketone 23 was obtained in all experi-
ments in a diastereomeric excess (de) of >98%. The
SCHEME 5. Addition of 2-nitropropane (16) to chalcone
(15).
between the nature of the side arms and the asym-
metric induction generated by catalyst.
The products of asymmetric reactions in all
cases were isolated by preparative thin-layer chro-
matography (TLC), and the asymmetric induction
expressed in terms of the enantiomeric excess
1
(ee%) was determined by H NMR spectroscopy in
the presence of Eu(hfc)3 as a chiral shift reagent
or chiral high-performance liquid chromatography
(HPLC) analysis.
The two Michael additions used as model reac-
tions were performed in a solid–liquid phase at room
temperature. The addition of 2-nitropropane (16) to
chalcone (15) was carried out in dry toluene in the
presence of solid sodium tert-butoxide (35 mol%)
and one of the chiral catalysts (7 mol%). Always
the (+)-(R)-antipode of the Michael adduct (17) was
formed (Scheme 5) [17].
Another Michael reaction, the conjugate ad-
dition of diethyl acetamidomalonate (19) to β-
nitrostyrene (18), was carried out in a 4:1 mixture
of ether–tetrahydrofuran (THF) as the solvent in the
presence of Na2CO3 (used in twofold excess) employ-
ing 15 mol% of the crown ether (Scheme 6) [18]. The
enantioselectivities were determined by chiral HPLC
analysis. Always the (–)-(S) enantiomer of compound
20 was formed.
The results of the two Michael addition reactions
carried out in the presence of different catalysts are
listed in Table 1.
It is shown in Table 1 that the effect of the crown
catalysts is different in the two types of Michael ad-
dition. Unsubstituted 2a induced an enantioselectiv-
ity (ee) of 61% and 53%. The presence of the side
arms resulted in dramatic changes. The substituents
without heteroatoms, as in lariat ethers 2b–d, in
general, decreased the extent of asymmetric induc-
tion (25–58% ee), except the allyl substituent, as in
2c, that resulted in an ee of 79% in the addition
reaction of 2-nitropropane (16). This phenomenon
may be explained assuming that the allyl group may
also participate in interaction with the Na cation
complexed by the crown ring. It is known that the
π-electron system of the allyl group may establish
a donor bond with certain metal cations, such as
Heteroatom Chemistry DOI 10.1002/hc

6
Rapi et al.
SCHEME 6. Addition of diethyl acetamidomalonate (19) to β-nitrostyrene (18).
SCHEME 7. Darzens condensation of phenacyl chloride (21) and benzaldehyde (22).
The lowest ee (8% and 0%) was detected in the pres-
ence of the pyridyl-containing side arms (2j–k). At
the same time, the models with the dihydroxypropyl
(2e) and hydroxypropyl (2f) substituents led to the
best ee values (76% and 94%, respectively). The op-
timal side arm may comprise a (CH2)3 chain with
a hydroxyl group at the end. It is worthy to men-
tion that species 2l with a MeO(CH2)2O(CH2)3 sub-
stituent was an efficient phase transfer catalyst in
both model reactions (with yield of 76% and 86%);
however, the ee generated was ࣘ8%.
SCHEME 8. Epoxidation of chalcone (15).
asymmetric induction expressed in the term of the ee
was determined by 1H NMR analysis in the presence
of Eu(hfc)3 as the chiral shift reagent. The trans-
epoxyketone (23) was obtained in all experiments,
with a configuration of (–)-(2R,3S).
CONCLUSIONS
We studied the relationship between the structure
of sugar-based phase transfer catalysts and their
ability for asymmetric induction. Regarding the D-
glucose-based lariat ethers, the enantioselectivity de-
pended strongly on the length of the side arm and on
the functionality at the end. The three-carbon atom
chain [(CH2)3] seems to be optimal. In the solid–
liquid phase Michael additions, the lariat ethers with
hydroxyl-, methoxy-, and dialkylamino substituents
at the end led to the best enantioselectivities. In-
terestingly, the N-allyl lariat ether induced also a
considerable ee in one of the reactions that was
comparable with the effect of the best catalysts
outlined above. The lariat ethers were not so effi-
cient in liquid–liquid phase reactions, where only the
hydroxypropyl-substituted catalyst induced a con-
siderable ee.
The epoxidation of chalcone (15) was carried out
with 2 equiv of tert-butyl hydroperoxide (TBHP) at
25°C in toluene, in a liquid–liquid two-phase system,
employing 20% aqueous NaOH (3.5 equiv) as the
base and 7 mol% of lariat ether as the catalyst [22].
The reactions took place after 4–8 h in variable yields
(28–86%). The trans-epoxyketone (23) was obtained
in all experiments, and the absolute configuration
was (–)-(2R,3S) (Scheme 8).
Table 2 presents unsubstituted 2a induced ee val-
ues of 21% and 33% in the test reactions under dis-
cussion. These data were changed significantly after
introducing the side arms. Regarding the Darzens
condensation, the crown compound with butyl (2b),
((methoxy)ethyloxy)propyl (2l), and dimethylamino-
propyl (2h) side arms induced the lowest ee values
(8–14%). The other lariat ethers, with the exception
of species 2f, resulted in ee values of 21–35%. The
best ee (72%) was obtained using the lariat ether
with a hydroxypropyl substituent (2f). Regarding the
epoxydation, lariat ethers 2e–f induced the best ee
values of 76% and 94%, respectively. The other cata-
lysts (2a–d and 2g–l) led to lower ee values than 36%.
EXPERIMENTAL
General
Melting points were taken using a Bu¨chi 510 appa-
ratus and are uncorrected. Optical rotations were
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Side-Arm Effect of a Methyl α-D-Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses
7
measured on a Perkin-Elmer 241 polarimeter at
20°C. 1H and 13C NMR spectra were recorded on
a Bruker 300 and a Bruker DRX-500 instrument in
CDCl3 with tetramethylsilane as the internal stan-
dard. The exact mass measurements were performed
using a Q-TOF Premier mass spectrometer (Wa-
ters, Milford, MA) in a positive electrospray ion-
ization mode. Analytical and preparative TLC was
performed on silica gel plates (60 GF-254, Merck,
Darmstadt, Germany), whereas column chromatog-
raphy was carried out using 70–230 mesh silica gel
(Merck). Chemicals were purchased from Aldrich
(St. Louis, MO, USA).
4.26 (dd, J = 9.6 Hz, 4.2 Hz, 1H), 4.02–3.88 (m, 2H),
3.85–3.52 (m, 14H), 3.48 (dd, J = 9.3 Hz, 3.9 Hz, 1H),
3.42 (s, 3H), 2.85–2.66 (m, 4H), 2.62 (t, J = 7.8 Hz,
2H), 2.52 (t, J = 7.8 Hz, 2H), 1.79 (qui, J = 7.5 Hz,
2H).
MS: m/z: [M + H]+ 558.4; [M + Na]+ 580.4.
Anal. calcd for C31H43NO8 (557.68): C, 66.76; H,
7.77; N, 2.51. Found: C, 62.72; H, 7.80; N, 2.49.
Methyl-4,6-O-benzylidene-2,3-dideoxy-
α-D-glucopyranosido[2,3-h]-N-((2S)-2,3-
dihydroxy)propyl-1,4,7,10-tetraoxa-13-
azacyclopentadecane (2e)
22
Yield: 64%; α
= +25.4 (c = 1, CHCl3).
[ ]D
1H NMR (CDCl3, 300 MHz), δ (ppm): 7.50–7.44
(m, 2H), 7.40–7.33 (m, 3H), 5.53 (s, 1H), 4.85 (d, J =
3 Hz, 1H), 4.26 (dd, J = 9 Hz, 2.4 Hz, 1H), 3.98–3.91
(m, 2H), 3.86–3.68 (m, 10H), 3.67–3.46 (m, 10H),
3.43 (s, 3H), 2.94–2.55 (m, 6H).
General Procedure for Preparation of Lariat
Ethers
Bisiodo compound 1 (9.0 g, 13.0 mmol) was
dissolved in dry CH3CN (200 mL) then in an-
hydrous Na2CO3 (6.3 g, 60 mmol), the appro-
priate amine (13.0 mmol) were added, and the
mixture was refluxed with stirring under Ar. After the
reaction was completed (32–40 h), the mixture was
filtered, evaporated, and the residue was dissolved
in CHCl3, washed with water, dried, and then con-
centrated in vacuo. The crude product was purified
by column chromatography on silica using CHCl3–
CH3OH 100:0 → 100:10 as an eluent.
MS: m/z: [M + H]+ 514.5; [M + Na]+ 536.4.
Anal. calcd for C25H39NO10 (513.58): C, 58.47; H,
7.65; N, 2.73. Found: C, 58.50; H, 7.62; N, 2.70.
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-3-hydroxypropyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane (2f) [16c]
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-3-methoxypropyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane (2g)
22
Yield: 70%; α
= +31.9 (c = 1, CHCl3).
[ ]D
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-1,4,7,10-tetraoxa-13-
azacyclopentadecane (2a) [16b]
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-butyl-1,4,7,10-tetraoxa-13-
azacyclopentadecane (2b) [16c]
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-allyl-1,4,7,10-tetraoxa-
13-azacyclopentadecane (2c)
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.48–7.42
(m, 2H), 7.39–7.33 (m, 3H), 5.57 (s, 1H), 4.83 (d, J
= 3.5 Hz, 1H), 4.26 (dd, J = 10 Hz, 5 Hz, 1H), 4.00–
3.46 (m, 19H), 3.44 (s, 3H), 3.38 (s, 3H), 3.06–2.98
(m, 1H), 2.85–2.74 (m, 2H), 2.65–2.58 (m, 1H), 2.48–
2.36 (m, 2H), 1.82–1.70 (m, 2H).
MS: m/z: [M + H]+ 512.7; [M + Na]+ 534.6. Anal.
calcd for C26H41NO9 (511.61): C, 61.04; H, 8.08; N,
2.74. Found: C, 61.02; H, 8.10; N, 2.73.
22
Yield: 71%; α
= +39 (c = 1, CHCl3).
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-(3-(N,N-dimethylamino))
propyl-1,4,7,10-tetraoxa-13-azacyclopentadecane
[ ]D
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.49–7.44
(m, 2H), 7.39–7.34 (m, 3H), 5.91–5.82 (m, 1H), 5.52
(s, 1H), 5.18–5.09 (m, 2H), 4.85 (d, J = 3.5 Hz, 1H),
4.28 (dd, J = 10 Hz, 4.5 Hz, 1H), 4.01–3.90 (m, 2H),
3.87–3.45 (m, 14H), 3.49 (dd, J = 9.5 Hz, 3.5 Hz, 1H),
3.43 (s, 3H), 3.15 (d, J = 6.5 Hz, 2H), 2.87–2.67 (m,
4H).
(2h)
22
Yield: 36%; α
= +23.7 (c = 1, CHCl3).
[ ]D
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.51–7.42
(m, 2H), 7.40–7.34 (m, 3H), 5.56 (s, 1H), 4.84 (d, J =
3.5 Hz, 1H), 4.26 (dd, J = 10 Hz, 5 Hz, 1H), 3.98–3.49
(m, 17H), 3.44 (s, 3H), 2.80–2.72 (m, 4H), 2.53–2.33
(m, 4H), 2.19 (s, 6H), 1.70–1.64 (m, 2H).
MS: m/z: [M + H]+ 480.6; [M + Na]+ 502.5.
Anal. calcd for C25H37NO8 (479.56): C, 62.61; H,
7.78; N, 2.92. Found: C, 62.60; H, 7.79; N, 2.92.
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
MS: m/z: [M + H]+ 525.3; [M + Na]+ 547.5.
Anal. calcd for C27H44N2O8 (524.65): C, 61.81; H,
8.45; N, 5.34. Found: C, 61.77; H, 8.50; N, 5.30.
Methyl-4,6-O-benzylidene-2,3-dideoxy-
glucopyranosido[2,3-h]-N-3-phenylpropyl-1,4,7,10-
tetraoxa-13-azacyclopentadecane (2d)
22
Yield: 43%; α
= +28.6 (c = 1, CHCl3).
α-D-glucopyranosido[2,3-h]-N-(3-(3-
[ ]D
1H NMR (CDCl3, 300 MHz), δ (ppm): 7.50–7.44
(m, 2H), 7.39–7.32 (m, 3H), 7.30–7.23 (m, 2H), 7.21–
7.15 (m, 3H), 5.51 (s, 1H), 4.84 (d, J = 3.6 Hz, 1H),
phenyl)thiocarbamido))
propyl-1,4,7,10-tetraoxa-
13-azacyclopentadecane (2i)
22
Yield: 25%; α
= +55.2 (c = 1, CHCl3).
[ ]D
Heteroatom Chemistry DOI 10.1002/hc

8
Rapi et al.
1H NMR (CDCl3, 500 MHz), δ (ppm): 8.38 (br s,
General procedure for the Michael addition of 2-
Nitropropane to Chalcone
NH), 8.32 (br s, NH), 7.50 (d, J = 7.5 Hz, 2H), 7.36–
7.33 (m, 5H), 7.29–7.24 (m, 2H), 7.12 (t, J = 7.5 Hz,
1H), 5.08 (s, 1H), 4.76 (d, J = 3.5 Hz, 1H), 4.31–4.24
(m, 1H), 4.15 (dd, J = 10 Hz, 5 Hz, 1H), 3.99 (td, J
= 8.5 Hz, 1.5 Hz, 1H), 3.89–3.70 (m, 6H), 3.67–3.39
(m, 9H), 3.37 (s, 3H), 3.25 (dd, J = 9 Hz, 3.5 Hz, 1H),
2.80 (t, J = 8.5 Hz, 1H), 2.71–2.52 (m, 6H), 2.01–1.91
(m, 1H), 1.73–1.65 (m, 1H).
The corresponding azacrown ether catalyst (0.10
mmol) and sodium tert-butoxide (0.05 g, 0.50 mmol)
were added to a solution of chalcone (15) (0.30 g, 1.4
mmol) and 2-nitropropane (16) (0.30 mL, 3.4 mmol)
in dry toluene (3 mL). The mixture was stirred at
room temperature under argon. After a reaction time
of 8–30 h, a new portion of toluene (7 mL) and water
(10 mL) was added and the mixture was stirred for
several minutes. The organic phase was washed with
water and dried (Na2SO4). The crude product ob-
tained after evaporating the solvent was purified by
preparative TLC (silica gel, hexane-ethyl acetate 10:1
MS: m/z: [M + H]+ 632.1; [M + Na]+ 654.2.
Anal. calcd for C32H45N3O8S (631.78): C, 60.83;
H, 7.18; N, 6.65. Found: C, 60.82; H, 7.20; N,
6.63.
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
glucopyranosido[2,3-h]-N-3-(piridyn-2-yl)ethyl-
1,4,7,10-tetraoxa-13-azacyclopentadecane (2j) [16d]
Methyl-4,6-O-benzylidene-2,3-dideoxy-α-D-
as an eluent) to give adduct 17 in a pure form. Yield:
20
0.22 g (52%). mp: 146–148°C. α
= + 69.7 (c = 1,
[ ]D
CH2Cl2), 87% ee for the (+)-(R) enantiomer (using
catalyst 2g). Its spectral parameters were identical
with those described in the literature [17].
glucopyranosido[2,3-h]-N-3-(pyridin-2-yl)
propyl-
1,4,7,10-tetraoxa-13-azacyclopentadecane (2k)
22
Yield: 44%; α
= +34 (c = 1, CHCl3).
[ ]D
1H NMR (CDCl3, 500 MHz), δ (ppm): 8.53 (d, J
= 7 Hz, 1H), 7.64–7.56 (m, 1H), 7.50–7.42 (m, 2H),
7.40–7.33 (m, 3H), 7.17 (d, J = 7.5 Hz, 1H), 7.10 (d,
J = 6 Hz, 1H), 5.52 (s, 1H), 4.85 (d, J = 3.5 Hz, 1H),
4.30–4.24 (m, 1H), 4.00–3.45 (m, 17H), 3.43 (s, 3H),
3.05–2.49 (m, 8H), 2.08–1.89 (m, 2H).
General Procedure for the Addition of Diethyl
Acetamidomalonate to Trans-β-Nitrostyrene
Trans-β-nitrostyrene (18) (0.15 g, 1.0 mmol), diethyl
acetamidomalonate (19) (0.32 g, 1.5 mmol), and the
crown ether (0.15 mmol) were dissolved in a mix-
ture of anhydrous THF (0.60 mL) and Et2O (2.4 mL),
and dry Na2CO3 (0.22 g, 2.1 mmol) was added. The
reaction mixture was stirred at room temperature.
After completion of the reaction (2–7 h), the organic
phase was concentrated in vacuo and the residue
was dissolved in toluene (10 mL) and washed with
cold 10% HCl (3 × 10 mL) and water (20 mL), dried
(Na2CO3), and concentrated. The crude product (20)
was purified on silica gel by preparative TLC with
hexane-EtOAc (3:1) as an eluent. Enantioselectivi-
ties were determined by chiral HPLC analysis us-
ing a Chiralpack AD column (20°C, 256 nm, 85/15
hexane/i-PrOH, 0.8 mL/min) in comparison with au-
thentic racemic sample; tR = 17.8 min (major), tR =
C30H42N2O8 (558.66 g/mol) MS: m/z: [M + H]+
559.8; [M + Na]+ 571.7. Anal. calcd for C30H42N2O8
(558.66): C, 64.50; H, 7.58; N, 5.01. Found: C, 64.45;
H, 7.62; N, 4.97.
Methyl-4,6-O-benzylidene-2,3-dideoxy-
α-D-glucopyranosido[2,3-h]-N-(3-(2-
methoxy)ethoxy)propyl-1,4,7,10-tetraoxa-13-
azacyclopentadecane (2l)
Crown ether 2f (0.50 g, 1.0 mmol) and powdered
KOH (0.17 g, 3.0 mmol) in dry THF (15 mL) was
refluxed for 1 h under Ar, then 2-methoxyethyl-p-
toluenesulphonate (14) (0.23 g, 1.0 mmol) in THF
(15 mL) was added dropwise. The mixture was
kept boiling for 35 h, and then filtered. The solvent
was evaporated, and the crude product was puri-
fied by column chromathography (using CHCl3 as an
27.7 min (minor).
20
Data for 20: Yield: 0.25 g (70%). α
= –44.7
[ ]D
(c = 1, CHCl3, 99% ee, using catalyst 2f). mp 126–
128°C. Its spectral parameters were identical with
those described [18].
eluent).
22
Yield: 63% (0.35 g); α = +38.4 (c = 1, CHCl3).
[ ]D
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.47 (dd,
J = 7.5 Hz, 1 Hz, 2H), 7.39–7.33 (m, 3H), 5.52 (s,
1H), 4.84 (d, J = 3.5 Hz, 1H), 4.27 (dd, J = 10 Hz, 4.5
Hz, 1H), 3.99–3.91 (m, 2H), 3.86–3.69 (m, 7H), 3.66–
3.46 (m, 14H), 3.43 (s, 3H), 3.38 (s, 3H), 2.85–2.65
(m, 4H), 2.59–2.54 (m, 1H), 1.83–1.71 (m, 3H).
MS: m/z: [M + H]+ 556.2; [M + Na]+ 578.1.
Anal. calcd for C28H45NO10 (555.66): C, 60.52;
H, 8.16; N, 2.52. Found: C, 60.50; H, 8.19; N,
2.50.
General Procedure for the Darzens Condensation
To a solution of phenacyl chloride (21) (0.20 g, 1.3
mmol), benzaldehyde (22) (0.20 g, 1.9 mmol), and
the crown catalyst (0.1 mmol) in 3 mL toluene,
1.0 mL 30% aqueous NaOH solution was added.
The mixture was stirred under argon atmosphere
at room temperature. After completion of the
Heteroatom Chemistry DOI 10.1002/hc

Side-Arm Effect of a Methyl α-D-Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses
9
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reaction, toluene (7 mL) was added to the mixture
and the organic phase was washed with 10% aque-
ous hydrochloric acid (2 ×10 mL) and then with wa-
ter (10 mL), dried (Na2CO3), and the solvent was
evaporated. The crude product (23) was purified by
preparative TLC using CH2Cl2 as an eluent. Yield:
20
0.23 g (69%); α
= –154.7 (c = l, CH2Cl2), 72%
[ ]D
ee for (2R,3S) enantiomer (using catalyst 2f); mp:
64–66°C. Its spectral parameters were identical with
those described [20b].
General Procedure for the Epoxidation of
Chalcones
A mixture of chalcone (15) (0.30 g, 1.44 mmol), the
appropriate catalyst (0.10 mmol) in 3 mL toluene,
and 1 mL 20% aqueous NaOH was treated with 5.5
M TBHP in decane (0.50 mL, 2.88 mmol). The mix-
ture was stirred at room temperature. New portion
of toluene (7 mL) and water (10 mL) was added after
the completion of the reaction, and the mixture was
stirred for several minutes. 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 af-
ter evaporating the solvent was purified by prepar-
ative TLC (silica gel, hexane-ethyl acetate, 10:1 as
[16] (a) Mako´, A.; Menyha´rd, K. D.; Bako´, P.; Keglevich,
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Menyha´rt, K. D.; Sefcsik, T.; Fekete, J. J Inclusion
Phenom 2006, 55, 295–302.
the eluent) to give 23 in a pure form. Yield: 0.26
20
g (82%); α
= –201.1 (c = l, CH2Cl2), 94% ee for
[ ]D
(2R,3S) enantiomer (using catalyst 2f). mp: 64–66°C.
Its spectral parameters were identical with those de-
scribed [22a].
´
[17] Bako´, P.; Szo¨llo˝sy A.; Bombicz, P.; To˝ke, L. Het-
eroatom Chem 1997, 8, 333–337.
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L.; Vigh, T.; Gru¨n, A.; Holczbauer, T. Tetrahedron
Lett 2011, 52, 1473–1476.
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Heteroatom Chemistry DOI 10.1002/hc