Enantioselective cyclopropanation of conjugated cyanosulfones using carbohydrate-based crown ether catalysts

Article abstract of DOI:10.1016/j.tet.2020.130965

A few new D-galactose- and D-glucose-based monoaza-15-crown-5 type lariat ethers have been synthesized. These macrocycles and their derivatives proved to be efficient catalysts in the cyclopropanation of (E)-3-phenyl-2-(phenylsulfonyl)acrylonitrile performed with diethyl bromomalonate under mild phase transfer conditions. Among the catalysts tested, the macrocycle having methyl α-D-galactopyranoside unit generated the highest asymmetric induction (80% ee). In the reactions of the aryl-substituted phenylsulfonyl-acrylonitrile derivatives, the cyclopropanation of the meta- and para-substituted starting materials took place with high ee values (75–84% ee). The cyclopropane derivatives synthesized from analogous α,β-unsaturated cyanosulfones containing naphthyl, pyridyl, furyl and thienyl groups were obtained with enantioselectivities up to 85%, and in excellent yields.

Full text of DOI:10.1016/j.tet.2020.130965

Journal Pre-proof
Enantioselective cyclopropanation of conjugated cyanosulfones using carbohydrate-
based crown ether catalysts
Tamás Nemcsok, Zsolt Rapi, Péter Bagi, Ying Hou Guan, István Orbán, György
Keglevich, Péter Bakó
PII:
S0040-4020(20)30057-0
https://doi.org/10.1016/j.tet.2020.130965
TET 130965
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 November 2019
Revised Date: 13 January 2020
Accepted Date: 17 January 2020
Please cite this article as: Nemcsok Tamá, Rapi Z, Bagi Pé, Guan YH, Orbán Istvá, Keglevich Gyö,
Bakó Pé, Enantioselective cyclopropanation of conjugated cyanosulfones using carbohydrate-based
crown ether catalysts, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.130965.
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1
Enantioselective cyclopropanation of conjugated cyanosulfones using
carbohydrate-based crown ether catalysts
Tamás Nemcsok, Zsolt Rapi, Péter Bagi, Ying Hou Guan, István Orbán, György Keglevich, Péter
Bakó*
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box
91, 1521 Budapest, Hungary, E-mail: pbako@mail.bme.hu
Abstract
A few new D-galactose- and D-glucose-based monoaza-15-crown-5 type lariat ethers
have been synthesized. These macrocycles and their derivatives proved to be efficient
catalysts in the cyclopropanation of (E)-3-phenyl-2-(phenylsulfonyl)acrylonitrile performed
with diethyl bromomalonate under mild phase transfer conditions. Among the catalysts tested,
the macrocycle having methyl α-D-galactopyranoside unit generated the highest asymmetric
induction (80% ee). In the reactions of the aryl-substituted phenylsulfonyl-acrylonitrile
derivatives, the cyclopropanation of the meta- and para-substituted starting materials took
place with high ee values (75-84% ee). The cyclopropane derivatives synthesized from
analogous α,β-unsaturated cyanosulfones containing naphthyl, pyridyl, furyl and thienyl
groups were obtained with enantioselectivities up to 85%, and in excellent yields.
Keywords
Phase transfer catalysis, Chiral crown ethers, Enantioselective cyclopropanation
1. Introduction
The chiral cyclopropane moiety is an important building block of numerous
biologically active compounds and natural products.1 Moreover, cyclopropane derivatives are
considered important intermediates in organic synthesis, particularly if electron-donating and
electron-withdrawing groups are introduced into the molecule in the appropriate position,
since the easy ring cleavage of the three-membered ring.2 The synthesis of optically active
cyclopropanes have been intensively studied, especially applying the Simmons-Smith
reaction3 and the decomposition of diazoalkanes as carbene precursors in the presence of
transition-metal complex catalysts.4 The Michael-initiated ring closure (MIRC) reaction is
another powerful method for the preparation of cyclopropanes, as it requires cheap and
readily available reagents along with mild reaction conditions. In the last two decades,
different chiral catalysts have been developed to perform MIRC reactions in an
enantioselective manner.5 Among them asymmetric phase transfer catalysis is an attractive

2
method to perform stereoselective MIRC reactions, as it offers several advantages, such as
operational simplicity, mild reaction conditions, inexpensive and environmentally benign
reagents and solvents, as well as suitability for large-scale syntheses.6 However, the
application of chiral phase transfer catalysts in enantioselective MIRC-type cyclopropanations
has been limited to only a few examples.7 Previously, in our group a few carbohydrate-based
crown ethers proved to be highly enantioselective in several Michael additions and MIRC
reactions.8 Crown ethers with carbohydrate moieties form a special group of chiral
macrocycles which can be used as phase transfer catalysts in asymmetric syntheses. Sugar-
based chiral catalysts have several advantages: carbohydrates used as starting materials are, in
most cases, inexpensive, and easily available commercial products; they are biocompatible;
and available in enantiomerically pure form with known chiroptical properties. Carbohydrates
have functionalities which can be used to establish secondary binding sites, as well as
catalytic sites. Chiral crown ethers have been synthesized from various carbohydrates, e.g.
from
sugar alcohols (such as
In our previous works the
D
-glucose9,
D
-galactose10,
-mannitol or
D
-mannose11,
-threitol).15
-galactose- and
D D- or L L
-altrose12, -xylose13, -arabinose14, and
D
L
D
D-glucose-based monoaza-15-crown-5
macrocycles with alkyl or aralkyl substituents on the N-atom proved to be the most efficient
in a few asymmetric reactions.16 In these molecules 4- and 6-hydroxy groups of the
hexopyranosides are protected as benzylidene acetals (Figure 1), which lend some rigidity to
the ring system. In the present work, this basic scaffold was preserved. Previously, the
structure-activity studies revealed that the R1 substituent on the C-1 atom of the sugar moiety,
and the side arm (R2) of the macrocycle have a significant impact on the asymmetric
induction during Michael additions,17,18 therefore the syntheses of a few new derivatives with
α-OMe, β-OMe, β-OPh and β-O-naphthyl groups in the C-1 position of the sugar moiety with
hydroxypropyl and methoxy substituted phenylethyl side arm on the N-atom of the crown ring
was planned.
Figure 1. The general structure of the most efficient catalysts so far

3
The asymmetric cyclopropanation of (E)-3-phenyl-2-(phenylsulfonyl)acrylonitrile, and
its derivatives, is an important reaction, since the formed, highly functionalized enantiopure
cyclopropanes can be further transformed to other siginifcant chiral products. Cobb et al. used
a quinine-derived organocatalyst for the cyclopropanation of α,β-unsaturated cyanosulfones
using dimethyl bromomalonate to afford chiral cyclopropanes in high yield, and in good
enantioselectivities (58-82%).19 Despite the good results, the applied methodology has the
disadvantage of long reaction time (120 h), and not too robust reaction conditions (-10 °C).
The authors also demonstrated the utility of the resulting cyclopropanes as synthetic
intermediates, for instance in the synthesis of δ3-amino acids. In this work, we intended to
extend the application of carbohydrate-based crown ethers to the aformentioned MIRC
reaction by using the new and the previously efficient catalysts of our group.
2. Results and discussion
2.1. Synthesis of the new monoaza crown ethers
D-Galactose-based macrocycles have been synthesized only with hydroxypropyl and
methoxypropyl side chain so far,8b,8e although other carbohydrate-based crown ethers with
phenylethyl side arm also proved to be effective.17 Thus, the syntheses of three new galactose-
based macrocycle with methoxy-substituted phenylethyl side arm was targeted. The starting
material for the syntheses of these crown compounds were the bisiodo podands 1a and 1b that
were synthesized according to methods reported by our group.8b,8e The ring closures were
performed by reaction with the appropriate primary amines in boiling acetonitrile in the
presence of Na2CO3. Intermediate 1a was cyclized with 2-(2-methoxyphenyl)ethylamine and
2-(3,4-dimethoxyphenyl)ethylamine, while bisiodo compound 1b was reacted only with 2-
(3,4-dimethoxyphenyl)ethylamine (Scheme 1). The
D-galactopyranoside-based monoaza
crown ethers 2a-c were isolated in moderate yields (55-64%) after purification by
chromatography.
The phenyl β-glucopyranoside-based macrocycles proved to be highly effective in a
few Michael additions,17 therefore we wished to study the effect of a more bulky aromatic
substituent, such as 2-naphthyl, in the C-1 position of the glucose unit on the
enantioselectivity. The starting material for the 2-naphthyl-substituted crown ether was the
2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (3), which was reacted with β-naphthol
under phase transfer conditions applying the method of Sidhu et al. (Scheme 2.).20 The β-
anomer 4 was isolated in 29% yield after recrystallization.

4
Scheme 1. Synthesis of the
D-galactose-based crown ethers 2a-c
Then, the acetyl groups were cleaved using the Zemplén deacetylation to afford
intermediate 5 in a yield of 99%. The 4- and 6-hydroxy groups of the glucopyranoside
moiety were protected with benzaldehyde dimethylacetal in DMF in the presence of p-
toluenesulfonic acid as the catalyst, affording protected glucose derivative 6 in 57% yield
after recrystallization from 2-propanol.
Scheme 2. The synthesis of 2-naphthyl 4,6-O-benzylidene-β-D-glucopyranoside (6)
The monoaza-15-crown ring was built on the free vicinal hydroxy groups of
monosaccharide 6, applying the method elaborated earlier (Scheme 3).9b The 2- and 3-
hydroxy groups of 6 were alkylated with bis(2-chloroethyl)ether in the presence of 50% aq.
NaOH and tetrabutylammonium hydrogensulfate, affording bischloro compound 7 in good
yield (71%) after recrystallization from a mixture of EtOH-hexane. The exchange of chlorine
to iodine in intermediate 7 was accomplished by reaction with NaI in boiling acetone to
provide the bisiodo intermediate 8a in excellent yield (93%).

5
Scheme 3. Synthesis of bisiodo podand 8a
The ring closure reaction of bisiodo derivative 8a was performed with two primary
amines (3-aminopropan-1-ol and 2-(3,4-dimethoxyphenyl)ethylamine), selected on the basis
of our previous experiments (Scheme 4).17,21 The reactions took place in acetonitrile in the
presence of Na2CO3, giving monoaza crown ethers 9a and 9b in moderate yields (46% and
61%, respectively) after purification by chromatography. The cyclization of the α-methyl and
β-methyl substituted bisiodo compounds (8b-c) with 2-(3,4-dimethoxyphenyl)ethylamine was
also realized under the same reaction conditions. The new crown compounds (9c-d) were
isolated in 59% and 65% yields (Scheme 4).
Y
Y
O
amine
CH3CN
O
O
O
O
O
O
I
I
O
O
N R
Na2CO3
reflux, Ar
O
O
O
O
O
Ph
Ph
8a
8b
8c
9a Y =
O(naphthalen-2-yl) R =
O(naphthalen-2-yl) R =
Me R =
(46%)
OH
Y =
Y =
Y =
O(naphthalen-2-yl)
Me
Me
9b
9c
Y =
Y =
(61%)
OMe
OMe
(59%)
(65%)
9d Y =
Me R =
amine: 3-aminopropan-1-ol or 2-(3,4-dimethoxyphenyl)ethylamine
Scheme 4. Synthesis of
D-glucose-based crown ethers 9a-c
2.2. Asymmetric MIRC reaction of α,β-unsaturated cyanosulfones
The utility of carbohydrate-based crown ethers in the asymmetric MIRC reaction of
(E)-3-phenyl-2-(phenylsulfonyl)acrylonitrile (10a) with diethyl bromomalonate (11) was
investigated. The catalysts applied for this cyclopropanation are presented in Figure 2. Beside
testing the new macrocycles, a few previously synthesized
D-glucose- and D-galactose-based
lariat ethers (2d,8b 2e,8e 2f,8e 9e22) were also used. The applied lariat ethers differ in the

6
configuration of the sugar unit, in the substituent at the C-1 position, and in the side chain on
the nitrogen atom of the crown ring. We hoped that a better understanding of the structure-
activity relationship may be achieved by using these differently substituted hexopyranoside-
based monoaza crown ethers in the aforementioned MIRC reaction.
Figure 2. Catalysts applied in the asymmetric MIRC reaction of cyanosulfone 10a
First, the screening of the catalysts was performed. The reactions of cyanosulfone 10a
with diethyl bromomalonate (1.5 equivalents) took place in dry dichloromethane, using 10
mol% crown ether as the catalyst, and 2 equivalents of Na2CO3 as the base. The crude
products were purified by preparative TLC, and the enantiomeric purity was determined by
chiral HPLC analysis. The results are summarized in Table 1. It can be seen from Table 1,
that the chiral cyclopropane 12a was isolated in good yields (85-94%), while the enantiomeric
excesses altered between 18-80% depending on the nature of the catalyst. A single
diastereomer was formed (as checked by NMR) in all cases. Relative configuration of the
cyclopropane ring in phenyl-substituted 12a and 2-naphthyl-substituted 12n was evaluated by
a series of NOE (Nuclear Overhauser Effect) measurements. Selective irradiation of the
ortho-protons of the phenylsulfonyl group resulted in the increase in the intensity of the signal

7
of the CH group of the cyclopropane ring and that of the CH2 group of one ethyl ester
function. Hence the proximity of these three functions was proved suggesting that they are
located on the same side of the cyclopropane ring. From this it follows that the sterically
demanding phenylsulfonyl and phenyl or naphthyl substituenst are located in the opposite, i.e.
in the anti (trans) disposition.The above explanation is only one of the two NOE
measurements. However, the conclusion was also proved from the other way round, i.e. on
irradiation of the CH signals, the intensity was increased on the signals of the ortho protons of
the phenylsulfonyl moiety, and on irradiation of the ortho hydrogens of the naphthyl group,
there was an intensity increase in the signals of the suitable protons of the ethyl ester.
Among the galactose-based lariat ethers (2a-2f), the highest enantioselectivity (80%)
was observed using methyl α-D-galactopyranoside-based macrocycle 2b having 2-(3,4-
dimethoxyphenyl)ethyl side chain (Table 1, entry 2). Catalyst 2a with 2-(2-
methoxyphenyl)ethyl side chain generated approximately the same enantiomeric excess
(76%), while the experiment with lariat ether 2d with hydroxypropyl side arm resulted in a
somewhat lower ee value (62%) (Table 1, entries 1 and 4). Using phenyl β-galactopyranoside-
based crown ethers 2c and 2e the product (12a) was isolated in 72% ee and 43% ee,
respectively (Table 1, entries 3 and 5). The β-isopropyl derivative 2f generated an asymmetric
induction of 61% (Table 1, entry 6). The reactions performed with D-glucose-based catalysts
(9a-e) resulted with somewhat weaker selectivities (18-73% ee) (Table 1, entries 7-11). If we
compare catalyst 9e with 2d, and 9d with 2b, differing only in the configuration of the sugar
unit, it may be concluded that regarding the enantioselectivity the
D-galactose-based crown
ethers are somewhat more efficient than the -glucose-based ones (2d: 62% ee, 9e: 50% ee,
D
2b: 80% ee, 9d: 73% ee). The presence of the more bulky β-2-naphthyloxy substituent in
position C-1 of the glucopyranoside-based catalysts 9a and 9b decreased drastically the
observed ee values (18% and 35%, respectively), as compared to the β-methyl analogue 9c
(58% ee). One can draw the conclusion that catalysts with substituted phenylethyl side arms
were more efficient in all cases, and that using
D-galactose-based macrocycles, the product
(12a) was formed in slightly higher ee values, than applying the
D-glucose-based ones. The
substituent of the C-1 position also had a significant impact on the selectivity. The alkyl
derivatives were more efficient than the more bulky aromatic derivatives.

8
Table 1. Catalyst screening in the asymmetric MIRC reaction of cyanosulfone 10a
Catalyst
Sugar unit
Me-α-galactose
Me-α-galactose
Ph-ß-galactose
Entry
Yield (%) ee (%)a
No.
2a
2b
2c
2d
2e
2f
9a
9b
9c
9d
9e
Side arm
(CH2)2-2-MeOC6H4
(CH2)2-3,4-(MeO)2C6H3
(CH2)2-3,4-(MeO)2C6H3
(CH2)3OH
1
2
3
4
5
6
7
8
9
95
93
90
85
91
93
88
90
91
94
89
76
80
72
62
43
61
18
35
58
73
50
Me-α-galactose
Ph-ß-galactose
(CH2)3OH
(CH2)3OH
(CH2)3OH
iPr-β-galactose
(naphthalen-2-yl)-β-glucose
(naphthalen-2-yl)-β-glucose (CH2)2-3,4-(MeO)2C6H3
Me-β-glucose
Me-α-glucose
Me-α-glucose
(CH2)2-3,4-(MeO)2C6H3
(CH2)2-3,4-(MeO)2C6H3
(CH2)3OH
10
11
a: based on chiral HPLC analysis
After screening the catalysts the influence of the solvent was investigated using
macrocycle 2b. It was found that applying CH2Cl2, CHCl3, Et2O, MTBE, toluene and EtOAc
as the solvent, the yield of cyclopropane 12a (86-95%) did not depend much on the medium
used, however, the enantiomeric purity of the product showed a significant dependence (51-
80% ee). It turned out that dichloromethane is the choice of solvent regarding the
enantioselectivity (Table 2.).
Table 2. Solvent screening in the asymmetric MIRC reaction of cyanosulfone 10a
Solvent
Time (h)
Yield (%)
ee (%)a
CH2Cl2
CHCl3
Et2O
24
24
48
48
24
48
93
91
95
94
86
87
80
75
69
60
67
51
MTBE
Toluene
EtOAc
a: based on chiral HPLC
Next, the effect of the substituents in the aromatic ring of cyanosulfone 10a on the
enantioselectivity was studied in the presence of methyl α-galactopyranoside-based lariat

9
ether 2b. The results of the experiments starting from chloro-, methyl-, nitro-, methoxy-
substituted cyanosulfones (10b-m) and other analogues (10n-q, Ar = 2-naphthyl, 3-pyridyl, 2-
furyl, 2-thienyl) are presented in Table 3. In the reaction of 2-Cl, 3-Cl and 4-Cl cyanosulfones
(10b, 10c, 10d) with bromomalonate 11, ee values of 2%, 84% and 81%, respectively, were
detected (Table 3, entries 1-3), while with the 2-Me-, 3-Me- and 4-Me-substituted
cyanosulfones (10e, 10f and 10g), the ee values were 3%, 81% and 78%, respectively (Table
3, entries 4-6). The 2-NO2, 3-NO2 and 4-NO2 cyclopropane derivatives (12h, 12i, and 12j)
were formed with ee values of 12%, 75% and 82%, respectively (Table 3, entries 7-9). In the
case of 2-MeO, 3-MeO and 4-MeO substituents, the cyclopropane derivatives 12k, 12l and
12m were obtained with 3%, 81% and 77% ee, respectively. If one regards the results
obtained for substituted cyclopropanes 12b-m, an interesting tendency can be observed (Table
3, entries 1-12). Within the above series, the maximum ee values were obtained with meta-
and para-substituted cyanosulfones (Table 3, entries 2-3, 5-6, 8-9 and 11-12). At the same
time, the ortho-substituents, which are closer to the reaction center, caused a significant
decrease in the ee values (Table 3, entries 1, 4, 7 and 10), as in these cases almost racemic
products were isolated (3-12% ee). The meta- and para-derivatives, with any kind of
substituents were formed with approximately the same enantiomeric excess (75-84%). These
values are very similar to that obtained in case of the unsubstituted cyclopropane 10a (80%
ee). The outcome seems to be almost independent of the nature of the substituent, no matter if
it is an electron-withdrawing or an electron-donating one. The above phenomenon definitely
refers to the importance of steric effect.
Cyclopropane derivatives 12n-q were obtained with moderate to good
enantioselectivities (40-85%), and in good yields (86-94%). The 2-naphthyl analogue 12n was
formed with the highest ee value (85% ee), while 3-pyridyl and 2-thienyl derivatives 12o and
12q were both isolated in an ee of 72%. The experiment giving cyclopropane 12p (Ar = 2-
furyl) resulted in the lowest enantioselectivity (40%).

10
Table 3. The asymmetric MIRC reaction of cyanosulfone derivatives 10b-q catalyzed by
crown catalyst 2b
Entry
Ar
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-naphtyl
72
24
24
48
24
24
24
24
24
24
24
24
48
24
24
24
12b: 83
12c: 91
12d: 94
12e: 95
12f: 90
12g: 87
12h: 91
12i: 91
12j: 87
12k: 89
12l: 95
12m: 94
12n: 92
12o: 88
12p: 86
12q: 94
2
84
81
1
81
78
12
75
82
3
81
77
85
72
40
72
3-pyridyl
2-furyl
2-thienyl
a: based on chiral HPLC
3. Conclusions
An efficient method have been developed for the enantioselective synthesis of a series
of highly substituted cyclopropane derivatives by the reaction of α,β-unsaturated
cyanosulfones with diethyl bromomalonate in the presence of carbohydrate-based lariat ethers
as the phase transfer catalysts under mild conditions. Comparing the sugar unit with two
different configurations in the macrocycles, it can be established that regarding
enantioselectivity, the
D-galactose-based crown ethers are slightly more efficient than the
D-
glucose-based ones. Among the tested catalysts, a new methyl α-D-galactopyranoside-based
macrocycle with a 2-(3,4-dimethoxyphenyl)ethyl side arm generated the highest asymmetric
induction (80% ee). It was found that in the presence of this catalyst, the position of the
substituents in the aromatic ring of 3-phenyl-2-(phenylsulfonyl)acrylonitrile had a significant
impact on the yield and enantioselectivity. The meta- and para-substituted cyclopropane
derivatives were isolated with high enantiomeric excesses (75-84%), while the ortho

11
analogues were formed almost as racemates (3-12% ee). This phenomenon refers to the role
of steric effect on the asymmetric induction. The new cyclopropane derivatives prepared in
our experiments can be important intermediates in other asymmetric syntheses.
4. Experimental
4.1. General
Melting points were determined by using a Stuart SMP10 apparatus and are uncorrected. The
specific rotation was measured on a Perkin-Elmer 341LC polarimeter at 22°C. Nuclear
magnetic resonance spectra were obtained on a Bruker (Billerica, MA) DRX-500 or Bruker-
300 instrument in CDCl3 with Me4Si as an internal standard. The exact mass measurements
were performed by using quadrupole time of flight mass spectrometer Premier mass
spectrometer (Waters, Milford, MA) in positive electrospray ionization mode. Analytical and
preparative thin-layer chromatography (TLC) was performed on silica gel plates (60 GF254,
Merck, Darmstadt, Germany). Chiral separation of the enantiomers was carried out on a
PerkinElmer Series 200 liquid chromatography system using different columns. In all cases,
isocratic elution was applied with a mobile phase flow rate of 0.8 mL/min. The temperature
was 20 °C, and the wavelength of the detector was 254 nm.
4.2.
Synthesis of bisiodo compound 8
4.2.1. 2-Naphthyl 4,6-O-benzylidene-β-D-glucopyranoside (6)
2-Naphthyl β-D-glucopyranoside (5) (9.04 g, 29.5 mmol) was dissolved in dry
dimethylformamide (50 ml), then benzaldehyde dimethylacetal (8.90 ml, 59 mmol) and
pTsOH (0.56 g, 3.0 mmol) were added. The mixture was stirred at 80 °C for 48 h under Ar.
After cooling to room temperature, Et3N was added, then the volatiles were removed by
vacuum distillation. The residue was dissolved in CHCl3, and the organic solution was
washed with saturated NaHCO3 solution. The organic layer was dried, filtered then
concentrated in vacuum. The crude product was crystallized from 2-propanol.
1
Yield: 57% (6.65 g); white solid, mp 200-201 °C;
= -39.2 (c = 1, CHCl3); H NMR
(500 MHz, CDCl3/TMS), δ (ppm): 7.80 (dd, J = 11.2, 7.6 Hz, 3H, ArH), 7.58-7.36 (m, 8H,
ArH), 7.28 (dd, J = 8.9, 2.6 Hz, 1H, ArH), 5.59 (s, 1H, ArCH); 5.20 (d, J = 7.5, 1H, H- );
1
4.43 (dd, J = 10.4, 3.9 Hz, 1H, H-6a), 4.05-3.80 (m, 3H, H-6b, H-4, H-5), 3.94-3.79 (m, 2H,
H-4, H-5), 3.74-3.61 (m, 2H, H-2, H-3), 3.01 (s, 1H, OH), 2.94 (s, 1H, OH).

12
4.2.2. 2-Naphthyl 4,6-O-benzylidene-2,3-bis-O-[(2-chloroethoxy)-ethyl)]-β-D-
glucopyranoside
(7)
To a mechanically stirred solution of 2-naphthyl 4,6-O-benzylidene-β-D-glucopyranoside
(6.65 g, 16.9 mmol) in bis(2-chloroethyl)ether (60 ml, 0.51 mol), 50% aq. NaOH solution (60
ml) and equimolar amount of Bu4NHSO4 (5.73 g, 16.9 mmol) was added. The reaction
mixture was stirred vigorously for 10 h at room temperature, then poured into a mixture of
CH2Cl2 and water. The phases were separated, and the aqueous layer was extracted with
CH2Cl2 three times. The combined organic layers were washed with water, dried and
concentrated in vacuum. The excess of the bis(2-chloroethyl)ether was removed by vacuum
distillation, and the crude product was purified by recrystallization from EtOH-hexane
mixture.
1
Yield: 71% (7.31 g); yellowish white solid, mp 85-87 °C;
= -19.3 (c = 1, CHCl3); H
NMR (500 MHz, CDCl3/TMS), δ (ppm): 7.83-7.73 (m, 3H, ArH), 7.53-7.44 (m, 3H, ArH),
7.40-7.37 (m, 5H, ArH), 7.28 (dd, J = 8.9, 2.6 Hz, 1H, ArH), 5.57 (s, 1H, ArCH), 5.21 (d, J =
7.6 Hz, 1H, H-1), 4.41 (dd, J = 10.6, 5.0 Hz, 1H, H-6a), 4.15-3.96 (m, 4H, H-2, H-4, H-5, H-
6b), 3.82 (t, J = 10.3 Hz, 1H, H-3), 3.77-3.49 (m, 16H, 6 x OCH2, 2 x CH2Cl).
4.2.3. 2-Naphthyl 4,6-O-benzylidene-2,3-bis-O-[(2-iodoethoxy)-ethyl)]-β-D-
glucopyranoside
(8)
To the solution of bischloro compound 7 (7.30 g, 12.0 mmol) in dry acetone (120 ml), NaI
(7.20g, 48.0 mmol) was added, and the solution was stirred at reflux temperature for 40 h. The
mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue
was dissolved in CHCl3, washed with water three times, and the aqueous phase was extracted
with CHCl3. The combined organic layer was dried and concentrated in vacuum.
1
Yield: 93% (8.82 g); white solid, mp 110-112 °C;
= -12.6 (c = 1, CHCl3); H NMR
(500 MHz, CDCl3/TMS), δ (ppm): 7.78 (dd, J = 17.8, 8.4 Hz, 3H, ArH), 7.54-7.44 (m, 3H,
ArH), 7.43-7.34 (m, 5H, ArH), 7.29-7.25 (m, 1H, ArH), 5.58 (s, 1H, ArCH), 5.21 (d, J = 7.6
Hz, 1H, H-1), 4.40 (dd, J = 10.6, 5.0 Hz, 1H, H-6a), 4.15-3.95 (m, 4H, H-2, H-4, H-5, H-6b),
3.82 (t, J = 10.3 Hz, 1H, H-3), 3.75-3.53 (m, 12H, 6 x OCH2), 3.25-3.13 (m, 4H, 2 x CH2I).
4.3. General procedure for the preparation of crown ethers
The appropriate bisiodo podand was dissolved in dry CH3CN and anhydrous Na2CO3 (6
equivalents), and the appropriate amine (1 equivalent) was added under Ar. The mixture was
refluxed for 50 hours. Then, the solvent was removed, the residue was dissolved in a mixture

13
of CHCl3 and water, the layers were separated, and the organic phase was washed with water,
dried (Na2SO4), then concentrated. The crude product was purified by column
chromatography.
4.3.1. Methyl 4,6-O-benzylidene-2,3-dideoxy-α-D-galactopyranosido-[2,3h]-N-(2-(2-
methoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (2a)
Bisiodo compound 1a (3.39 g, 5.0 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (3.18 g,
30.0 mmol); 2-(2-methoxyphenyl)ethylamine (0.76 g, 5.0 mmol). Eluent: CHCl3:MeOH
100:2 → 100:8 (silica gel). Yield: 61% (1.75 g), brown oil; = +79.0 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 7.52 (dd, J = 7.7, 1.5 Hz, 2H, ArH), 7.37-7.31 (m, 3H,
ArH), 7.18-7.11 (m, 2H, ArH), 6.86 (td, J = 7.4, 1.2 Hz, 1H, ArH), 6.82 (dd, J = 8.2, 1.1 Hz,
1H, ArH), 5.55 (s, 1H, PhCH), 4.96 (d, J = 3.4 Hz, 1H, H-1), 4.33 (s, 1H, H-3), 4.28 (dd, J =
12.4, 1.6 Hz, 1H, H-6a), 4.08 (dd, J = 12.5, 1.8 Hz, 1H, H-6b), 3.93 (dd, J = 10.0, 3.5 Hz, 1H,
H-5), 3.79-3.53 (m, 17H, OCH3, 6 x OCH2, H-2, H-4), 3.43 (s, 3H, OCH3), 2.96-2.69 (m, 8H,
13
NCH2, ArCH2). C NMR (75 MHz, CDCl3/TMS) δ (ppm): 157.49, 137.88, 130.48, 128.91,
128.13, 127.44, 126.43, 126.32, 120.54, 110.29, 101.03, 98.66, 77.27, 75.72, 73.66, 73.63,
70.56, 70.24, 69.55, 62.51, 55.53, 55.29, 54.23.
4.3.2. Methyl 4,6-O-benzylidene-2,3-dideoxy-α-D-galactopyranosido-[2,3h]-N-(2-(3,4-
dimethoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (2b)
Bisiodo compound 1a (3.39 g, 5.0 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (3.18 g,
30.0 mmol); 2-(3,4-dimethoxyphenyl)ethylamine (0.91 g, 5.0 mmol). Eluent: CHCl3:MeOH
100:0 → 100:3 (silica gel). Yield: 55% (1.66 g), brown oil; = +92.4 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 7.51 (dd, J = 7.8, 1.8 Hz, 2H, ArH), 7.38-7.31 (m, 3H,
ArH), 6.77 (d, J = 8.2 Hz 1H, ArH), 6.73-6.69 (m, 2H, ArH), 5.54 (s, 1H, PhCH), 4.96 (d, J =
3.2 Hz, 1H, H-1), 4.34 (s, 1H, H-3), 4.28 (dd, J = 12.5, 1.5 Hz, 1H, H-6a), 4.08 (dd, J = 12.5,
1.9 Hz, 1H, H-6b), 3.95-3.90 (m, 1H, H-5), 3.89-3.53 (m, 21H, 2 x OCH3, 6 x OCH2, H-2, H-
3, H-4), 3.43 (s, 3H, OCH3), 3.11-2.68 (m, 8H, 3 x NCH2, ArCH2). 13C NMR (75 MHz,
CDCl3/TMS) δ (ppm): 148.94, 137.37, 128.98, 128.25, 126.05, 126.02, 120.61, 112.11,
111.30, 101.33, 98.17, 82.32, 79.75, 77.94, 77.25, 72.55, 70.64, 70.40, 70.13, 69.05, 62.21,
55.93, 55.24.

14
4.3.3. Phenyl 4,6-O-benzylidene-2,3-dideoxy-β-D-galactopyranosido-[2,3h]-N-(2-(3,4-
dimethoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (2c)
Bisiodo compound 1b (3.70 g, 5.0 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (3.18 g,
30.0 mmol); 2-(3,4-dimethoxyphenyl)ethylamine (0.91 g, 5.0 mmol). Eluent: CHCl3:MeOH
100:0 → 100:3 (silica gel). Yield: 64% (2.12 g), brown oil; = -4.3 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 7.57-7.49 (m, 2H, ArH), 7.38-7.31 (m, 3H, ArH), 7.30-
7.26 (m, 2H, ArH), 7.08-7.00 (m, 3H, ArH), 6.79-6.67 (m, 3H, ArH), 5.54 (s, 1H, PhCH),
4.98 (d, J = 7.8 Hz, 1H, H-1), 4.38-4.29 (m, 2H, H-3, H-6a), 4.12-3.96 (m, 3H, H-6b, OCH2),
3.91-3.48 (m, 19H, 5 x OCH2, 2 x OCH3, H-2, H-4, H-5), 3.10-2.53 (m, 8H, 3 x NCH2,
13
ArCH2). C NMR (75 MHz, CDCl3/TMS) δ (ppm): 157.53, 148.95, 137.77, 129.43, 129.01,
128.14, 126.48, 122.71, 120.65, 117.31, 112.22, 111.40, 102.15, 101.33, 79.52, 72.51, 70.74,
70.23, 69.27, 68.70, 66.58, 55.97.
4.3.4. 2-Naphthyl 4,6-O-benzylidene-2,3-dideoxy-β-D-glucopyranosido-[2,3h]-N-(3-
hydroxypropyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (9a)
Bisiodo compound 8a (3.30 g, 4.2 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (2.66 g,
25.1 mmol); 3-aminopropan-1-ol (0.31 g, 4.2 mmol). Eluent: CHCl3:MeOH 100:1 (Al2O3).
1
Yield: 46% (1.17 g), white amorphous solid; = -26.6 (c = 1, CHCl3). H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 7.81-7.73 (m, 3H, ArH), 7.51-7.43 (m, 3H, ArH), 7.41-7.34 (m, 5H,
ArH), 7.22 (dd, J = 8.9, 2.5 Hz, 1H, ArH), 5.56 (s, 1H, ArCH), 5.22 (d, J = 7.7 Hz, 1H, H-1),
4.39 (dd, J = 10.5, 5.0 Hz, 1H, H-6a), 4.14-4.97 (m, 4H, H-2, H-4, H-5, H-6b), 3.84-3.54 (m,
16H, H-3, 6 x OCH2, CH2OH, OH), 2.88-2.80 (m, 2H, NCH2), 2.75-2.66 (m, 4H, 2 x NCH2),
1.75-1.62 (m, 2H, CH2CH2OH). 13C NMR (75 MHz, CDCl3/TMS) δ 154.82, 137.26, 134.21,
130.05, 129.65, 129.01, 128.27, 127.67, 127.17, 126.53, 126.05, 124.54, 118.86, 111.54,
102.20, 101.24, 81.81, 81.46, 80.99, 77.23, 72.55, 72.35, 70.37, 70.26, 68.76, 66.19, 64.14,
56.53, 54.27, 54.22, 28.38.
4.3.5. 2-Naphthyl 4,6-O-benzylidene-2,3-dideoxy-β-D-glucopyranosido-[2,3h]-N-(2-(3,4-
dimethoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (9b)
Bisiodo compound 8a (3.30 g, 4.2 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (2.66 g,
25.1 mmol); 2-(3,4-dimethoxyphenyl)ethylamine (0.76 g, 4.2 mmol). Eluent: CHCl3:MeOH
100:0 → 100:3 (silica gel). Yield: 61% (1.82 g), white amorphous solid; = -19.7 (c = 1,
1
CHCl3). H NMR (500 MHz, CDCl3/TMS) δ (ppm): 7.82-7.74 (m, 3H, ArH); 7.51-7.44 (m,
3H, ArH); 7.42-7.34 (m, 5H, ArH); 7.23 (dd, J = 8.9, 2.5 Hz, 1H, ArH); 6.80-6.76 (m, 1H,
ArH); 6.75-6.71 (m, 2H, ArH), 5.57 (s, 1H, ArCH); 5.23 (d, J = 7.6 Hz, 1H, H-1); 4.40 (dd, J

15
= 10.6, 5.1 Hz, 1H, H-6a), 4.16-4.00 (m, 4H, H-2, H-4, H-5, H-6b); 3.87 (s, 3H, OCH3); 3.84
(s, 3H, OCH3); 3.82-3.54 (m, 13H, H-3, 6 x OCH2); 3.16-2.60 (m, 8H, 3 x NCH2, ArCH2).
13C NMR (75 MHz, CDCl3/TMS) δ (ppm): 154.78, 148.85, 147.37, 137.23, 134.21, 130.06,
129.70, 129.10, 129.05, 128.29, 127.68, 127.16, 126.58, 126.04, 124.60, 120.57, 118.81,
112.10, 111.53, 111.26, 102.23, 101.26, 81.75, 81.55, 80.98, 72.55, 72.38, 70.54, 68.75,
66.19, 58.75, 55.93, 54.00.
4.3.6. Methyl 4,6-O-benzylidene-2,3-dideoxy-β-D-glucopyranosido-[2,3h]-N-(2-(3,4-
dimethoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (9c)
Bisiodo compound 8b (3.39 g, 5.0 mmol); dry CH3CN (50 mL), anhydrous Na2CO3 (3.18 g,
30.0 mmol); 2-(3,4-dimethoxyphenylethyl)amine (0.91 g, 5.0 mmol). Eluent: CHCl3:MeOH
100:0 → 100:6 (silica gel). Yield: 59% (1.78 g), brown oil; = -42.4 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 7.48-7.44 (m, 2H, ArH), 7.39-7.33 (m, 3H, ArH), 6.80-
6.77 (m, 1H, ArH), 6.73 (dd, J = 5.9, 2.1 Hz, 2H, ArH), 5.53 (s, 1H, PhCH), 4.38-4.31 (m,
2H, H-1, H-6a), 3.99-3.94 (m, 2H, H-4, H-5), 3.90 (dt, J = 10.6, 3.5 Hz, 1H, OCH2), 3.87 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 3.79-3.67 (m, 3H, H-2, OCH2), 3.58 (dd, J = 10.0, 5.7 Hz,
6H, 3 x OCH2), 3.54 (s, 3H, OCH3), 3.37 (td, J = 9.3, 4.9 Hz, 1H, OCH2), 3.22 (t, J = 8.0 Hz,
1H, H-3), 2.98-2.67 (m, 8H, 3 x NCH2, ArCH2). 13C NMR (125 MHz, CDCl3/TMS) δ (ppm):
149.02, 147.51, 137.53, 129.16, 128.45, 126.20, 120.76, 112.32, 111.46, 105.37, 101.32,
82.08, 81.99, 81.20, 77.42, 72.47, 72.44, 70.67, 70.60, 68.99, 66.06, 57.60, 56.14, 56.06,
54.31, 54.23.
4.3.7. Methyl 4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranosido-[2,3h]-N-(2-(3,4-
dimethoxyphenyl)ethyl)-1,4,7,10-tetraoxa-13-azacyclopentadecane (9d)
Bisiodo compound 8c (2.03 g, 3.0 mmol); dry CH3CN (30 mL), anhydrous Na2CO3 (1.91 g,
18.0 mmol); 2-(3,4-dimethoxyphenylethyl)amine (0.54 g, 3.0 mmol). Eluent: CHCl3:MeOH
100:0 → 100:6 (silica gel). Yield: 59% (1.78 g), brown oil; = -42.4 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 7.47 (dd, J = 7.4, 1.6 Hz, 2H, ArH), 7.39-7.33 (m, 3H,
ArH), 6.80-6.76 (m, 1H, ArH), 6.75-6.71 (m, 2H, ArH), 5.53 (s, 1H, PhCH), 4.86 (d, J = 3.7
Hz, 1H, H-1), 4.28 (dd, J = 10.0, 4.6 Hz, 1H, H-6a), 4.00-3.90 (m, 2H, H-4, H-5), 3.87 (s, 3H.
OCH3), 3.85 (s, 3H, OCH3), 3.82-3.54 (m, 14H, 6 x OCH2, H-2, H-3), 3.49 (dd, J = 9.4, 3.6
13
Hz, 1H, H-6b), 3.43 (s, 3H, OCH3), 2.95-2.64 (m, 8H, 3 x NCH2, ArCH2). C NMR (125
MHz, CDCl3/TMS) δ (ppm): 148.77, 137.40, 128.95, 128.24, 126.03, 120.57, 112.09, 111.24,
101.31, 98.32, 82.26, 79.87, 78.08, 77.22, 72.51, 70.57, 70.07, 69.07, 62.24, 55.92, 55.22,
54.46.

16
4.4. General procedure for the enantioselective MIRC reaction
Unsaturated cyanosulfone (0.5 mmol), diethyl bromomalonate (0.75 mmol), and the crown
ether (0.05 mmol) were dissolved in dichloromethane, and dry Na2CO3 (0.12 g, 1.0 mmol)
was added. The reaction mixture was stirred at room temperature. After completion of the
reaction (followed by TLC), the mixture was filtered, then concentrated in vacuum. The crude
product was purified by preparative TLC (silica gel) with hexane‐EtOAc (5:1) as eluent.
Enantioselectivity was determined by chiral HPLC analysis by using 5AmyCoat or Lux 5u
cellulose-1 column with hexane‐EtOH mixture as eluent, in comparison with authentic
racemic materials.
4.4.1. Diethyl 2-cyano-3-phenyl-2-(phenylsulfonyl)cyclopropane-1,1-dicarboxylate (12a)
Yield: 93%; mp 58-59 °C, = +18.5 (c = 1, CHCl3); 80% ee, 5AmyCoat column,
1
Hexane:EtOH 85:15, major enantiomer tr = 18.6 min, minor enantiomer tr = 14.2 min. H
NMR (500 MHz, CDCl3/TMS) δ (ppm): 8.13 (dd, J = 8.5, 1.3 Hz, 2H, ArH), 7.81 (tt, J = 7.5,
1.2 Hz, 1H, ArH), 7.68 (t, J = 7.9 Hz, 2H, ArH), 7.31 (dd, J = 4.9, 2.0 Hz, 3H, ArH), 7.17-
7.11 (m, 2H, ArH), 4.50-4.37 (m, 2H, OCH2), 4.16 (s, 1H, PhCH), 4.13 (qd, J = 7.1, 2.6 Hz,
2H, OCH2), 1.42 (t, J = 7.1 Hz, 3H, CH3), 1.10 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz,
CDCl3/TMS) δ (ppm): 162.94, 162.06, 136.12, 135.59, 130.13, 129.59, 128.98, 128.94,
128.65, 128.27, 111.52, 63.55, 63.46, 48.24, 47.58, 36.95, 13.82, 13.60. HRMS calcd for
C22H21NO6S 427.1090; found 427.1095.
4.4.2.
Diethyl
3-(2-chlorophenyl)-2-cyano-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12b)
Yield: 83%; mp 121-122 °C, = +0.4 (c = 1, CHCl3); 2% ee, Lux 5u cellulose-1 column,
Hexane:EtOH 85:15, major enantiomer tr = 9.3 min, minor enantiomer tr = 10.1 min. 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 8.13 (dd, J = 7.7, 1.1 Hz, 2H ArH), 7.80 (tt, J = 7.5, 1.3
Hz, 1H, ArH), 7.66 (t, J = 8.1 Hz, 2H, ArH), 7.36 (dd, J = 8.0, 1.3 Hz, 1H, ArH), 7.30-7.25
(m, 1H, ArH), 7.20 (td, J = 7.6, 1.4 Hz, 1H, ArH), 7.09 (dt, J = 7.7, 1.3 Hz, 1H, ArH), 4.49-
4.38 (m, 2H, OCH2), 4.12 (q, J = 7.2 Hz, 2H, OCH2), 4.08 (s, 1H, ArCH), 1.42 (t, J = 7.1 Hz,
3H, CH3), 1.11 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3/TMS) δ (ppm): 162.48,
162.20, 136.03, 135.63, 134.60, 130.32, 130.12, 130.11, 129.84, 129.54, 127.18, 127.11,
111.53, 63.45, 63.29, 48.44, 47.09, 36.09, 13.77, 13.46. HRMS calcd for
C22H20ClNO6S 461.0700; found 461.0704.

17
4.4.3.
Diethyl
3-(3-chlorophenyl)-2-cyano-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12c)
Yield: 91%; oil, = +14.0 (c = 1, CHCl3); 84% ee, 5AmyCoat column, Hexane:EtOH 85:15,
1
major enantiomer tr = 15.4 min, minor enantiomer tr = 12.6 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.15 (d, J = 7.8 Hz, 2H, ArH), 7.84 (t, J = 7.4 Hz, 1H, ArH), 7.70 (t, J
= 7.7 Hz, 2H, ArH), 7.36-7.23 (m, 2H, ArH), 7.16 (s, 1H, ArH), 7.06 (d, J = 7.3 Hz, 1H,
ArH), 4.55-4.36 (m, 2H, OCH2), 4.27-4.14 (m, 2H, OCH2), 4.12 (s, 1H, ArCH), 1.44 (t, J =
7.1 Hz, 3H, CH3), 1.18 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 162.65,
161.83, 135.87, 135.73, 134.86, 130.59, 130.36, 130.16, 129.64, 129.28, 128.55, 126.58,
111.23, 63.71, 48.17, 47.47, 36.01, 13.82, 13.71. HRMS calcd for C22H20ClNO6S 461.0700;
found 461.0707.
4.4.4.
Diethyl
3-(4-chlorophenyl)-2-cyano-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12d)
Yield: 94%; oil, = +30.0 (c = 1, CHCl3); 81% ee, Lux 5u cellulose-1 column, Hexane:EtOH
1
85:15, major enantiomer tr = 9.2 min, minor enantiomer tr = 8.5 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.12 (dd, J = 8.5, 1.3 Hz, 2H, ArH), 7.82 (tt, J = 7.5, 1.7 Hz, 1H, ArH),
7.68 (t, J = 7.9 Hz, 2H, ArH), 7.30 (d, J = 8.5 Hz, 2H, ArH), 7.09 (d, J = 7.6 Hz, 2H, ArH),
4.49-4.38 (m, 2H, OCH2), 4.15 (q, J = 7.2 Hz, 2H, OCH2), 4.09 (d, J = 1.0 Hz, 1H, ArCH),
1.42 (t, J = 7.2 Hz, 3H, CH3), 1.14 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3/TMS)
δ (ppm): 162.71, 161.88, 135.93, 135.71, 135.18, 130.14, 129.70, 129.64, 129.29, 127.17,
111.35, 77.26, 63.66, 48.23, 47.54, 36.14, 13.82, 13.69. HRMS calcd for
C22H20ClNO6S 461.0700; found 461.0709.
4.4.5.
Diethyl
2-cyano-3-(2-methylphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12e)
Yield: 95%; mp 128-130 °C,
= +0.3 (c = 1, CHCl3); 1% ee, Lux 5u cellulose-1 column,
Hexane:EtOH 85:15, major enantiomer tr = 8.1 min, minor enantiomer tr = 8.6 min. 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 8.16 (dd, J = 8.1, 1.4 Hz, 2H, ArH), 7.81 (tt, J = 7.5, 1.2
Hz, 1H, ArH), 7.68 (t, J = 7.8 Hz, 2H, ArH), 7.27-7.17 (m, 2H, ArH), 7.11 (td, J = 7.3, 1.9
Hz, 1H, ArH), 7.03 (d, J = 7.7 Hz, 1H, ArH), 4.47 (qd, J = 7.2, 5.2 Hz, 2H, OCH2), 4.17-4.02
(m, 3H, OCH2, ArCH), 2.41 (s, ArCH3), 1.45 (t, J = 7.1 Hz, 3H, CH2CH3), 1.05 (t, J = 7.1 Hz,
3H, CH2CH3). 13C NMR (75 MHz, CDCl3/TMS) δ (ppm): 163.03, 162.29, 137.85, 136.21,

18
135.55, 130.69, 130.16, 129.54, 128.85, 128.01, 127.02, 126.13, 111.93, 63.39, 63.30, 48.06,
47.04, 36.87, 19.27, 13.75, 13.40. HRMS calcd for C23H23NO6S 441.1246; found 441.1240.
4.4.6.
Diethyl
2-cyano-3-(3-methylphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12f)
Yield: 90%; mp 90-92 °C, = +16.0 (c = 1, CHCl3); 81% ee, Lux 5u cellulose-1 column,
Hexane:EtOH 85:15, major enantiomer tr = 8.7 min, minor enantiomer tr = 7.8 min. 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 8.15 (dd, J = 7.6, 1.3 Hz, 2H, ArH), 7.83 (tt, J = 7.5, 1.3
Hz, 1H, ArH), 7.69 (t, J = 7.7 Hz, 2H, ArH), 7.25-7.09 (m, 2H, ArH), 7.00-6.86 (m, 2H,
ArH), 4.53-4.37 (m, 2H, OCH2), 4.24-4.08 (m, 3H, OCH2, ArCH), 1.44 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.14 (t, J = 7.1 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3/TMS) δ (ppm):
163.00, 162.10, 138.77, 136.14, 135.54, 130.14, 129.71, 129.56, 128.94, 128.88, 128.47,
125.24, 111.53, 63.54, 63.41, 48.27, 47.58, 36.91, 21.30, 13.82, 13.66. HRMS calcd for
C23H23NO6S 441.1246; found 441.1243.
4.4.7.
Diethyl
2-cyano-3-(4-methylphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12g)
Yield: 87%; mp 100-101 °C, = +20.0 (c = 1, CH2Cl2); 78% ee, Lux 5u cellulose-1 column,
Hexane:EtOH 85:15, major enantiomer tr = 8.7 min, minor enantiomer tr = 8.1 min. 1H NMR
(500 MHz, CDCl3/TMS) δ (ppm): 8.13 (dd, J = 8.4, 1.3 Hz, 2H, ArH), 7.80 (tt, J = 7.5, 1.6
Hz, 1H, ArH), 7.67 (t, J = 8.3 Hz, 1H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.01 (d, J = 7.8
Hz, 2H, ArH), 4.50-4.37 (m, 2H, OCH2), 4.14 (qd, J = 7.2, 1.6 Hz, 2H, OCH2), 4.11 (s, 1H,
ArCH), 2.30 (s, 3H, ArCH3), 1.41 (t, J = 7.1 Hz, 3H, CH2CH3), 1.13 (t, J = 7.1 Hz, 3H,
CH2CH3). 13C NMR (75 MHz, CDCl3) δ 163.00, 162.09, 138.90, 136.20, 135.53, 130.10,
129.67, 129.56, 128.12, 125.49, 111.57, 63.51, 63.42, 48.32, 47.65, 36.87, 21.21, 13.82,
13.66. HRMS calcd for C23H23NO6S 441.1246; found 441.1248.
4.4.8.
Diethyl
2-cyano-3-(2-nitrophenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12h)
Yield: 91%; mp 165-167 °C, = +6.6 (c = 1, CHCl3); 12% ee, Lux 5u cellulose-1 column,
1
Hexane:EtOH 85:15, major enantiomer tr = 15.9 min, minor enantiomer tr = 13.8 min. H
NMR (500 MHz, CDCl3/TMS) δ (ppm): 8.17 (dd, J = 8.0, 1.4 Hz, 2H, ArH), 8.07 (dd, J =
8.2, 1.4 Hz, 1H, ArH), 7.83 (tt, J = 7.5, 1.3 Hz, 1H, ArH), 7.70 (t, J = 7.8 Hz, 2H, ArH), 7.66
(td, J = 7.6, 1.4 Hz, 1H, ArH), 7.55 (t, J = 7.8 Hz, 1H, ArH), 7.42 (d, J = 7.8 Hz, 1H, ArH),
4.52 (s, 1H, ArCH), 4.51-4.39 (m, 2H, OCH2), 4.09 (q, J = 7.2 Hz, 2H, OCH2), 1.45 (t, J = 7.1

19
Hz, 3H, CH3), 1.15 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3/TMS) δ (ppm):
162.27, 161.84, 148.69, 135.79, 135.70, 133.89, 132.14, 130.45, 129.96, 129.58, 125.05,
124.61, 111.54, 63.99, 63.53, 49.65, 47.37, 36.00, 13.81, 13.49. HRMS calcd for
C22H20N2O8S 472.0940; found 472.0945.
4.4.9.
Diethyl
2-cyano-3-(3-nitrophenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12i)
Yield: 91%; mp 118 °C, = +22.2 (c = 1, CHCl3); 75% ee, 5AmyCoat column, Hexane:EtOH
1
50:50 major enantiomer tr = 9.8 min, minor enantiomer tr = 7.8 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.22 (dt, J = 8.0, 1.2 Hz, 1H, ArH), 8.15 (dd, J = 7.7, 1.3 Hz, 2H,
ArH), 7.99 (s, 1H, ArH), 7.86 (tt, J = 7.6, 1.0 Hz, 1H, ArH), 7.72 (t, J = 8.1 Hz, 2H, ArH),
7.60-7.51 (m, 2H, ArH), 4.54-4.40 (m, 2H, OCH2), 4.27-4.15 (m, 3H, OCH2, ArCH), 1.45 (t,
J = 7.1 Hz, 3H, CH3), 1.22 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3/TMS) δ
(ppm): 162.33, 161.73, 148.38, 135.94, 135.64, 134.68, 130.84, 130.32, 130.17, 129.74,
124.01, 123.61, 110.99, 64.07, 63.88, 48.34, 47.48, 35.70, 13.83, 13.75. HRMS calcd for
C22H20N2O8S 472.0940; found 472.0948.
4.4.10.
Diethyl
2-cyano-3-(4-nitrophenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12j)
Yield: 87%; mp 98-99 °C, = +40.1 (c = 1, CHCl3); 82% ee, Lux 5u cellulose-1 column,
1
Hexane:EtOH 85:15, major enantiomer tr = 17.2 min, minor enantiomer tr = 19.7 min. H
NMR (500 MHz, CDCl3/TMS) δ (ppm): 8.21 (d, J = 8.8 Hz, 2H, ArH), 8.14 (dd, J = 8.3, 1.3
Hz, 2H, ArH), 7.85 (tt, J = 7.5, 1.2 Hz, 1H, ArH), 7.71 (t, J = 7.8 Hz, 2H, ArH), 7.36 (d, J =
8.2 Hz, 2H, ArH), 4.53-4.40 (m, 2H, OCH2), 4.23-4.12 (m, 3H, OCH2, ArCH), 1.44 (t, J = 7.1
13
Hz, 3H, CH3), 1.17 (t, J = 7.2 Hz, 3H, CH3). C NMR (75 MHz, CDCl3) δ (ppm): 162.35,
161.70, 148.17, 135.94, 135.88, 135.65, 130.20, 129.73, 129.59, 124.18, 111.07, 63.93, 63.87,
48.17, 47.42, 35.92, 13.83, 13.73. HRMS calcd for C22H20N2O8S 472.0940; found 472.0942.
4.4.11.
Diethyl
2-cyano-3-(2-methoxyphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12k)
Yield: 89%; mp 138-139 °C, = +0.3 (c = 1, CHCl3); 3% ee, Lux 5u cellulose-1 column,
1
Hexane:EtOH 85:15, major enantiomer tr = 10.1 min, minor enantiomer tr = 11.9 min. H
NMR (500 MHz, CDCl3/TMS) δ (ppm): 8.13 (dd, J = 8.4, 1.3 Hz, 2H, ArH), 7.79 (tt, J = 7.6,
1.3 Hz, 1H, ArH), 7.66 (t, J = 7.7 Hz, 2H, ArH), 7.30-7.25 (m, 1H, ArH), 6.96 (dt, J = 7.5, 1.4
Hz, 1H, ArH), 6.86 (td, J = 7.5, 0.7 Hz, 1H, ArH), 6.80 (d, J = 8.5 Hz, 1H, ArH), 4.42 (qd, J =

20
7.1, 5.0 Hz, 2H, OCH2), 4.14 (q, J = 7.1, 2H, OCH2), 3.94 (s, 1H, ArCH), 3.48 (s, 3H, OCH3),
13
1.40 (t, J = 7.1 Hz, 3H, CH2CH3), 1.12 (t, J = 7.2 Hz, 3H, CH2CH3). C NMR (75 MHz,
CDCl3) δ (ppm): 163.18, 162.62, 157.78, 136.71, 135.26, 130.47, 130.32, 129.50, 129.37,
120.72, 116.88, 111.85, 110.79, 63.19, 63.12, 55.02, 48.39, 46.86, 34.47, 13.84, 13.63.
HRMS calcd for C23H23NO7S 457.1195; found 457.1190.
4.4.12.
Diethyl
2-cyano-3-(3-methoxyphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12l)
Yield: 95%; oil, = +18.9 (c = 1, CHCl3); 81% ee, Lux 5u cellulose-1 column, Hexane:EtOH
1
85:15, major enantiomer tr = 10.6 min, minor enantiomer tr = 9.6 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.13 (dd, J = 7.8, 1.3 Hz, 2H, ArH), 7.81 (tt, J = 7.5, 1.1 Hz, 1H, ArH),
7.68 (t, J = 7.8 Hz, 2H, ArH), 7.21 (t, J = 8.0 Hz, 1H, ArH), 6.84 (dd, J = 8.2, 2.5 Hz, 1H,
ArH), 6.70 (d, J = 7.6 Hz, 1H, ArH), 6.64-6.60 (m, 1H, ArH), 4.49-4.37 (m, 2H, OCH2), 4.19-
4.10 (m, 3H, OCH2, ArCH), 3.71 (s, 3H, OCH3), 1.42 (t, J = 7.2 Hz, 3H, CH2CH3), 1.13 (t, J
13
= 7.1 Hz, 3H, CH2CH3). C NMR (75 MHz, CDCl3/TMS) δ (ppm): 162.90, 162.02, 159.85,
136.14, 135.56, 130.14, 130.08, 129.91, 129.58, 120.39, 114.80, 113.72, 111.54, 63.55, 63.48,
55.25, 48.20, 47.60, 36.98, 13.82, 13.65. HRMS calcd for C23H23NO7S 457.1195; found
457.1198
4.4.13.
Diethyl
2-cyano-3-(4-methoxyphenyl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12m)
Yield: 94%; oil, = +24.4 (c = 1, CHCl3); 77% ee, Lux 5u cellulose-1 column, Hexane:EtOH
1
85:15, major enantiomer tr = 11.8 min, minor enantiomer tr = 10.6 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.12 (dd, J = 8.2, 0.8 Hz, 2H, ArH), 7.81 (tt, J = 7.5, 1.2 Hz, 1H, ArH),
7.68 (t, J = 7.8 Hz, 2H, ArH), 7.05 (d, J = 8.4 Hz, 2H, ArH), 6.82 (d, J = 8.8 Hz, 2H, ArH),
4.49-4.36 (m, 2H, OCH2), 4.15 (q, J = 7.1 Hz, 2H, OCH2), 4.10 (s, 1H, ArCH), 3.77 (s, 3H,
13
OCH3), 1.41 (t, J = 7.2 Hz, 3H, CH2CH3), 1.14 (t, J = 7.2 Hz, 3H, CH2CH3). C NMR (75
MHz, CDCl3/TMS) δ (ppm): 162.94, 162.05, 159.92, 136.16, 135.50, 130.05, 129.53, 129.50,
120.29, 114.40, 111.57, 63.48, 63.40, 55.27, 48.37, 47.72, 36.55, 13.78, 13.66. HRMS calcd
for C23H23NO7S 457.1195; found 457.1194.
4.4.14.
Diethyl
2-cyano-3-(naphthalen-2-yl)-2-(phenylsulfonyl)cyclopropane-1,1-
dicarboxylate (12n)
Yield: 92%; oil, = +49.1 (c = 1, CHCl3); 85% ee, 5AmyCoat column, Hexane:EtOH 50:50,
1
major enantiomer tr = 13.6 min, minor enantiomer tr = 10.2 min. H NMR (500 MHz,

21
CDCl3/TMS) δ (ppm): 8.17 (dd, J = 8.4, 1.3 Hz, 2H, ArH), 7.84-7.77 (m, 3H, ArH), 7.74-7.66
(m, 3H, ArH), 7.62 (s, 1H, ArH), 7.51-7.44 (m, 2H, ArH), 7.20 (dd, J = 8.6, 1.8 Hz, 1H,
ArH), 4.53-4.40 (m, 2H, OCH2), 4.31 (s, 1H, ArCH), 4.17-4.06 (m, 2H, OCH2), 1.44 (t, J =
7.1 Hz, 3H, CH2CH3), 1.07 (t, J = 7.1 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3/TMS) δ
(ppm): 162.99, 162.08, 136.14, 135.61, 133.13, 133.04, 130.19, 129.62, 128.99, 127.92,
127.79, 126.91, 126.77, 125.93, 125.28, 111.57, 63.63, 63.52, 48.39, 47.74, 37.02, 13.86,
13.67. HRMS calcd for C26H23NO6S 477.1246; found 477.1239.
4.4.15.
Diethyl
2-cyano-2-(phenylsulfonyl)-3-(pyridin-3-yl)cyclopropane-1,1-
dicarboxylate (12o)
Yield: 88%; oil, = +15.0 (c = 1, CHCl3); 72% ee, Lux 5u cellulose-1 column, Hexane:EtOH
1
85:15, major enantiomer tr = 14.6 min, minor enantiomer tr = 15.5 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.59 (d, J = 5.0 Hz, 1H, ArH), 8.40 (d, J = 2.4 Hz, 1H, ArH), 8.17 (dd,
J = 8.2, 1.4 Hz, 2H, ArH), 7.82 (tt, J = 7.6, 1.2 1H, ArH), 7.69 (t, J = 7.9 Hz 2H, ArH), 7.58-
7.51 (m, 1H, ArH), 7.30 (dd, J = J = 8.0, 4.9 Hz, 1H, ArH), 4.51-4.39 (m, 2H, OCH2), 4.17
(q, J = 7.1 Hz, 2H, OCH2), 4.10 (s, 1H, ArCH), 1.42 (t, J = 7.2 Hz, 3H, CH3), 1.15 (t, J = 7.2
13
Hz, 3H, CH3). C NMR (75 MHz, CDCl3/TMS) δ (ppm): 162.38, 161.72, 149.71, 149.23,
136.27, 135.83, 135.74, 130.11, 129.67, 125.31, 123.71, 111.08, 63.86, 63.76, 47.90, 47.25,
34.29, 13.78, 13.65. HRMS calcd for C21H20N2O6S 428.1042; found 428.1046.
4.4.16. Diethyl 2-cyano-3-(furan-2-yl)-2-(phenylsulfonyl)cyclopropane-1,1-dicarboxylate
(12p)
Yield: 86%; oil, = -10.3 (c = 1, CHCl3); 40% ee, Lux 5u cellulose-1 column, Hexane:EtOH
1
85:15, major enantiomer tr = 10.1 min, minor enantiomer tr = 9.5 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.07 (dd, J = 8.6, 1.1 Hz, 2H, ArH), 7.77 (tt, J = 7.5, 1.2 Hz, 1H, ArH),
7.64 (t, J = 7.9 Hz, 2H, ArH), 7.35 (d, J = 1.8 Hz, 1H, ArH), 6.39 (d, J = 3.4 Hz, 1H, ArH),
6.33 (dd, J = 3.4, 1.9 Hz, 1H, ArH), 4.44-4.35 (m, 2H, OCH2), 4.22 (qd, J = 7.1, 5.3 Hz, 2H,
OCH2), 4.08 (s, 1H, ArCH), 1.39 (t, J = 7.2 Hz, 3H, CH2CH3), 1.20 (t, J = 7.1 Hz, 3H,
CH2CH3). 13C NMR (75 MHz, CDCl3) δ 162.06, 161.46, 143.69, 142.19, 136.03, 135.61,
129.93, 129.58, 111.19, 111.06, 110.86, 63.79, 63.68, 47.41, 46.98, 31.21, 13.78, 13.67.
HRMS calcd for C20H19NO7S 417.0882; found 417.0884.

22
4.4.17.
Diethyl
2-cyano-2-(phenylsulfonyl)-3-(thiophen-2-yl)cyclopropane-1,1-
dicarboxylate (12q)
Yield: 94%; oil, = -7.5 (c = 1, CHCl3); 72% ee, 5AmyCoat column, Hexane:EtOH 85:15,
1
major enantiomer tr = 23.6 min, minor enantiomer tr = 16.8 min. H NMR (500 MHz,
CDCl3/TMS) δ (ppm): 8.09 (dd, J = 7.4, 1.2 Hz, 2H, ArH), 7.79 (tt, J = 7.5, 1.2 Hz, 1H, ArH),
7.65 (t, J = 7.9 Hz, 2H, ArH), 7.26 (dd, J = 5.1, 1.3 Hz, 1H, ArH), 6.96 (dt, J = 2.7, 1.3 Hz,
1H, ArH), 6.93 (dd, J = 5.1, 3.6 Hz, 1H, ArH), 4.47-4.35 (m, 2H, OCH2), 4.27-4.13 (m, 3H,
OCH2, ArCH), 1.40 (t, J = 7.1 Hz, 3H, CH2CH3), 1.18 (t, J = 7.1 Hz, 3H, CH2CH3). 13C NMR
(75 MHz, CDCl3/TMS) δ (ppm): 161.28, 160.51, 135.05, 134.58, 128.91, 128.58, 127.17,
126.32, 126.02, 110.26, 62.67, 47.82, 47.29, 31.96, 12.74, 12.62.
HRMS calcd for C20H19NO6S2 433.0654; found 433.0660.
5. Acknowledgement
The research reported in this paper has been supported by the National Research Development
and Innovation Fund (TUDFO/51757/2019-ITM, Thematic Excellence Program). We thank
Dr. Tibor Bakó for his help with the NOE NMR measurements.
Supplementary data
Supplementary data related to this article can be found on this article’s webpage.
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Highlights
-
-
New
A new
D
-glucose- and
D-galactose-based crown ethers have been synthesized.
D
-galactose-based macrocycle induced significant enantioselectivity (up to
85%) in the MIRC reaction of some α,β-unsaturated cyanosulfones.
The m- and p-substituted products were formed with higher enantioselectivity (75-
84%), than the o-substituted cyclopropanes (0-12%).
The new chiral cyclopropanes may be important intermediates in asymmetric
syntheses.
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: