Synthesis of l-threitol-based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions

Article abstract of DOI:10.1002/chir.22678

A few new l-threitol-based lariat ethers incorporating a monoaza-15-crown-5 unit were synthesized starting from diethyl l-tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2-nitropropane to trans-chalcone, and the reaction of diethyl acetamidomalonate with β-nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee) values (99% ee) were measured in the case of 4-chloro- and 4-methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene-malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol-based crown ethers.

Full text of DOI:10.1002/chir.22678

Received: 21 October 2016
DOI: 10.1002/chir.22678
Revised: 5 December 2016
Accepted: 15 December 2016
R E G U L A R A R T I C L E
Synthesis of L‐threitol‐based crown ethers and their application as
enantioselective phase transfer catalyst in Michael additions
Zsolt Rapi | Tamás Nemcsok | Ádám Pálvölgyi | György Keglevich | Alajos Grün |
Péter Bakó
Department of Organic Chemistry and
Abstract
Technology, Budapest University of
A few new L‐threitol‐based lariat ethers incorporating a monoaza‐15‐crown‐5 unit
were synthesized starting from diethyl L‐tartrate. These macrocycles were used as
Technology and Economics, Budapest,
Hungary
phase transfer catalysts in asymmetric Michael addition reactions under mild
Correspondence
Péter Bakó, Department of Organic
Chemistry and Technology, Budapest
University of Technology and Economics,
1111 Budapest, Műegyetem rkp. 3, Hungary.
Email: pbako@mail.bme.hu
conditions to afford the adducts in a few cases in good to excellent
enantioselectivities. The addition of 2‐nitropropane to trans‐chalcone, and the
reaction of diethyl acetamidomalonate with β‐nitrostyrene resulted in the chiral
Michael adducts in good enantioselectivities (90% and 95%, respectively). The
substituents of chalcone had a significant impact on the yield and enantioselectivity
in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee)
values (99% ee) were measured in the case of 4‐chloro‐ and 4‐methoxychalcone.
The phase transfer catalyzed cyclopropanation reaction of chalcone and
benzylidene‐malononitriles using diethyl bromomalonate as the nucleophile (MIRC
reaction) was also developed. The corresponding chiral cyclopropane diesters were
obtained in moderate to good (up to 99%) enantioselectivities in the presence of
the threitol‐based crown ethers.
Funding Information
New Széchenyi Development Plan, Grant/
Award Number: TÁMOP‐4.2.1/B‐09/1/
KMR‐2010‐0002; Országos Tudományos
Kutatási Alapprogramok, Grant/Award
Number: PD 112166
KEYWORDS
asymmetric Michael reactions, cyclopropanation, enantioselectivity, phase transfer catalysis, sugar‐based
crown ethers
1 | INTRODUCTION
conditions. Chiral phase transfer catalysis has become an
attractive area in the “green” chemical discipline, and many
The development of new methodologies for efficient
asymmetric Michael additions is of tremendous importance
due to the increasing demand for optically active compounds.
It is particularly important to develop new and efficient
catalysts for the asymmetric reactions, and this task
constitutes an attractive yet challenging area in current
organic chemistry.1-10 One of the catalytic methods is asym-
metric phase transfer catalysis utilizing structurally well‐
defined chiral catalysts. This topic became of great scientific
interest, and recent efforts have resulted in notable synthetic
achievements. A variety of C‐C bond‐formation reactions
were elaborated under mild phase transfer catalytic
types of chiral catalysts have been developed and applied
over the past few decades.11-13
Cram and Sogah published first the asymmetric phase
transfer technique, in which the enantioselectivity was
generated by a chiral crown ether catalyst.14 Crown ethers
with carbohydrate moieties form a special group of the chiral
phase transfer catalysts. Over the past three decades, a lot of
macrocycles containing one or more monosaccharide units
(D‐glucose, D‐galactose, D‐mannose, D‐ or L‐xylose, etc.)
were synthesized.15-17 A few of them proved to be efficient
phase transfer catalysts in certain asymmetric reactions.18-25
Tartaric acid is also a useful source for chirality in the
Chirality. 2017;1–16.
wileyonlinelibrary.com/journal/chir
© 2017 Wiley Periodicals, Inc.
1

2
RAPI ET AL.
synthesis of crown compounds. It has several advantages,
being an inexpensive and easily available natural compound;
moreover, the L‐threitol can be derived from it in an
enantiomerically pure form.26,27
and preparative thin‐layer chromatography was performed
on silica gel plates (60 GF‐254, Merck, Darmstadt,
Germany), while column chromatography was carried out
using 70–230 mesh silica gel (Merck). Chemicals were
purchased from Aldrich Chemical (Milwaukee, WI).
Stoddart performed pioneering work in preparing and
investigating macrocycles built up from sugar alcohols such
as L‐iditol, L‐threitol, and D‐mannitol.15-17,26,27 At that time,
they had not yet studied the catalytic effects of these com-
pounds in phase transfer reactions. Later on, a few articles
were published on the synthesis of chiral crown ethers
derived from diethyl L‐tartrate,28-37 but from among the
macrocycles prepared, only a few were investigated as chiral
phase transfer catalysts, which were not too efficient.38 The
attachment of a side arm (linear or branched heteroatom‐
containing podand arms) with potential cation coordination
sites to the rings leads to complexing agents, called “lasso”
or lariat ethers that have unique binding properties towards a
variety of guest cations.
Previously, chiral monoaza‐15‐crown‐5 type lariat ethers
incorporating an α‐D‐glucopyranoside unit were synthesized
in our laboratory. The new lariat ethers showed catalytic
effects in a few asymmetric reactions.18-25,39,40 In the struc-
ture–activity relationships study of the crown ethers it was
found that the molecules with a monoaza‐15‐crown‐5 moiety
are optimal as enantioselective catalysts, when the N atom of
the ring bears a hydroxypropyl or a methoxypropyl side arm.
In order to benefit from the preferential catalytic property,
this structural motif was kept in the synthesis of the new L‐
threitol‐based macrocycles.
2.1.1 | 1,4‐Di‐O‐methyl‐2,3‐O‐isopropylidene‐
L‐threitol (2a).41
A suspension of NaH (60%, 20.7 g, 517 mmol) in dry THF
(100 ml) was cooled to 5 °C with an ice bath, and 2,3‐O‐
isopropylidene‐L‐threitol (1) (15.0 g, 92.6 mmol) and CH3I
(31.7 ml, 510 mmol) in anhydrous THF (75 ml) was added
dropwise. The mixture was stirred at room temperature
(RT) for 30 min, then refluxed for 1.5 h. After cooling, the
mixture was concentrated in vacuum. The residue was
suspended in CHCl3 and the mixture was filtered. The
residue was washed three times with CHCl3. The combined
organic phases were dried (Na2SO4) and concentrated. The
crude product was distilled in vacuum (15 Hgmm, 90 °C)
to give the pure product.
Yield: 93% (3.77 g); [α]D = −1 (c = 1, CHCl3);1H
22
NMR (CDCl3, 500 MHz), δ (ppm): 3.98–3.96 (m, 2H, 2 x
CH), 3.54–3.51 (m, 4H, 2 x CH2), 3.41 (s, 6H, 2x OCH3),
1.43 (s, 6H, 2 x CCH3); HRMS calcd for C9H18O4
190.1205, found 190.1201; Elem. Anal. calcd for C9H18O4
C 56.82, H 9.54, found C 56.80, H 9.57.
Herein we report the synthesis of a new monoaza‐15‐
crown‐5 type macrocycle family annelated to L‐threitol
(6–8), and the results of the catalytic activity of the new
species in a few Michael addition reactions. The nucleophilic
addition of malonates to electron‐deficient alkenes, such as
α,β‐unsaturated carbonyl compounds is an important class
of asymmetric C‐C bond forming Michael addition
reactions.1-10 The products of the Michael reactions tested
by us may be useful intermediates for a variety of biologically
active materials. There are new model reactions among the
asymmetric Michael additions investigated.
2.1.2 | 1,4‐Di‐O‐butyl‐2,3‐O‐isopropylidene‐L‐
threitol (2b).
To a solution of 2,3‐O‐isopropylidene‐L‐threitol (1) (5.21 g,
32 mmol) in dry THF (110 ml) was added NaH (60%,
5.15 g, 129 mmol) in small portions under Ar. After 30 min
stirring at RT, butyl bromide (13.8 ml, 129 mmol)) was
added to the mixture dropwise. Then the reaction mixture
was refluxed for 10 h. After cooling, the mixture was filtered
and then all volatiles were evaporated in vacuum. The residue
was dissolved in CHCl3 (100 ml), then washed with water (3
x 50 ml). The organic layer was dried, filtered, and
evaporated to give the pure product.
2 | MATERIALS AND METHODS
2.1 | General
Yield: 86% (7.60 g); [α]D = −13.2 (c = 1, CHCl3);1H
22
NMR (CDCl3, 500 MHz), δ (ppm): 4.00–3.94 (m, 2H, 2 x
CH), 3.59–3.54 (m, 4H, 2 x OCH2CH), 3.52–3.44 (m, 4H,
2x OCH2CH2), 1.57 (qui, J = 7 Hz, 4H, 2 x CH2CH2CH3),
1.42 (s, 6H, 2 x CCH3), 1.37 (sex, J = 7 Hz, 4H, 2 x
CH2CH3), 0.92 (t, J = 7 Hz, 6H, 2 x CH2CH3); 13C NMR
(CDCl3, 75 MHz), δ (ppm): 109.22, 78.67, 71.64, 70.81,
31.84, 26.43, 19.29, 14.05; HRMS calcd for C15H30O4
274.2144, found 274.2150; Elem. Anal. calcd for C15H30O4
C 65.66, H 11.02, found C 65.69, H 11.00.
Melting points were determined using a Büchi 510 apparatus
and are uncorrected. The specific rotation was measured on a
Perkin‐Elmer (Boston, MA) 241 polarimeter at 22 °C. NMR
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
using Q‐TOF Premier mass spectrometer (Waters, Milford,
MA) in positive electrospray ionization mode. Analytical

RAPI ET AL.
3
was washed with water (2 x 15 ml). The organic phase was
dried and evaporated to give the pure product.
2.1.3 | 1,4‐Di‐O‐benzyl‐2,3‐O‐isopropylidene‐
L‐threitol (2c).42,43
22
1
Yield: 94% (6.06 g); [α]D = −3.8 (c = 1, CHCl3); H
NMR (CDCl3, 300 MHz), δ (ppm): 3.87–3.79 (m, 2H, 2 x
CH), 3.61–3.54 (m, 4H, 2 x OCH2CH), 3.48 (t, J = 7.2 Hz,
4H, 2x OCH2CH2), 2.90 (br s, 2H, 2 x OH), 1.57 (qui,
J = 7.2 Hz, 4H, 2 x CH2CH2CH3), 1.36 (sex, J = 7.2 Hz,
4H, 2 x CH2CH3), 0.92 (t, J = 7.2 Hz, 6H, 2 x CH2CH3);
13C NMR (CDCl3, 75 MHz), δ (ppm): 73.59, 70.75, 68.97,
31.83, 19.37, 13.92; HRMS calcd for C12H26O4 234.1831,
found 234.1835; Elem. Anal. calcd for C12H26O4 C 61.54
H 11.18, found C 61.55, H 11.19.
A solution of 2,3‐O‐isopropylidene‐L‐threitol (1) (7.61 g,
47 mmol) in dry THF (35 ml) was added dropwise to a
suspension of NaH (60%, 5.8 g, 0.15 mol) in dry THF
(35 ml) under Ar. The mixture was stirred at RT for 9 h, then
benzyl chloride (13 ml, 0.11 mol) was added dropwise. The
reaction mixture was stirred at RT for 16 h, then refluxed
for 3 h. After cooling, water (20 ml) was added, the organic
layer was separated, and the aqueous layer was extracted with
toluene. The combined organic solutions were dried then
evaporated to give the pure product.
Yield: 96% (15.40 g); [α]D22 = −7.6 (c = 1, CH2Cl2); 1H
NMR (CDCl3, 500 MHz), δ (ppm): 7.40–7.24 (m, 10H,
ArH), 4.60–4.54 (m, 4H, 2 x PhCH2), 4.05–4.02 (m, 2H, 2
x CH), 3.62–3.59 (m, 4H, 2 x CHCH2), 1.43 (s, 6H, 2 x
CCH3); HRMS calcd for C21H26O4 342.1831, found
342.1841; Elem. Anal. calcd for C21H26O4 C 73.66, H
7.65, found C 73.70, H 7.74.
2.2.3 | 1,4‐Di‐O‐benzyl‐L‐threitol (3c).38
1,4‐Di‐O‐benzyl‐2,3‐O‐isopropylidene‐L‐threitol
(2c)
(38.14 g, 0.11 mol), methanol (100 ml, then 15 ml and 2 x
50 ml), 0.5 M aq. HCl (10 ml, then 5 ml). After the distilla-
tion, the residue was diluted with water (20 ml), then the
solution was extracted with toluene (3 x 30 ml). The organic
phase was dried, evaporated, and the crude product was
purified by crystallization (diethyl‐ether‐petrol ether 2:1).
2.2 | General procedure for preparation of
di‐O‐alkyl‐L‐threitols
Yield: 56% (18.7 g); [α]D = −7.2 (c = 1, CH2Cl2);1H
22
NMR (CDCl3, 300 MHz), δ (ppm): 7.39–7.27 (m, 10H,
ArH), 4.56 (d, J = 12 Hz, 2H, PhCH2), 4.54 (d, J = 12 Hz,
2H, PhCH2), 3.91–3.85 (m, 2H, 2 x CH), 3.66–3.55 (m,
4H, 2 x CHCH2), 2.78 (br s, 2H, 2 x OH). HRMS calcd for
C18H22O4 302.1518, found 302.1522; Elem. Anal. calcd for
C181H22O4 C 71.50, H 7.33, found C 71.51; H 7.35.
To a solution of 1,4‐di‐O‐alkyl‐2,3‐O‐isopropylidene‐L‐
threitol in methanol 0.5 M aq. HCl was added and after the
mixture was stirred at RT for 2 h, then the methanol was
distilled off. To the residue 0.5 M aq. HCl and methanol were
added, then the solvents were removed by distillation. The
last step was repeated twice after adding methanol. The
work‐up procedure is described for each compound.
2.3 | General procedure for preparation of
bischloro compounds
2.2.1 | 1,4‐Di‐O‐methyl‐L‐threitol (3a).44
A
solution
of
1,4‐di‐O‐alkyl‐L‐threitol
and
1,4‐Di‐O‐methyl‐2,3‐O‐isopropylidene‐L‐threitol
(2a)
tetrabutylammonium hydrogensulphate in bis(2‐chloroethyl)
ether was vigorously stirred with 50% aq. NaOH solution at
RT for 10 h. Then the mixture was poured into a mixture of
CH2Cl2 and water 1:1 (three times the volume of the reaction
mixture) and the phases were separated. The water layer was
extracted with CH2Cl2 twice, the combined organic layer was
washed with water, dried, and the solvent was evaporated.
The remaining bis(2‐chloroethyl)ether was removed by vacuum
distillation. The crude product was purified by column
chromatography on silica gel to give the pure product.
(10.8 g, 56.7 mmol), methanol (50 ml, 15 ml, and 2 x
20 ml), 0.5 M aq. HCl (5 ml, then 3 ml). After the distillation,
the residue was diluted with brine (20 ml), then the solution
was extracted with CHCl3 (6 x 15 ml). The organic phase
was dried and evaporated to give the pure product.
Yield: 99% (8.50 g); [α]D22 = −3.3 (c = 0.4, CHCl3); 1H
NMR (CDCl3, 300 MHz), δ (ppm): 4.07 (br s, 2H, 2 x OH),
3.84–3.78 (m, 2H, 2 x CH), 3.54–3.49 (m, 4H, 2 x CH2),
3.39 (s, 6H, 2x OCH3); HRMS calcd for C6H14O4
150.0892, found 150.0895; Elem. Anal. calcd for C6H14O4
C 47.99, H, 9.40, found C 48.01, H 9.37.
2.3.1 | (7S,8S)‐1,14‐dichloro‐7,8‐bis
(methoxymethyl)‐3,6,9,12‐tetraoxatetradecane
(4a).
2.2.2 | 1,4‐Di‐O‐butyl‐L‐threitol (3b).
1,4‐Di‐O‐butyl‐2,3‐O‐isopropylidene‐L‐threitol (2b) (7.60 g,
27.7 mmol), methanol (40 ml, then 10 ml, and 2 x 15 ml),
0.5 M aq. HCl (4 ml, then 2.5 ml). After the distillation,
the residue was dissolved in CHCl3 (30 ml) and the solution
1,4‐Di‐O‐methyl‐L‐threitol (3a) (8.5 g, 62 mmol);
Bu4NHSO4 (16.27 g, 48 mmol); bis(2‐chloroethyl)ether
(120 ml, 1 mol); 50% aq. NaOH (120 ml). Eluent: CHCl3‐
CH3OH 100:0
→
100:5). Yield: 37% (7.55 g);

4
RAPI ET AL.
[α]D22 = −1.9 (c = 1, CHCl3);1H NMR (CDCl3, 300 MHz),
δ (ppm): 3.83–3.39 (m, 22H, 2 x CHCH2, 2 x CH, 6 x
OCH2, 2 x CH2Cl), 3.36 (s, 6H, 2 x OCH3); 13C NMR
(CDCl3, 75 MHz), δ (ppm): 79.31, 72.18, 71.83, 70.72,
70.43, 59.20, 42.64; HRMS calcd for C14H28Cl2O6
362.1263, found 362.1267; Elem. Anal. calcd for
C14H28Cl2O6 C 46.29, H 7.77, Cl 19.52, found C 46.32,
H 7.80, Cl 19.51.
The residue was dissolved in a mixture of CHCl3 and water
(1:1), the layers were separated and the organic phase was
washed with water and dried (NaSO4). Evaporation of the
solvent afforded the products.
2.4.1 | (7S,8S)‐1,14‐diiodo‐7,8‐bis
(methoxymethyl)‐3,6,9,12‐tetraoxatetradecane
(5a).
Bischloro compound 4a (7.55 g, 20.8 mmol); NaI (12.5 g,
2.3.2 | (7S,8S)‐7,8‐bis(butoxymethyl)‐1,14‐
dichloro‐3,6,9,12‐tetraoxatetradecane (4b).
83.2 mmol); dry acetone (160 ml). Yield: 76% (8.55 g);
22
[α]D
= −3.5 (c =
1, CHCl3);1H NMR (CDCl3,
1,4‐Di‐O‐butyl‐L‐threitol (3b) (6.0 g, 25.6 mmol);
Bu4NHSO4 (8.69 g, 25.6 mmol); bis(2‐chloroethyl)ether
(60 ml, 512 mmol); 50% aq. NaOH (60 ml). Eluent:
CHCl3‐CH3OH 100:0 → 100:2); Yield: 79% (9.05 g); [α]
300 MHz), δ (ppm): 3.85–3.39 (m, 18H, 2 x CHCH2, 2 x
CH, 6 x OCH2), 3.36 (s, 6H, 2 x OCH3), 3.26 (t, J = 6.9 Hz,
4H, 2 x CH2I); 13C NMR (CDCl3, 75 MHz), δ (ppm): 79.23,
72.19, 71.87, 70.69, 70.45, 59.18, 3.05; HRMS calcd for
C14H28I2O6 545.9975, found 545.9980; Elem. Anal. calcd for
C14H28I2O66 C 30.79, H 5.17, I 46.47, found C 30.82,
H 5.21, I 46.46.
22
1
= +5.3 (c = 1, CHCl3); H NMR (CDCl3, 500 MHz), δ
(ppm): 3.85–3.79 (m, 2H, 2 x CH), 3.72–3.70 (m, 6H, 2 x
OCH2CH2O, OCH2CH), 3.67–3.59 (m, 12H,
D
4
x
OCH2CH2O, 2 x CH2Cl), 3.54–3.48 (m, 2H, OCH2CH),
3.46–3.40 (m, 4H, 2x OCH2CH2CH2), 1.55 (qui, J = 7 Hz,
4H, 2 x CH2CH2CH3), 1.36 (sex, J = 7 Hz, 4H, 2 x
CH2CH3), 0.92 (t, J = 7 Hz, 6H, 2 x CH2CH3); 13C NMR
(CDCl3, 75 MHz), δ (ppm): 79.80, 72.09, 71.87, 70.59,
70.46, 70.39, 42.68, 31.75, 19.37, 13.92; HRMS calcd for
C20H40Cl2O6 446.2202, found 446.2210; Elem. Anal. calcd
for C20H40Cl2O6 C 53.69, H 9.01, Cl 15.85, found C 53.72,
H 9.05, Cl 15.87.
2.4.2 | (7S,8S)‐7,8‐bis(butoxymethyl)‐1,14‐
diiodo‐3,6,9,12‐tetraoxatetradecane (5b).
Bischloro compound 4b (7.63 g, 17.1 mmol); NaI (10.24 g,
68.4 mmol); dry acetone (150 ml). Yield: 91% (9.75 g); [α]
= + 5.9 (c = 1, CHCl3);1H NMR (CDCl3, 300 MHz), δ
22
D
(ppm): 3.86–3.78 (m, 2H, 2 x CH), 3.78–3.71 (m, 6H, 2 x
OCH2CH2O, OCH2CH), 3.68–3.57 (m, 8H,
4
x
OCH2CH2O,), 3.55–3.48 (m, 2H, OCH2CH), 3.44 (td,
J = 7.2 Hz, 1.8 Hz, 4H, 2x OCH2CH2CH2), 3.26 (t,
J = 7.2 Hz, 4H, 2 x CH2I), 1.55 (qui, J = 7.2 Hz, 4H, 2 x
CH2CH2CH3), 1.36 (sex, J = 7.2 Hz, 4H, 2 x CH2CH3),
0.92 (t, J = 7.2 Hz, 6H, 2 x CH2CH3); 13C NMR (CDCl3,
75 MHz), δ (ppm): 79.72, 72.05, 71.93, 70.61, 70.49,
70.43, 31.81, 19.38, 13.90, 3.01; HRMS calcd for
C20H40I2O6 630.0914, found 630.0917; Elem. Anal. calcd
for C20H40I2O6 C 38.11, H 6.40, I 40.27, found C 38.10, H
6.38, I 40.27.
2.3.3 | (7S,8S)‐7,8‐bis((benzyloxy)methyl)‐1,14‐
dichloro‐3,6,9,12‐tetraoxatetradecane (4c).
1,4‐Di‐O‐benzyl‐L‐threitol (3c) (18.74 g, 62 mmol);
Bu4NHSO4 (16.27 g, 48 mmol); bis(2‐chloroethyl)ether
(117 ml, 1 mol); 50% aq. NaOH (117 ml). Eluent: CHCl3‐
22
CH3OH 100:0 → 100:5. Yield: 25% (8.10 g); [α]D = +
15.2 (c = 1, CH2Cl2); 1H NMR (CDCl3, 500 MHz), δ
(ppm): 7.36–7.26 (m, 10H, ArH), 4.52 (d, J = 12 Hz,
PhCH2O, 2H), 4.50 (d, J = 12 Hz, PhCH2O, 2H), 3.84–
3.53 (m, 22H, 2 x OCH, 2 x OCH2CH, 4 x OCH2CH2);
138.33, 128.30, 127.66, 127.49, 79.85, 77.18, 72.06, 71.90,
70.51, 70.43, 42.34; HRMS calcd for C26H36Cl2O6
514.1889, found 514.1896; Elem. Anal. calcd for
C26H36Cl2O6 C 60.58, H, 7.04, Cl 13.76, found C 60.60, H
7.02, Cl, 13.78.
2.4.3 | (7S,8S)‐7,8‐bis((benzyloxy)methyl)‐1,14‐
diiodo‐3,6,9,12‐tetraoxatetradecane (5c).
Bischloro compound 4c (7.29 g, 14.1 mmol); NaI (8.51 g,
56.7 mmol); dry acetone (150 ml). Yield: 90% (8.90 g);
[α]D = + 13.2 (c = 1, CH2Cl2);1H NMR (CDCl3,
22
300 MHz), δ (ppm): 7.37–7.24 (m, 10H, ArH), 4.53–4.50
(m, 4H, 2 x PhCH2), 3.87–3.52 (m, 18H, 2 x CHCH2, 2 x
CH, 6 x OCH2), 3.19 (t, J = 6.9 Hz, 4H, 2 x CH2I); 13C
NMR (CDCl3, 75 MHz), δ (ppm): 138.27, 128.32, 127.74,
127.48, 79.81, 77.20, 72.11, 71.88, 70.55, 70.38, 3.11;
HRMS calcd for C26H36I2O6 698.0601, found 698.0610;
Elem. Anal. calcd for C26H36I2O6 C 44.72, H 5.20, I 36.34,
found C 44.69, H 5.17, I 36.36.
2.4 | General procedure for preparation of
bisiodo compounds
A mixture of bischloro compound 4 and NaI in dry acetone
was stirred under reflux for 40 h. After cooling, the
precipitate was filtered and washed with acetone. The
combined acetone solutions were evaporated in vacuum.

RAPI ET AL.
5
2.5 | General procedure for preparation of
threitol‐based crown ethers
2.5.3 | 3‐[(5S,6S)‐5,6‐Bis((benzyloxy)methyl)‐
1,4,7,10‐tetraoxa‐13‐azacyclopentadecan‐13‐yl]
propan‐1‐ol (7a).
Bisiodo compound 5 was dissolved in dry CH3CN,
anhydrous Na2CO3 and the appropriate amine was added
under Ar. The mixture was refluxed for 50 h. Then the
solvent was removed, the residue was dissolved in a mixture
of CHCl3 and water, the layers were separated, and the
organic phase was washed with water, dried, then concen-
trated. The crude product was purified by column
chromatography.
Bisiodo compound 5b (5.5 g, 7.9 mmol); dry CH3CN
(115 ml), anhydrous Na2CO3 (5.69 g, 53.7 mmol);
3‐hydroxypropylamine (0.66 ml, 8.7 mmol). Eluent: CHCl3
(Al2O3). Yield: 62% (2.50 g); [α]D22 = + 4.2 (c = 1, toluene);
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.35–7.24 (m, 10H,
ArH), 4.49 (d, J = 12.5 Hz, 2H, PhCH2), 4.46 (d,
J = 12.5 Hz, 2H, PhCH2), 3.87–3.42 (m, 20H, 2 x CHCH2,
2 x CH, 6 x OCH2, CH2OH), 2.84–2.53 (m, 6H, 3 x
NCH2), 1.71–1.59 (m, 2H, CH2CH2OH); 13C NMR (CDCl3,
75 MHz), δ (ppm): 138.30, 128.30, 127.70, 127.52, 79.79,
77.14, 73.63, 73.53, 73.12, 72.95, 71.66, 70.96, 70.75,
70.38, 69.54, 69.05, 64.01, 56.30, 54.36, 53.86, 28.37; MS
m/z: [M + H]+ 518.1, [M + Na]+ 540.0; HRMS calcd for
C29H43NO7 517.3040, found 517.3045; Elem. Anal. calcd
for C29H43NO7 C 67.29, H 8.37, N 2.71, found C 67.31, H
8.40, N 2.69.
2.5.1 | 3‐[(5S,6S)‐5,6‐Bis(methoxymethyl)‐
1,4,7,10‐tetraoxa‐13‐azacyclopentadecan‐13‐yl]
propan‐1‐ol (6a).
Bisiodo compound 5a (8.55 g, 15.7 mmol); dry CH3CN
(115 ml), anhydrous Na2CO3 (11.3 g, 106.6 mmol);
3‐hydroxypropylamine (1.31 ml, 17.2 mmol). Eluent:
CHCl3‐CH3OH 100:0 → 100:10 silica gel). Yield: 41%
22
1
(1.50 g); [α]D = −5.9 (c = 1, CHCl3); H NMR (CDCl3,
500 MHz), δ (ppm): 3.84–3.54 (m, 18H, 2 x CHCH2, 2 x
CH, 6 x OCH2), 3.46–3.39 (m, 2H, CH2OH), 3.36 (s, 6H, 2
x OCH3), 2.79–2.61 (m, 6H, 3 x NCH2), 1.74–1.63 (m, 2H,
CH2CH2OH); 13C NMR (CDCl3, 75 MHz), δ (ppm): 79.62,
77.24, 72.21, 72.09, 71.44, 71.03, 70.62, 70.29, 68.95,
66.96, 63.91, 59.21, 59.15, 56.15, 54.37, 53.83, 28.33; MS
m/z: [M + H]+ 366.1, [M + Na]+ 388.3; HRMS calcd for
C17H35NO7 365.2414, found 365.2416; Elem. Anal. calcd
for C17H35NO7 C 55.87, H 9.65, N 3.83, found C 55.90, H
9.66, N 3.79.
2.5.4 | (5S,6S)‐5,6‐Bis((benzyloxy)methyl)‐13‐
(3‐methoxypropyl)‐1,4,7,10‐tetraoxa‐13‐
azacyclopentadecane (7b).
Bisiodo compound 5b (3.3 g, 6.4 mmol); dry CH3CN
(115 ml), anhydrous Na2CO3 (4.61 g, 43.5 mmol);
3‐methoxypropylamine (0.65 ml, 6.4 mmol). Eluent:
CHCl3‐CH3OH 100:0 → 100:10 (silica gel). Yield: 71%
(2.40 g), [α]D22 = + 32.4 (c = 1, CHCl3); 1H NMR (CDCl3,
500 MHz), δ (ppm): 7.37–7.26 (m, 10H, ArH), 4.52–4.48
(m, 4H, 2 x PhCH2), 3.93–3.45 (m, 20H, 2 x CHCH2, 2 x
CH, 6 x OCH2, CH2OCH3), 3.36 (s, 3H, OCH3), 2.83 (t,
J = 6.5 Hz, 2H, NCH2), 2.69–2.62 (m, 1H, NCH2),
2.48–2.41 (m, 1H, NCH2), 2.26 (d, J = 14 Hz, 2H, NCH2),
1.63–1.55 (m, 2H, CH2CH2OH); 13C NMR (CDCl3,
75 MHz), δ (ppm): 138.32, 128.27, 127.73, 127.50, 79.75,
77.11, 73.64, 73.56, 73.11, 72.93, 71.69, 71.05, 70.95,
70.74, 70.40, 69.50, 69.07, 58.37, 56.31, 54.32, 53.87,
28.38; MS m/z: [M + H]+ 532.2, [M + Na]+ 554.1; HRMS
calcd for C30H45NO7 531.3196, found 532.0001; Elem.
Anal. calcd for C30H45NO7 C 67.77, H 8.53, N 2.63, found
C 67.80, H 8.57, N 2.60.
2.5.2 | (5S,6S)‐5,6‐Bis(methoxymethyl)‐13‐(3‐
methoxypropyl)‐1,4,7,10‐tetraoxa‐13‐
azacyclopentadecane (6b).
Bisiodo compound 5a (4.50 g, 8.3 mmol); dry CH3CN
(100 ml), anhydrous Na2CO3 (11.3 g, 106.6 mmol);
3‐methoxypropylamine (0.85 ml, 8.3 mmol). Eluent:
CHCl3‐CH3OH 100:1 → 100:7 (silica gel). Yield: 73%
22
1
(2.29 g); [α]D = +4.8 (c = 1, CHCl3); H NMR (CDCl3,
500 MHz), δ (ppm): 3.79–3.30 (m, 29H, 2 x CHCH2, 2 x
CH, 6 x OCH2CH2, CH3OCH2, CH3OCH2, 2 x OCH3),
2.79–2.61 (m, 6H, 3 x NCH2), 1.72–1.70 (m, 2H,
CH2CH2OH); 13C NMR (CDCl3, 75 MHz), δ (ppm): 79.66,
77.23, 72.26, 72.04, 71.48, 71.06, 70.94, 70.60, 70.33,
68.99, 66.93, 59.20, 59.17, 58.30, 56.11, 54.33, 53.86,
28.32; MS m/z: [M + H]+ 380.5, [M + Na]+ 402.5; HRMS
calcd for C18H37NO7 379.2570, found 379.2575; Elem.
Anal. calcd for C18H37NO7 C 56.97, H 9.83, N 3.69, found
C 57.00, H 9.85, N 3.70.
2.5.5 | 3‐[(5S,6S)‐5,6‐Bis(butoxymethyl)‐
1,4,7,10‐tetraoxa‐13‐azacyclopentadecan‐13‐yl]
propan‐1‐ol (8a).
Bisiodo compound 5c (3.15 g, 5 mmol); dry CH3CN
(50 ml), anhydrous Na2CO3 (3.18 g, 30 mmol);
3‐hydroxypropylamine (0.38 ml, 5 mmol). Eluent: CHCl3
22
(Al2O3). Yield: 64% (2.88 g); [α]D = + 4 (c = 1, CHCl3);
1H NMR (CDCl3, 300 MHz), δ (ppm): 3.84–3.74 (m, 6H, 2

6
RAPI ET AL.
x CH, 2 x OCH2CH), 3.72–3.53 (m, 12H, 6 x OCH2CH2O,),
3.51–3.35 (m, 6H, 2x OCH2CH2CH2, CH2OH), 2.86–2.63
(m, 6H, 3 x NCH2), 1.71–1.62 (m, 2H, CH2CH2OH), 1.54
(qui, J = 7.2 Hz, 4H, 2 x CH2CH2CH3), 1.36 (sex,
J = 7.2 Hz, 4H, 2 x CH2CH3), 0.91 (t, J = 7.2 Hz, 6H, 2
x CH2CH3); 13C NMR (CDCl3, 75 MHz), δ (ppm): 79.85,
71.30, 71.29, 70.81, 70.32, 70.29, 63.90, 54.34, 54.07,
53.35, 31.85, 31.76, 19.37, 19.34, 13.92; MS m/z:
[M + H]+ 450.6, [M + Na]+ 472.7; HRMS calcd for
C23H47NO7 449.3305, found 449.3309; Elem. Anal. calcd
for C23H47NO7 C 61.44, H 10.54, N 3.12, found C 61.46,
H 10.55, N 3.11.
89%; 1H NMR (CDCl3, 500 MHz), δ (ppm): 7.85 (d,
J = 7.5 Hz, 2H, ArH), 7.53 (t, J = 7.5 Hz, 1H, ArH), 7.42
(t, J = 7.5 Hz, 2H, ArH), 7.32–7.18 (m, 5H, ArH), 4.15
(dd, J = 10.5 Hz, 3.5 Hz, 1H, CH), 3.67 (dd, J = 17.5 Hz,
10.5 Hz, 1H, CH2), 3.27 (dd, J = 17.5 Hz, 3.5 Hz, 1H,
CH2), 1.63 (s, 3H, CH3), 1.54 (s, 3H, CH3).
2.6 | General procedure for asymmetric model
reactions using malonates46-48
Unsaturated compound (1 mmol), substituted malonate
(1.5 mmol) and the crown ether (0.15 mmol) were
dissolved in a mixture of anhydrous THF (0.6 ml) and
Et2O (2.4 ml) and dry Na2CO3 (0.22 g, 2 mmol) was
added. The reaction mixture was stirred at RT. After
completion of the reaction the organic phase was con-
centrated in vacuum and the residue was dissolved in
CH2Cl2 (10 ml), washed with cold 10% aq. HCl (3 x
10 ml) and water (10 ml), dried (Na2CO3 and Na2SO4),
and concentrated. The crude product was purified on
silica gel by preparative TLC with hexane‐EtOAc (5:1)
as eluent. Enantioselectivities were determined by chiral
high‐performance liquid chromatography (HPLC) analyz-
2.5.6 | (5S,6S)‐5,6‐Bis(butoxymethyl)‐13‐(3‐
methoxypropyl)‐1,4,7,10‐tetraoxa‐13‐
azacyclopentadecane (8b).
Bisiodo compound 5c (3.15 g, 5 mmol); dry CH3CN
(50 ml), anhydrous Na2CO3 (3.18 g, 30 mmol);
3‐methoxypropylamine (0.51 ml, 5 mmol). Eluent: CHCl3‐
CH3OH 100:0 → 100:4 (Al2O3). Yield: 86% (1.98 g);
22
1
[α]D = +5 (c = 1, CHCl3); H NMR (CDCl3, 300 MHz),
δ (ppm): 3.84–3.36 (m, 24H, 2 x CH, 2 x OCH2CH, 6 x
OCH2CH2O, 2x OCH2CH2CH2, CH2OCH3), 3.32 (s, 3H,
OCH3), 2.85–2.52 (m, 6H, 3 x NCH2), 1.71–1.62 (m, 2H,
CH2CH2OH), 1.54 (qui, J = 7.2 Hz, 4H, 2 x CH2CH2CH3),
1.36 (sex, J = 7.2 Hz, 4H, 2 x CH2CH3), 0.91 (t,
J = 7.2 Hz, 6H, 2 x CH2CH3); 13C NMR (CDCl3,
75 MHz), δ (ppm): 79.81, 71.33, 71.27, 71.00, 70.82,
70.34, 70.29, 58.65, 54.31, 54.10, 53.34, 31.86, 31.75,
19.38, 19.35, 13.93; MS m/z: [M + H]+ 464.4, [M + Na]+
486.5; HRMS calcd for C24H49NO7 463.3509, found
463.3512; Elem. Anal. calcd for C24H49NO7 C 62.17, H
10.65, N 3.02, found C 62.16, H 10.67, N 3.01.
ing using
a
Chiralpak column with hexane‐iPrOH
mixture as eluent, in comparison with authentic racemic
materials.
2.6.1 | Diethyl 2‐acetamido‐2‐(2‐nitro‐1‐
phenylethyl)malonate (14).
Yield: 65% (0.24 g); white solid; mp 135–136 °C;
22
[α]D = −40.7; (c = 1, CHCl3); ee 95%; AD‐H column,
hexane:iPrOH 85:15, major tr = 14.6 min, minor tr = 20.5 min;
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.31–7.28 (m, 3H,
ArH), 7.22–7.18 (m, 2H, ArH), 6.89 (br s, 1H, NH),
5.54–5.48 (m, 1H, CH2NO2), 4.73–4.66 (m, 2H,CH2NO2,
PhCH), 4.34–4.23 (m, 2H, CH2CH3), 4.20–4.13 (m, 1H,
CH2CH3), 4.08–4.01 (m, 1H, CH2CH3), 2.12 (s, 3H,
COCH3), 1.27 (t, J = 7 Hz, 3H, CH2CH3), 1.25 (t,
J = 7 Hz, 3H, CH2CH3).
2.5.7 | 4‐Methy‐4‐nitro‐1,3‐diphenylpentan‐1‐
one (11).45
Chalcone (0.29 g, 1.4 mmol), 2‐nitropropane (0.31 ml,
3.4 mmol) and crown catalyst (0.1 mmol) were dissolved
in dry toluene (3 ml), and sodium tert‐butoxide (50 mg,
0.5 mmol) was added. After completion of the reaction,
the mixture was diluted with water (10 ml) and toluene
(7 ml). The phases were separated. The organic layer was
washed with cold 10% HCl (3 x 10 ml) and then with
water (10 ml), dried (Na2CO3 and Na2SO4), and concen-
trated. The crude product was purified by preparative
TLC using silica gel and hexane‐EtOAc (10:1) as the
eluent. The enantioselectivity was determined by 1H
NMR spectroscopy in the presence of Eu(hfc)3 as a chiral
shift reagent.
2.6.2 | Diethyl 2‐acetoxy‐2‐(3‐oxo‐1,3‐
diphenylpropyl)malonate (16a).
Yield: 68% (0.29 g); yellow oil; [α]D22 = 9.3; (c = 1, CHCl3);
ee 96%; AS‐H column, hexane:iPrOH 90:10, major enantio-
mer tr = 9.9 min, minor enantiomer tr = 13.2 min; 1H
NMR (500 MHz, CDCl3), δ (ppm): 7.90 (d, J = 7.5 Hz,
2H, ArH), 7.53 (t, J = 7.5 Hz, 1H, ArH), 7.43 (t,
J = 7.5 Hz, 2H, ArH), 7.35 (d, J = 7.5 Hz, 2H, ArH),
7.26–7.20 (m, 3H, ArH), 4.37 (dd, J = 8.5 Hz, 4 Hz, 1H,
PhCH), 4.24–4.16 (m, 2H, OCH2), 4.02–3.89 (m, 2H,
OCH2), 3.67 (dd, J = 16 Hz, 4 Hz, 1H, COCH2), 3.59 (dd,
Yield: 68% (0.28 g); white solid; mp. 146–148 °C;
22
[α]D = +71.4 (c = 1, CHCl3); enantiomeric excess (ee)

RAPI ET AL.
7
J = 17.5 Hz, 8.5 Hz, 1H, COCH2), 2.23 (s, 3H, COCH3),
1.23 (t, J = 7 Hz, 3H, CH2CH3), 1.06 (t, J = 7 Hz, 3H,
CH2CH3); 13C NMR (CDCl3, 75 MHz), δ (ppm): 196.75,
169.50, 165.95, 165.34, 138.35, 136.76, 133.13, 129.47,
128.56, 128.10, 128.01, 127.65, 84.38, 62.45, 62.03, 45.49,
39.87, 20.76, 13.82, 13.68; HRMS calcd for C24H26O7
426.1679, found 426.1680.
4.25–4.18 (m, 2H, OCH2), 4.02–3.87 (m, 3H, COCH2,
OCH2), 3.55 (dd, J = 18 Hz, 8.5 Hz, 1H, COCH2),
2.24 (s, 3H, COCH3), 1.25 (t, J = 7 Hz, 3H, CH2CH3),
1.07 (t, J = 7 Hz, 3H, CH2CH3); HRMS calcd for
C24H25NO9 471.1529, found 471.1527.
2.6.6 | Diethyl 2‐acetoxy‐2‐(1‐(3‐methoxyphenyl)‐
3‐oxo‐3‐phenylpropyl)malonate (16e).
2.6.3 | Diethyl 2‐acetoxy‐2‐(1‐(4‐chlorophenyl)‐
3‐oxo‐3‐phenylpropyl)malonate (16b).
22
Yield: 64% (0.29 g); yellow oil; [α]D = +12.8; (c = 1,
CHCl3); ee 57%; AD‐H column, hexane:iPrOH 90:10,
major enantiomer tr = 23.1 min, minor enantiomer
tr = 17.5 min; 1H NMR (500 MHz, CDCl3), δ (ppm):
7.90 (d, J = 7.5 Hz, 2H, ArH), 7.54 (t, J = 7.5 Hz, 1H,
ArH), 7.43 (t, J = 7.5 Hz, 2H, ArH), 7.14 (t, J = 8 Hz,
1H, ArH), 6.96–6.90 (m, 2H, ArH), 6.75 (dd, J = 8 Hz,
2.5 Hz, 1H, ArH), 4.35 (dd, J = 9 Hz, 4 Hz, 1H, ArCH),
4.25–4.15 (m, 2H, OCH2), 4.05–3.94 (m, 2H, OCH2), 3.76
(s, 3H, ArOCH3), 3.71 (dd, J = 18 Hz, 4 Hz, 1H,
COCH2), 3.56 (dd, J = 18 Hz, 9 Hz, 1H, COCH2), 2.23
(s, 3H, COCH3), 1.23 (t, J = 7 Hz, 3H, CH2CH3), 1.09
(t, J = 7 Hz, 3H, CH2CH3); HRMS calcd for C25H28O8
456.1784, found 456.1788.
22
Yield: 76% (0.35 g); yellow oil; [α]D = +21.1; (c = 1,
CHCl3); ee 99%; AD‐H column, hexane:iPrOH 90:10, major
enantiomer tr = 13.7 min, minor enantiomer tr = 11.9 min;
1H NMR (500 MHz, CDCl3), δ (ppm): 7.89 (d, J = 7.5 Hz,
2H, ArH), 7.55 (t, J = 7.5 Hz, 1H, ArH), 7.44 (t,
J = 7.5 Hz, 2H, ArH), 7.29 (d, J = 8.5 Hz, 2H, ArH), 7.22
(d, J = 8.5 Hz, 2H, ArH), 4.34 (dd, J = 9 Hz, J = 4 Hz,
1H, ArCH), 4.24–4.17 (m, 2H, OCH2), 4.06–3.92 (m, 2H,
OCH2), 3.73 (dd, J = 17.7 Hz, 4.5 Hz, 1H, COCH2), 3.56
(dd, J = 18 Hz, 9 Hz, 1H, COCH2), 2.23 (s, 3H, COCH3),
1.24 (t, J = 7 Hz, 3H, CH2CH3), 1.10 (t, J = 7 Hz, 3H,
CH2CH3); HRMS calcd for C24H25ClO7 460.1289, found
460.1294.
2.6.7 | Diethyl 2‐acetoxy‐2‐(1‐(4‐methoxyphenyl)‐
3‐oxo‐3‐phenylpropyl)malonate (16f).
2.6.4 | Diethyl 2‐acetoxy‐2‐(1‐(3‐nitrophenyl)‐
3‐oxo‐3‐phenylpropyl)malonate (16c).
22
Yield: 33% (0.15 g); light yellow; [α]D = +19.7 (c = 1,
22
Yield: 79% (0.37 g); orange oil; [α]D = +14.5; (c = 1,
CHCl3); ee 99%; AD‐H column, hexane:iPrOH 90:10, major
enantiomer tr = 24.9 min, minor enantiomer tr = 22.8 min;
1H NMR (500 MHz, CDCl3), δ (ppm): 7.89 (dd,
J = 7.5 Hz, 1 Hz, 2H, ArH), 7.53 (t, J = 7.5 Hz, 1H,
ArH), 7.43 (t, J = 7.5 Hz, 2H, ArH), 7.26 (d, J = 8.5 Hz,
2H, ArH), 6.77 (d, J = 8.5 Hz, 2H, ArH), 4.31 (dd,
J = 8.5 Hz, J = 4 Hz, 1H, ArCH), 4.24–4.15 (m, 2H,
OCH2), 4.06–3.92 (m, 2H, OCH2), 3.75 (s, 3H, ArOCH3),
3.71 (dd, J = 18 Hz, 4 Hz, 1H, COCH2), 3.56 (dd,
J = 18 Hz, J = 9 Hz, 1H, COCH2), 2.23 (s, 3H, COCH3),
1.23 (t, J = 7 Hz, 3H, CH2CH3), 1.10 (t, J = 7 Hz, 3H,
CH2CH3); HRMS calcd for C25H28O8 456.1784, found
456.1785.
CHCl3); ee 48%; AD‐H column, hexane:iPrOH 90:10,
major enantiomer tr = 25.0 min, minor enantiomer
tr = 21.1 min; 1H NMR (500 MHz, CDCl3), δ (ppm):
8.30 (s, 1H, ArH), 8.10 (d, J = 8 Hz, 1H, ArH), 7.91 (d,
J = 7 Hz, 2H, ArH), 7.71 (d, J = 7.5 Hz, 1H, ArH),
7.57 (t, J = 7.5 Hz, 1H, ArH), 7.45 (td, J = 8 Hz, 2 Hz,
3H, ArH), 4.49 (dd, J = 9.2 Hz, 4 Hz, 1H, ArCH),
4.27–4.20 (m, 2H, OCH2), 4.08–3.95 (m, 2H, OCH2),
3.81 (dd, J = 18.2 Hz, 4 Hz, 1H, COCH2), 3.64 (dd,
J = 18.2 Hz, 9 Hz, 1H, COCH2), 2.25 (s, 3H, COCH3),
1.26 (t, J = 7 Hz, 3H, CH2CH3), 1.12 (t, J = 7 Hz, 3H
CH2CH3); HRMS calcd for C24H25NO9 471.1529, found
471.1531.
2.6.8 | Diethyl 2‐benzoyl‐3‐phenylcyclopropane‐
1,1‐dicarboxylate (18).
2.6.5 | Diethyl 2‐acetoxy‐2‐(1‐(4‐nitrophenyl)‐
3‐oxo‐3‐phenylpropyl)malonate (16d).
22
Yield: 28% (0.10 g); yellow oil; [α]D = +28.0; (c = 1,
Yield: 85% (0.40 g); yellowish‐brown powder; mp
93–96 °C; [α]D = +3.9; (c = 1, CHCl3); ee 86%; AD‐
CHCl3); ee 99%; AS‐H column, hexane:iPrOH 90:10,
major enantiomer tr = 5.0 min, minor enantiomer
22
H
column, hexane:iPrOH 90:10, major enantiomer
tr = 9.3 min;1H NMR (500 MHz, CDCl3), δ (ppm): 8.11
(d, J = 7.5 Hz, 2H, ArH), 7.62 (t, J = 7.5 Hz, 1H,
ArH), 7.51 (t, J = 7.5 Hz, 2H, ArH), 7.33–7.26 (m, 5H,
ArH), 4.14 (q, J = 7 Hz, 2H, OCH2), 4.12 (d,
J = 7.5 Hz, 1H, COCH), 4.00 (q, J = 7 Hz, 2H, OCH2),
tr = 54.1 min, minor enantiomer tr = 40.5 min; 1H
NMR (500 MHz, CDCl3), δ (ppm): 8.27 (d, J = 9 Hz,
2H, ArH), 8.04 (d, J = 9 Hz, 2H, ArH), 7.35–7.21 (m,
5H, ArH), 4.36 (dd, J = 8.2 Hz, 5 Hz, 1H, ArCH),

8
RAPI ET AL.
3.89 (d, J = 7.5 Hz, 1H, PhCH), 1.11 (t, J = 7 Hz, 3H,
CH3), 0.99 (t, J = 7 Hz, 3H, CH3). 13C NMR (CDCl3,
75 MHz), δ (ppm): 193.58, 165.93, 165.69, 136.78,
133.62, 133.61, 133.47, 128.73, 128.61, 128.60, 128.58,
128.50, 128.31, 128.30, 127.66, 61.97, 61.89, 49.10,
35.87, 35.00, 13.85, 13.80; HRMS calcd for C22H22O5
366.1467, found 366.1470.
2.6.12 | Diethyl 2,2‐dicyano‐3‐(4‐methyphenyl)
cyclopropane‐1,1‐dicarboxylate (20d).
Yield: 86% (0.28 g); orange oil; [α]D = −15.5; (c = 1,
22
CHCl3); ee 86%; AD‐H column, hexane:iPrOH 80:20, major
1
enantiomer tr = 4.3 min, minor enantiomer tr = 5.0 min; H
NMR (500 MHz, CDCl3), δ (ppm): 7.25 (d, J = 8 Hz, 2H,
ArH), 7.20 (d, J = 8 Hz, 2H, ArH), 4.42 (q, J = 7 Hz, 2H,
OCH2), 4.30–4.20 (m, 2H, OCH2), 3.92 (s, 1H, ArCH),
2.35 (s, 3H, ArCH3), 1.38 (t, J = 7 Hz, 3H), 1.21 (t,
J = 7 Hz, 3H). HRMS calcd for C18H18N2O4 326.1267,
found 326.1270.
2.6.9 | Diethyl 2,2‐dicyano‐3‐
phenylcyclopropane‐1,1‐dicarboxylate (20a).
22
Yield: 81% (0.25 g); yellow oil; [α]D = −14.1; (c = 1,
CHCl3); ee 85%; AS‐H column, hexane:iPrOH 90:10, major
enantiomer tr = 13.5 min, minor enantiomer tr = 12.2 min;
1H NMR (300 MHz, CDCl3), δ (ppm): 7.45–7.35 (m, 5H,
ArH), 4.43 (q, J = 7.2 Hz, 2H, OCH2), 4.30–4.18 (m, 2H,
OCH2), 3.96 (s, 1H, ArCH), 1.39 (t, J = 7.2 Hz, 3H,
CH2CH3), 1.19 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR
(75 MHz, CDCl3), δ (ppm): 163.05, 161.06, 129.67,
129.10, 128.76, 127.31, 111.86, 109.71, 64.50, 63.62,
46.39, 40.08, 16.32, 13.97, 13.60; HRMS calcd for
C17H16N2O4 312.111, found 312.1104.
2.6.13 | Diethyl 2,2‐dicyano‐3‐(4‐nitrophenyl)
cyclopropane‐1,1‐dicarboxylate (20e).
Yield: 67% (0.24 g); orange oil; [α]D = −2.0; (c = 1,
CHCl3); ee 75%; AD‐H column, hexane:iPrOH 90:10, major
enantiomer tr = 26.4 min, minor enantiomer tr = 31.3 min;
1H NMR (500 MHz, CDCl3), δ (ppm): 8.29 (d, J = 8.5 Hz,
2H, ArH), 7.62 (d, J = 8.5 Hz, 2H, ArH), 4.46 (q,
J = 7 Hz, 2H, OCH2), 4.32–4.23 (m, 2H, OCH2), 4.01 (s,
1H, ArCH), 1.41 (t, J = 7 Hz, 3H, CH2CH3), 1.24 (t,
J = 7 Hz, 3H, CH2CH3); HRMS calcd for C17H15N3O6
357.0961, found 357.0958.
22
2.6.10 | Diethyl 2,2‐dicyano‐3‐(2‐methyphenyl)
cyclopropane‐1,1‐dicarboxylate (20b).
Yield: 72% (0.23 g); yellow oil; [α]D = +7.8; (c = 1,
CHCl3); ee 23%;Yellow oil; AD‐H column, hexane:iPrOH
2.6.14 | Diethyl 2,2‐dicyano‐3‐(4‐chlorophenyl)
cyclopropane‐1,1‐dicarboxylate (20f).
Yield: 80% (0.25 g); yellow oil; [α]D = −27.0; (c = 1,
22
22
CHCl3); ee 59%; AD‐H column, hexane:iPrOH 90:10, major
80:20, major enantiomer tr = 3.7 min, minor enantiomer
1
1
enantiomer tr = 4.5 min, minor enantiomer tr = 4.0 min; H
tr = 3.3 min; H NMR (300 MHz, CDCl3), δ (ppm): 7.37
NMR (500 MHz, CDCl3), δ (ppm): 7.39 (d, J = 8.5 Hz,
2H, ArH), 7.33 (d, J = 8.5 Hz, 2H, ArH), 4.43 (q,
J = 6 Hz, 2H, OCH2), 4.30–4.20 (m, 2H, OCH2), 3.91 (s,
1H, ArCH), 1.39 (t, J = 6 Hz, 3H, CH3), 1.39 (t, J = 6 Hz,
3H, CH3); HRMS calcd for C17H15ClN2O4 346.0720, found
346.0726.
(d, J = 7.2 Hz, 1H, ArH), 7.33–7.26 (m, 2H, ArH), 7.20
(td, J = 7.2 Hz, 1.2 Hz, 1H, ArH), 4.44 (q, J = 6.9 Hz, 2H,
OCH2), 4.23 (q, J = 6.9 Hz, 2H, OCH2), 3.87 (s, 1H, ArCH),
2.43 (s, 3H, ArCH3), 1.40 (t, J = 6.9 Hz, 3H), 1.17 (t,
J = 6.9 Hz, 3H); HRMS calcd for C18H18N2O4 326.1267,
found 326.1265.
2.6.15 | Diethyl 2,2‐dibenzoyl‐3‐
2.6.11 | Diethyl 2,2‐dicyano‐3‐(3‐methyphenyl)
cyclopropane‐1,1‐dicarboxylate (20c).
Yield: 74% (0.24 g); orange oil; [α]D = −22.2.; (c = 1,
phenylcyclopropane‐1,1‐dicarboxylate (22).
22
Yield: 38% (0.18 g); yellow oil; [α]D = +64.9 (c = 1,
22
CHCl3); ee 57%; AD‐H column, hexane:iPrOH 90:10, major
enantiomer tr = 11.9 min, minor enantiomer tr = 41.1 min;
1H NMR (500 MHz, CDCl3), δ (ppm) = 7.53 (d,
J = 7.5 Hz, 2H, ArH), 7.44 (d, J = 7.5 Hz, 2H, ArH), 7.33
(d, J = 7 Hz, 2H, ArH), 7.26–7.19 (m, 5H, ArH), 7.14 (t,
J = 7.5 Hz, 2H, ArH), 7.10 (t, J = 7.5 Hz, 2H, ArH), 5.64
(s, 1H, PhCH), 4.47–4.40 (m, 1H, OCH2), 4.38–4.29 (m,
1H, OCH2), 3.87–3.80 (m, 1H, OCH2), 3.64–3.57 (m, 1H,
OCH2), 1.35 (t, J = 7 Hz, 3H, CH3), 0.84 (t, J = 7 Hz, 3H,
CH3). 13C NMR (CDCl3, 75 MHz), δ (ppm): 191.77,
CHCl3); ee 99%; AD‐H column, hexane:iPrOH 80:20,
major enantiomer tr
= 4.1 min, minor enantiomer
tr = 5.7 min; 1H NMR (300 MHz, CDCl3), δ (ppm):
7.29 (t, J = 7.2 Hz, 1H, ArH), 7.22 (s, 1H, ArH),
7.21–7.13 (m, 2H, ArH), 4.42 (q, J = 6.9 Hz, 2H,
OCH2), 4.24 (q, J = 6.9 Hz, 2H, OCH2), 3.93 (s, 1H,
ArCH), 2.36 (s, 3H, ArCH3), 1.39 (t, J = 6.9 Hz, 3H),
1.20 (t, J = 6.9 Hz, 3H); HRMS calcd for C18H18N2O4
326.1267, found 326.1268.

RAPI ET AL.
9
185.72, 166.92, 165.33, 138.20, 136.88, 131.80, 131.79,
130.58, 129.64, 129.11, 128.78, 128.33,128.32, 127.83,
127.82, 114.79, 91.73, 62.95, 62.07, 57.43, 14.05, 13.43;
HRMS calcd for C29H26O6 470.1729, found 470.1733.
cyclized with 3‐aminopropanol and 3‐methoxypropylamine
in boiling acetonitrile, in the presence of Na2CO3 to result
in the formation of lariat ethers 6–8. The ring closure
reactions with 3‐aminopropanol took place in yields of 41%
(6a), 62% (7a), and 64% (8a), respectively, while with
3‐methoxypropylamine the yields were 73% (6b), 71% (7b),
and 86% (8b) (Scheme 1).
3 | RESULTS AND DISCUSSION
The macrocycles synthesized (6–8) were tested as chiral
catalysts in Michael addition reactions under solid–liquid
phase transfer conditions, at RT. The corresponding products
were obtained by preparative TLC, and the enantiomeric
purity was measured by H NMR spectroscopy or chiral
HPLC.
The addition of 2‐nitropropane (10) to trans‐chalcone (9)
was carried out in toluene, in the presence of solid sodium
tert‐butoxide (35 mol%) using one of the chiral catalysts
(7 mol%) prepared by us as reported previously16,45
(Scheme 2).
The 2,3‐O‐isopropylidene‐L‐threitol (1) was prepared from
commercially available diethyl L‐tartrate according to a
known procedure.49-52 The dialkylation of diol 1 by methyl
iodide,41 n‐butyl bromide, and benzyl chloride42 in THF
using NaH afforded intermediates 2a, 2b, and 2c, respec-
tively. The isopropylidene protecting groups were then
removed by HCl/MeOH,38,44 to furnish optically active diols
3a–c in good yields.
The vicinal hydroxyl groups of compounds 3a–c were
then alkylated with bis(2‐chloroethyl) ether in the presence
of 50% aq. NaOH as the base and tetrabutylammonium
hydrogensulfate (Bu4HSO4) as the phase transfer catalyst in
a liquid–liquid two‐phase system to give key intermediates
4a–c in 37%, 79%, and 25% yields, respectively, after
chromatography. The exchange of chlorine to iodine in
intermediates 4a–c was accomplished by reaction with NaI
in boiling acetone to provide bis‐iodo derivatives 5a–c in
good yields (in average 90%). These species (5a–c) were then
1
SCHEME 2 Michael addition of 2‐nitropropane to chalcone
SCHEME 1 The synthesis of L‐threitol‐
based crown ethers from diethyl L‐tartrate

10
RAPI ET AL.
Another Michael reaction, the conjugate addition of
while dimethyl substituted catalyst 6a led to a lower ee of
58% (Table 1, entries 7 and 5). Comparison of the effect of
catalysts 6a and 6b as well as the effect of 8a and 8b referred
to the advantage of the hydroxyl end‐group (58% and 95% ee,
respectively) in relation to a methoxy group (38% and 51%
ee, respectively) (Table 1, entries 5 and 6). This observation
may be in accord with the hydrogen bond forming ability of
the OH moiety.
The asymmetric addition of dialkyl malonates to
trans‐chalcones have been studied in the presence of chiral
catalysts in several reports. For example, the reaction was
investigated in the presence of La‐BINOL complexes,53,54
L‐proline derivatives,55 chiral aminoalcohol‐Al com-
plexes,56,57 pyrrolidylalkyl ammonium hydroxide, and chiral
ammonium salts58 as the catalysts. There are also a few
examples in this field for chiral phase transfer catalysis.59,60
Recently, successful applications of cinchona alkaloids‐
derived quaternary ammonium salts have been reported in
catalytic asymmetric syntheses.61
Previously, we found that a glucopyranoside‐based
macrocycle generated asymmetric induction in the reaction
of chalcone 9a with diethyl acetoxymalonate (15).46 It was
a challenge for us to test the threitol‐based lariat ethers in this
reaction. In our experiments, the conjugate addition of
diethylmalonate (15) to trans‐chalcones 9a–f was carried in
a mixture of THF‐ether as the solvent in the presence of
Na2CO3 (used in 2‐fold excess) employing 15 mol% of the
crown ether at room temperature to afford the chiral Michael
adducts 16a–f. The experimental data obtained by the
application of the threitol‐based lariat ethers are shown in
Table 2.
diethyl acetamidomalonate 13 to β‐nitrostyrene 12 was
carried out in a mixture of THF‐ether in the presence of dry
Na2CO3 employing 15 mol% of the crown ether
(Scheme 3).39,40 Experimental data of the two asymmetric
Michael addition reactions are shown in Table 1.
It can be seen from Table 1 that the outcome of the
Michael additions depended on the substituent of the
threitol‐based crown ether. In the addition of 2‐nitropropane
to chalcone, from the point of view of yield and
enantioselectivity, the most efficient catalyst was threitol‐
based lariat ether with hydroxypropyl side arm (6a) giving
product (11) in a yield of 68% and in an ee of 89%. In the
case, where there was MeO end‐group instead of the OH
function (6b), the product was obtained in a lower yield
(56%) and in a lower ee (67%) (Table 1, entry 2).
Comparative results were obtained applying macrocycle
8a with two benzyl groups (Table 1, entry 4), while the use
of lariat ether with butyl groups (7a) gave the lowest yield
(20%) and ee (31%). In the case of the reaction of nitrostyrene
12 with diethyl acetamidomalonate (13), surprisingly, the
dibenzyl substituted crown ether (8a) induced an ee of 95%,
SCHEME 3 Michael addition of diethyl acetamidomalonate to β‐
nitrostyrene
In the reaction of chalcone 9a, the highest asymmetric
induction (96% ee) was generated by threitol‐based crown
ether 6a with two methyl groups. Species 16a was isolated
in a yield of 68% (Table 2, entry 1). Somewhat lower ee
values (83–87% ee) were detected using the dibutyl and
dibenzyl catalysts 7a and 8a (Table 2, entries 3 and 5). The
catalysts with MeO end‐group (6b and 7b) led again to lower
ee values than the species with OH groups (Table 2, entries 2
and 4).
In general, the reaction of 4‐chlorochalcone (9b) gave the
products (16b) in higher ee values of 82–99%, but the ten-
dency was different as in the previous case. The higher ee
value (99% ee) was obtained with the dibenzyl substituted
macrocycle 8a (Table 2, entry 9), followed by catalysts 7a
and 6a resulting in ee values of 98% and 90%, respectively,
(Table 2, entries 7 and 6). The lowest induction (82% ee)
was shown by dibutyl macrocycle 7b with a MeO end‐group
(Table 2, entry 8). It is noteworthy that in reaction of the 3‐
nitrochalcone, catalysts 6a, 7a, and 8a with hydroxypropyl
side arm gave the adducts (16c) in relative good yields,
but in rather modest ee values of 38–48% ee (Table 2,
entries 10–12). The use of catalyst 7a in the reaction of
TABLE 1 Asymmetric Michael addition of 2‐nitropropane (10) and
diethyl acetamidomalonate (13) to chalcone (9a) and nitrostyrene (12),
respectively, in the presence of threitol‐based lariat ethers
a
Entry
Catalysts
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
6a
6b
7a
8a
6a
6b
8a
8b
28
22
24
24
8
11: 68
11: 56
11: 20
11: 62
14: 67
14: 56
14: 65
14: 22
89 (R)b
67 (R)b
31 (R)b
75 (R)b
58 (S)c
38 (S)c
95 (S)c
51 (S)c
7
9
27
aBased on isolation by preparative TLC.
bEnantioselectivities were determined by 1H NMR spectroscopy; The (+)‐(R)‐
antipode of 11 was formed in excess.
cDetermined by chiral HPLC analysis, the (−)‐(S) enantiomer predominated.
Absolute configurations were assigned by comparison of specific rotations with
the literature value.

RAPI ET AL.
11
TABLE 2 The addition of diethyl acetoxymalonate (15) to trans‐chalcones (9a–f) in the presence of threitol‐based lariat ethers
a
Entry
Catalyst
R
Time (h)
Yield (%)
ee (%)b
1
6a
6b
7a
7b
8a
6a
7a
7b
8a
6a
7a
8a
7a
8a
7a
9a:H
170
120
72
16a: 68
16a: 49
16a: 65
16a: 62
16a: 65
16b: 67
16b: 72
16b: 57
16b: 76
16c: 64
16c: 79
16c: 59
16d: 85
16e: 64
16f: 33
96
61
87
77
83
90
98
82
99
38
48
42
86
57
99
2
9a:H
3
9a:H
4
9a:H
120
130
72
5
9a:H
6
9b:4‐Cl
9b:4‐Cl
9b:4‐Cl
9b:4‐Cl
9c:3‐NO2
9c:3‐NO2
9c:3‐NO2
9d:4‐NO2
9e:3‐OMe
9f:4‐OMe
7
48
8
48
9
48
10
11
12
13
14
15
72
72
72
72
140
168
aBased on isolation by preparative TLC.
bThe enantioselectivities were determined by chiral HPLC analysis.
4‐NO2‐chalcone was more successful, as the ee value was in
this case 86% (Table 2, entry 13). The same can be said about
the reaction of 4‐MeO‐chalcone in the presence of catalyst
7a, as the ee was as high as 99%, although the yield was
low (33%) (Table 2, entry 15). The 3‐MeO substituted model
led again to a lower ee value of 57% using catalyst 8a in this
case. It can be concluded that beside the steric factors, the
electronic properties also have an impact on the outcome of
the additions. However, in this series it is not possible to
establish a general rule. The only thing that can be said is that
the application of the dimethyl and the dibutyl substituted
macrocycles with hydroxypropyl side arm (6a and 7a) is
advantageous.
The cyclopropane moiety is an important building block
in a large number of biologically active compounds;
therefore, the development of novel strategies to make these
important compounds available is a challenge. The Michael
Initiated Ring Closure (MIRC) reaction represents an elegant
approach, which has been applied extensively for the
construction of cyclopropane derivatives. The MIRC reaction
strategy may also be utilized through a one‐pot multicompo-
nent reaction, which has been gaining interest by synthetic
organic chemists in recent times.62-71
Surprisingly, the use of chiral phase transfer catalysts to
established asymmetric cyclopropanation reactions has so
far been limited to only a few examples.72-74 Previously
Waser and Herchl investigated the asymmetric reaction of
bromomalonates with trans‐chalcones in the presence of
cinchona alkaloid ammonium salt catalysts to furnish
cyclopropane derivatives.75
We performed the reaction of bromomalonate 17 with
chalcone 9a under solid–liquid phase transfer catalytic
conditions discussed above (Table 3).
The cyclopropane diester (18) was obtained in modest
yields (28–33%) from the reaction under discussion, but high
ee values were detected. Lariat ethers 6a and 7a generated ee
values of 98/99%, while macrocycle 8a allowed an ee of
86%. The reason for the low yields may be the base‐catalyzed
dimerization side reaction of diethyl bromomalonate (17).
In the next stage, the model reaction of
benzylidenemalononitriles
(19a–f)
with
diethyl
bromomalonate was investigated under solid–liquid phase
transfer catalytic conditions discussed above in the presence
of lariat ethers incorporating L‐threitol (Table 4).
The corresponding chiral cyclopropane derivatives
20a–f, with one exception, were formed in acceptable to

12
RAPI ET AL.
TABLE 3 Phase transfer catalysis‐promoted MIRC‐reaction of diethyl bromomalonate (17) with chalcone (9a)
a
Entry
Catalyst
Time (day)
Yield (%)
[α]b
ee (%) c
1
2
3
6a
7a
8a
8
8
18: 31
18: 28
18: 33
27.8
28.0
20.4
98
99
86
10
aBased on isolation by preparative TLC.
bIn CHCl3, c 1.
cThe enantioselectivities were determined by chiral HPLC analysis.
TABLE 4 Scope of the phase transfer catalyzed MIRC‐reaction of bromomalonate (17) with benzylidenemalononitrile derivatives (19a–f)
a
Entry
Catalyst
R
Time (h)
Yield (%)
ee (%)b
1
6a
6b
7a
7b
8a
6a
6a
6a
8a
8a
8a
6a
8a
6a
8a
H
H
H
H
H
20
20
24
24
72
24
24
24
24
24
24
24
24
20
20
20a: 74
20a: 69
20a: 81
20a: 32
20a: 58
20b: 84
20c: 74
20d: 76
20b: 72
20c: 74
20d: 86
20e: 67
20e: 60
20f: 72
20f: 80
51
45
85
38
42
15
99
99
23
34
86
74
72
20
59
2
3
4
5
6
2‐Me
3‐Me
4‐Me
2‐Me
3‐Me
4‐Me
4‐NO2
4‐NO2
4‐Cl
7
8
9
10
11
12
13
14
15
4‐Cl
aBased on isolation by preparative TLC.
bThe enantioselectivities were determined by chiral HPLC analysis.
good (58–86%) yields. Five macrocycles synthesized by us
were tested as catalysts in the reaction of unsubstituted
benzylidenemalononitrile (Table 4, entries 1–5). The highest
ee value (85%) was generated by the dibutyl lariat ether 7a
bearing hydroxypropyl side arm to afford the product 20a
in a yield of 81% (Table 4, entry 3). The lowest ee value
(38%) was produced by its methoxypropyl substituted
version 7b (Table 4, entry 4).
It was again a general experience that the catalysts with
hydroxyl end‐groups (6a and 7a) induced a higher
enantioselectivity than the species with methoxy end‐groups
(6b and 7b). From the next experiments it can be seen that
the enantioselectivity is strongly dependent on the substituent
of the benzylidenemalononitrile (Table 4, entries 6–15).
Performing the reaction of the 2‐, 3‐, and 4‐Me substituted
malononitriles in the presence of catalyst 6a, the

RAPI ET AL.
13
TABLE 5 The MIRC reaction of diethyl bromomalonate (17) with 2‐benzylidene‐1,3‐diphenylpropane‐1,3‐dione (21)
a
Entry
Catalyst
Time (h)
Yield (%)
[α]b
ee (%) c
1
2
7a
8a
240
240
51
38
61.7
64.9
50
57
aBased on isolation by preparative TLC.
bIn CHCl3, c 1.
cThe enantioselectivities were determined by chiral HPLC analysis.
corresponding cyclopropane derivatives (20b–d) were
formed in ee values of 15%, 99%, and 99%, respectively
(Table 4, entries 6–8).
phase transfer conditions at ambient temperature. We could
not find a relationship between the structure of the
unsaturated substrates/catalysts and the enantioselectivity.
Different lariat ethers were found optimal in the different
model reactions. In the addition of 2‐nitropropane to
chalcone, catalyst 6a generated the best enantioselectivity;
at the same time, in the reaction of diethyl
acetamidomalonate with nitrostyrene, dibenzyl substituted
8a proved to be the most efficient. Three new model
reactions were studied, in which the L‐threitol‐based catalysts
developed by us induced good enantioselectivities. In the
reaction of diethyl acetoxymalonate with trans‐chalcones,
the stereochemical outcome was strongly dependent on the
substituents of the chalcone. The highest ee values were
obtained with the unsubstituted, 4‐chloro and 4‐methoxy
chalcones. In these cases, catalysts 7a and 8a generated
excellent ee values (98% and 99% ee).
The new catalysts were also tried out in cyclopropanation
reactions using diethyl bromomalonate as the nucleophile.
Excellent enantioselectivities were obtained in the reaction
with chalcone, but the yields were low. In the reaction with
benzylidenemalononitriles, it was found that the substituents
in the aromatic ring had a strong impact on the outcome of
the reaction. The highest ee values were observed in the
reaction of the 3‐Me and 4‐Me substituted malononitriles.
The MIRC reaction of 2‐benzylidene‐1,3‐diphenylpropane‐
1,3‐dione with diethyl bromomalonate afforded the
corresponding cyclopropane derivatives in moderate
optical purity. This novel reaction is to be explored further,
and the evaluation of the absolute configuration is also a
challenge.
Using dibenzyl lariat ether 8a in the same reaction,
products 20b–d were formed with enantioselectivity of
23%, 34%, and 86%, respectively (Table 4, entries 9–11).
It seems that the farther the methyl group is located from
the reaction center, the higher the optical purity of the
products is. The highest enantioselectivities (99% and 86%
ee) were detected with the 4‐Me substituted acceptors. Then
the 4‐NO2 and the 4‐Cl substrates (19e and 19f, respectively)
were reacted in the presence of dimethyl and dibenzyl
macrocycles 6a and 8a. The 4‐NO2 cyclopropane derivative
20e was obtained in ee values of 74% and 72% (Table 4,
entries 12 and 13), while the 4‐chloro product 20f was
formed in lower ee values of 20% and 59% (Table 4, entries
14 and 15). In most cases, the relatively high yields of
60–86% suggested that following the 20–72‐h reaction times
the base‐catalyzed dimerization of bromomalonate was not
significant.
As a new model reaction, the cyclopropanation of
2‐benzylidene‐1,3‐diphenylpropane‐1,3‐dione (21) with
diethyl bromomalonate (17) was also investigated (Table 5).
Conditions of the solid–liquid phase transfer catalytic
reaction were the same, as described above. Application of
the dibutyl substituted 7a and the dibenzyl substituted 8a
macrocycles led to rather similar ee values of 50% and
57%, respectively (Table 5, entries 1 and 2). This new model
reaction is to be studied further.
4 | CONCLUSION
ACKNOWLEDGEMENTS
In summary, six members of a new chiral crown ether family
with substituents of different lipophilicity were synthesized
from diethyl L‐tartrate. These macrocycles proved to be
efficient enantioselective catalysts in a few Michael additions
and cyclopropanation reactions carried out under solid–liquid
Financial support by the Hungarian Scientific Research
Found (OTKA No. PD 112166) is gratefully acknowledged.
This work was financially supported by the New Széchenyi
Development Plan (TÁMOP‐4.2.1/B‐09/1/KMR‐2010‐0002).

14
RAPI ET AL.
α‐D‐glucose‐ and α‐D‐mannose‐based crown ethers. Tetrahedron:
Asymmetry. 2010;21:919‐925.
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How to cite this article: Rapi Z, Nemcsok T,
Pálvölgyi Á, Keglevich G, Grün A, Bakó P. Synthesis
of L‐threitol‐based crown ethers and their application
as enantioselective phase transfer catalyst in Michael
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