Synthesis of an Enantiomerically Pure Inherently Chiral Calix[4]Arene Phosphonic Acid and Its Evaluation as an Organocatalyst

Article abstract of DOI:10.1021/acs.joc.7b02312

A facile method for the preparation of enantiomerically pure inherently chiral calix[4]arene phosphonic acid (cR,pR)-7 in four steps starting from the readily available and previously synthesized (cS)-enantiomer of calix[4]arene acetic acid 1 or its methyl ester 2 was developed. The first tests of this unique calixarene Br?nsted acid with inherent chirality in organocatalysis of the aza-Diels-Alder reaction of imines with Danishefsky's diene and epoxide ring opening by benzoic acid were performed. The calixarene phosphonic acid (cR,pR)-7 shows good catalytic activities but with low enantioselectivities in these reactions.

Full text of DOI:10.1021/acs.joc.7b02312

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Article
Synthesis of an enantiomerically pure inherently chiral
calix[4]arene phosphonic acid and its evaluation as organocatalyst.
Andrii Karpus, Oleksandr Yesypenko, Vyacheslav Boiko, Jean-
Claude Daran, Zoia Voitenko, Vitaly Kalchenko, and Eric Manoury
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02312 • Publication Date (Web): 11 Jan 2018
Downloaded from http://pubs.acs.org on January 11, 2018
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Synthesis of an enantiomerically pure inherently chiral calix[4]arene
phosphonic acid and its evaluation as organocatalyst.
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Andrii Karpus, a,b,c* Oleksandr Yesypenko,d Vyacheslav Boiko,d JeanꢀClaude Daran,a,b Zoia
Voitenko,c* Vitaly Kalchenko,d* Eric Manourya,b*
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b
a Université Toulouse III ꢀ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9.
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse
c
cedex 4. Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska st., 01033,
d
Kyiv, Ukraine. Institute of Organic Chemistry NAS of Ukraine, Murmanska st. 5, 02660,
Kyiv, Ukraine.
Abstract: A facile method for the preparation of enantiomerically pure inherently
chiral calix[4]arene phosphonic acid (cR,pR)ꢀ7 in four steps starting from the readily available
and previously synthesized (cS)ꢀenantiomer of calix[4]arene acetic acid 1 or its methyl ester 2
was developed. The first tests of this unique calixarene Brönsted acid with inherent chirality
in organocatalysis of the azaꢀDiels–Alder reaction of imines with Danishefsky's diene and
epoxide ring opening by benzoic acid were performed. The calixarene phosphonic acid
(cR,pR)ꢀ7 shows good catalytic activities but with low enantioselectivities in these reactions.
For Table of Contents Only:
INTRODUCTION
Calixarenes are fascinating cupꢀshaped macrocyclic molecules synthesized by
selective oneꢀpot cyclocondensation of paraꢀsubstituted phenols with formaldehyde and are
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ready for easy chemical modification at both the upper and lower rims.1 This synthetic
versatility and their ability to form hostꢀguest supramolecular complexes has raised great
interest in recent years for calixarene derivatives which have been used in numerous
applications, such as in biomedicine,2 nanoscience3 or as sensors.4 Efficient catalytic systems
based on calixarenes have also been developed.5,6 In particular, many chiral calixarene
derivatives containing chiral residues at the upper or lower rims have been synthesized
allowing the development of new chiral receptors for asymmetric recognition7 which proved
to be powerful tools to mimic and to obtain stereochemical insights on biochemical systems8
as well as efficient systems for asymmetric catalysis.9 Challenging trends in design of chiral
receptors is by using of ‘‘inherently’’chiral calixarene derivatives possessing asymmetrical
disposition of achiral substituents at the threeꢀ dimensional macrocyclic platform.10 During
the past three decades, a diversity of inherently chiral calixarenes were synthesized, but only
few of them could be obtained as pure enantiomers6,11 and even less have been used in
asymmetric catalysis. 6a,12,13
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We recently developed a novel and efficient gram scale method for the synthesis of
enantiomerically pure inherently chiral calix[4]arene carboxylic acids.11a In this article, we
will present an efficient method for preparation of the inherently chiral calix[4]arene
phosphonic acid in high yields and the first tests of this unique calixarene Brönsted acid in
organocatalysis. Indeed, chiral organophosphorus Brönsted acids (see Figure 1) are currently
used as organocatalysts showing in some cases very good catalytic activities and
enantioselectivities (ee up to 99%).14 However, calixarene based organophosphorus Brönsted
acids with inherent chirality has not yet been explored in organocatalysis to the best of our
knowledge.
Figure 1: Phosphorus organocatalysts and ligands bearing chiral diol units.
RESULTS AND DISCUSSION
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The target enantiopure inherently chiral calixarene phosphonic acid (cR,pR)ꢀ7 was
obtained in four steps (Scheme 1) from the early synthesized (cS)ꢀenantiomer of calix[4]arene
acetic acid (cS)ꢀ1 or its methyl ester (cS)ꢀ2.11a The first step is the reduction of compounds 1,
2 into 2ꢀhydroxyethoxycalixarene (cS)ꢀ3 by LiAlH4. Since, there are two phenolic OH groups
in the compounds, a 5ꢀfold excess of lithium aluminum hydride was used for acid (cS)ꢀ1.
After 1 hour reaction, alcohol (cS)ꢀ3 was isolated with practically quantitative yields. In the
same conditions, ester (cS)ꢀ2 was also easily reduced, but a 4 eq. excess of lithium aluminum
hydride was used. 13C NMR resonance peaks of bridged methylene groups (ArCꢀCH2ꢀCAr) are
in the 33.9 – 34.2 ppm range which are characteristic values for calix[4]arenes in the cone
conformation.15 The cone conformation of (cS)ꢀ3 was confirmed by the Xꢀray diffraction
method (Figure 2). In the crystal packing of (cS)ꢀ3, there are two independent molecules and
three CH3CN solvent molecules by asymmetric unit. Each calix[4]arene molecule contains
CH3CN molecule incorporated inside its cavity whereas the third CH3CN is located along a
twoꢀfold axis. Because of the absence of heavy atoms in the structure of (cS)ꢀ3, the
determination of the absolute configuration was not possible unambiguously (Flack’parameter
= 0.2(3), see Table S1 in the Supporting Information file). OꢀH...O or CꢀH...O hydrogen
bonds are described in Table S2.
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Figure 2: ORTEP view of compound (cS)ꢀ3. Only one of the two independent calixarene
molecules complexed with CH3CN “guest” is represented. Ellipsoids are drawn at the 30%
probability level. The solvent CH3CN molecules and H atoms have been omitted for clarity.
The next step is the substitution of the OH group in 2ꢀhydroxyethyl moiety of (cS)ꢀ3
by chlorine or bromine atom. All attempts to synthesise the chloro derivative (cS)ꢀ4 by
reaction of alcohol (cS)ꢀ3 with thionyl chloride failed. After boiling of (cS)ꢀ3 with thionyl
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chloride in chloroform, no reaction was observed. Boiling in pure thionyl chloride yields a
complex mixture of degradation products. However, the Appel reaction of alcohol (cS)ꢀ3 in
the carbon tetrachloride/THF mixture (1:4 v/v) in presence of triphenylphosphine was
successful.16 After refluxing the mixture for 4ꢀ6 hours and purification of the crude products
by flash column chromatography, the chloride (cS)ꢀ4 was obtained with 88% yield as a white
solid. Similarly, bromide (cS)ꢀ5 was prepared using carbon tetrabromide with slightly better
yields (see Scheme 1). The substitution of the OH group of (cS)ꢀ3 could easily followed by
13C NMR on the terminal carbon bearing OH group in (cS)ꢀ3 (62.2 ppm) or chlorine atom in
(cS)ꢀ4 (72.2 ppm) or bromine atom in (cS)ꢀ5 (77.2 ppm). Again, 13C NMR resonance peaks of
bridged methylene groups (ArCꢀCH2ꢀCAr) in the 33.8 – 34.3 ppm range for both (cS)ꢀ4 and
(cS)ꢀ5 shows the cone conformation is preserves during the substitution.15
We used Michaelis–Arbuzov reaction17 to introduce a phosphoryl group. The reaction
of chloride (cS)ꢀ4 overnight in refluxing triisopropyl phosphite gives surprisingly not the
expected Michaelis–Arbuzov product, namely calixarene diisopropylphosphonate A, but the
calixarene spiroꢀphosphonate (cR,pR)ꢀ6 in 80% yield, as a single diastereoisomer with full
control of the phosphorus atom geometry. We can suppose that, in the hard condition (180
°C), calixarene diisopropylphosphonate A, formed in a first step by the classical Michaelisꢀ
Arbuzov reaction, immediately undergoes intramolecular transesterification with two
neighboring OH groups at the lower rim.18 The Michaelis–Arbuzov reaction of bromide (cS)ꢀ
5 in the same condition gave only a complex mixture of not identified products. Peaks of
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vinyl protons can be found in H NMR spectra of the crude mixture at 5.2 – 6.2 ppm
indicating the presence of HBr elimination product. Probably, the hard conditions cause
elimination of HBr from 2ꢀbromoethoxy moiety followed by different the acidꢀinduced side
reactions. Lowering temperature to less than 150 °C gave no reaction.
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Scheme 1: Synthesis of enantiomerically pure calix[4]arene phosphonic acid (cR,pR)ꢀ7 from
chiral (cS)ꢀcalix[4]arene carboxylic acid (cS)ꢀ1 or its ester (cS)ꢀ2.
The transformation of chloride (cS)ꢀ4 to spirophosphonate (cR,pR)ꢀ6) dramatically
changes chemical shifts of the terminal carbon atoms respectively from 77.2 ppm (CH2Cl) to
36.6 ppm (CH2P) in the 13C NMR spectra. . Two carbon atoms ArCꢀOꢀP in (cR,pR)ꢀ6 showed
2
coupling constants JCꢀP 10.4 Hz and 10.7 Hz suggesting the cyclic structure of (cR,pR)ꢀ6.
Again, 13C resonance peaks of bridged methylene groups (ArCꢀCH2ꢀCAr) could be found in the
33.4 – 34.4 ppm range showing a cone conformation15 for (cR,pR)ꢀ6. Indeed, the molecular
structure of (cR,pR)ꢀ6 was fully established by Xꢀray diffraction method (see Figure 3).
Calixarene (cR,pR)ꢀ6 absolute configuration (inherent chirality and central chirality on
phosphorus) could be determined thanks to the presence of the heavy phosphorus atom in the
molecule (Flack’parameter = 0.01, see Table S1 in the Supporting Information file). Two
independent molecules appears to be linked though weak CꢀH...O interactions (C(29)ꢀO(15)
and C(26)AꢀO(15) (see Table S2).
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Figure 3: ORTEP view of compound (cR,pR)ꢀ6. Only one of two independent molecules is
represented. Ellipsoids are drawn at the 30% probability level. H atoms have been omitted for
clarity.
Finally, stereoselective hydrolysis of one PꢀOꢀCAr bond of the spirophosphonate
(cR,pR)ꢀ6 in a waterꢀmethanol solution of sodium hydroxide gives enantiomerically pure
phosphonic acid (cR,pR)ꢀ7 with ABCH type of substitution on the lower rim. Similar protocol
were previously applied by Gloede and coworkers to hydrolyze selectively only one bond of
three PꢀOꢀCAr bonds in Pꢀbridged calixarene derivative.19 Nevertheless, such stereoselective
hydrolysis is an unprecedented example to the best of our knowledge. The 1H NMR spectrum
of calixarene (cR,pR)ꢀ7 shows a set of four AB systems for the methylene bridges at 4.75,
4.43, 4.24 and 4.04 ppm for the axial protons, and at 3.49, 3.29, 3.25 ppm for the equatorial
2
13
protons with JHꢀH 12.8 Hz, 13.6 Hz, 13.8 Hz and 14.2 Hz. The C NMR spectrum shows
resonance peaks of bridged methylene groups (ArCꢀCH2ꢀCAr) in the 33.4– 34.4 ppm range.
The 1H and 13C NMR data indicate clearly that (cR,pR)ꢀ7 exists in the cone conformation with
inherent chirality. The cone conformation and absolute configuration of (cR,pR)ꢀ7 could be
fully determined by Xꢀray diffraction method (see Figure 4): the (Flack’parameter = ꢀ0.02,
see Table S1 in the Supporting Information file). In the crystal, two independent (cR,pR)ꢀ7
molecules are linked through PꢀOꢀH…O=P strong hydrogen bonds (see Figure 4 and Table
2
S2). These hydrogen bonds build up a R2 (8) graph set motif.20,21
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Figure 4: ORTEP view of compound (cR,pR)ꢀ7. The two independent molecules linked by Pꢀ
OꢀH...O=P hydrogen bonds are represented. Ellipsoids are drawn at the 30% probability level.
The application of inherently chiral calixarenes as chiral catalysts is a worthy
challenge in organic synthesis. However, as already pointed out in the introduction, the
reported examples of asymmetric organocatalysis with inherently chiral calixarenes are still
quite scarce, essentially in aldol and Michael reactions.7b,7e,9e,13aꢀd AzaꢀDiels–Alder reaction is
an effective tool to synthesize various tetrahydropyridine derivatives. Nitrogen atom may be
part of a diene or dienophile. There are a number of successful synthetic developments both in
achiral22 and stereoselective variants of the reaction:23 tetrahydropyridine derivatives could be
obtained with good yields and ee in the 3 – 91% range.
Organocatalytic properties of the chiral calixarene phosphonic acid (cR,pR)ꢀ7 were
examined first in the azaꢀDiels–Alder reaction of imines possessing electronꢀwithdrawing or
electron
donor
substituents,
with
Eꢀ1ꢀmethoxyꢀ3ꢀtrimethylsilyloxyꢀ1,3ꢀbutadiene
(Danishefsky's diene) (Table 1).
Calixarene (cR,pR)ꢀ7 effectively catalyses the reaction (up to 95% yield, Table 1).
However, enantioselectivity of the reaction was still moderate (up to 21% ee, see entry 6,
Table 1). The yields of the reaction in acetonitrile are slightly higher than in toluene. The
effects of the substituents of the imine substrates are small as usually observed24 and more
mechanistic insights25 would be necessary to understand their rather subtle effects.
Table 1. Asymmetric azaꢀDiels–Alder reactions catalyzed by (cR,pR)ꢀ7.
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R3
R4
N
R1 = H, Cl, NO2, OCH3
R2 = H, OH
acid (cR)ꢀ7,
5 mol %
OCH3
N
R4
+
R3 = H, OH, iꢀPr
R4 = H, iꢀPr
R3
solvent, rt
H
O
OTMS
R1
R2
R1
R2
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Isolated yield,
№
Solvent
R1
R2
R3
R4
ее, %
%
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85
95
72
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74
56
69
76
1.
2.
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
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3.
NO2
H
H
0
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OCH3
H
H
H
5
5.
OH
H
H
9
6.
H
H
21
3
7.
Cl
H
H
8.
NO2
OCH3
H
H
H
4
9.
H
H
3
10.
11.
OH
H
H
11
10
H
OH
Conditions: imine/diene = 1/2, 5 mol. % of the catalyst, 25°C, 200 h.
Asymmetric epoxide ring opening is another important synthetic transformation26 and
is also applied industrially. The first asymmetric version of the epoxide ring opening with
benzoic acid catalyzed by chiral binolꢀderived phosphoric acids was described by the List
group (yields of the opened products were 55 – 86% and ee up to 93%).27 Calixarene
phosphonic acid (cR,pR)ꢀ7 was examined as chiral organocatalyst for the asymmetric ring
opening of several cyclic meso epoxides (Table 2). Cyclohexene and cyclopentene oxides
were opened by benzoic acid with good yields but low enantiomeric excesses (71% yield,
18% ee; and 75% yield, 11% ee respectively). Cyclooctene oxide was found to be poorly
reactive with conversions of less than 10%.
Table 2. Asymmetric ring opening of epoxides catalyzed by (cR,pR)ꢀ7.
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PhCOOH (3 eq.)
cat. 10 mol. %
HO
OBz
n
O
5
6
7
toluene, rt, 24 h
n= 0, 1 or 3
n
8
9
№
1.
2.
3.
Substrate
Isolated yield, %
ее, %
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cyclopentene oxide (n= 0)
cyclohexene oxide (n=1)
cyclooctene oxide (n= 3)
75
71
8
18
ꢀ
Conditions: benzoic acid/epoxide = 1.5/1, 10 mol. % of catalyst, 25°C, 24 h.
CONCLUSIONS
In the present study an efficient and straightforward method for preparation of
enantiomerically pure inherently chiral calix[4]arene phosphonic acid (cR,pR)ꢀ7 in four steps
starting from the readily available calix[4]arene acetic acid (cS)ꢀ1 or its methyl ester (cS)ꢀ2
was developed. The first tests of this unique calix[4]arene Brönsted acid with inherent
chirality as organocatalyst in the asymmetric AzaꢀDiels–Alder reaction of imines with
Danishefsky's diene and in the asymmetric ring opening of epoxides by benzoic acid were
performed. The calixarene phosphonic acid (cR,pR)ꢀ7 demonstrates good catalytic activities
but with low enantioselectivities in these reactions. The evaluation of catalytical efficiency of
the calixarene phosphonic acid (cR,pR)ꢀ7 for other asymmetrical reactions as well as the
design of more efficient inherently chiral calixarene catalysts are in progress.
EXPERIMENTAL SECTION
General experimental
All reactions were carried out under an argon atmosphere using standard Schlenk
techniques. Melting points were determined on the Boetius apparatus and were uncorrected.
Solvents were carefully dried by conventional methods and distilled under argon before use.
Column chromatography was performed on Carlo Erba silica gel 60, 0.035ꢀ0.070 mm. (cS)ꢀ
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀcarboxylmethoxyꢀ28ꢀpropoxycalix[4]arene
(cS)ꢀ1 and (cS)ꢀ5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀmethoxycarbonylmethoxyꢀ28ꢀ
propoxycalix[4]arene (cS)ꢀ2 were prepared according to literature procedures.11a All
commercially available chemicals (LiAlH4, powder, 97%, Alfa Aesar; PPh3, 99%, Sigma
Aldrich; (iPrO)3P, 90+%, Alfa Aesar) were used as received. H, C{1H} and P{1H} NMR
1
13
31
spectra of compounds were recorded with a Bruker Avance 400 FTꢀNMR spectrometer. The
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resonances were calibrated relative to the residual solvent peaks and are reported with positive
values downfield from TMS. For all characterized compounds, the peak assignments in the 1H
and 13C NMR spectra were based on COSY, HSQC and HMBC 2D experiments. HRMS were
obtained from dichloromethane solutions with a Xevo G2 Q TOF spectrometer by the
electrospray ionization method.
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(
cS)ꢀ5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀhydroxyethoxyꢀ28ꢀ
propoxycalix[4]arene (cS)ꢀ3.
To lithium aluminum hydride (0.40 g, 10.5 mmol) in a schlenk tube under argon
atmosphere absolute diethyl ether (50 mL) was added. The slurry was stirred at room
temperature for 0.5 h, cooled to 0 ˚C and small portions (1.72 g, 2.3 mmol) of ((cS)ꢀ
5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀcarboxylmethoxyꢀ28ꢀpropoxycalix[4]arene)
(cS)ꢀ1 or corresponding ester ((cS)ꢀ5,11,17,23ꢀtetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀ
methoxycarbonylmethoxyꢀ28ꢀpropoxycalix[4]arene) (cS)ꢀ2 were added. The resulting mixture
was stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC),
5 mL of ethyl acetate was added dropwise and the mixture was stirred for 15ꢀ20 min. Then,
methanol (10 mL), water (25 mL) and H2SO4 (25 mL of 10% water solution) was added in
corresponding order. Ether solution was separated, washed twice with 25 mL of distilled
water and 25 mL of brine, dried over Na2SO4 and evaporated to give the product as a white
1
crystalline solid (1.66 g, 98% yield and 95% purity according to H NMR) which was used
without further purification. If needed, product can be crystallized from acetonitrile.
1H NMR (δ (ppm), 400MHz, CDCl3): 1.16 (t, 3Н, OСН2СН2СН3, JHꢀH = 7.4 Hz),
3
1.17 (s, 9Н, tꢀBu), 1.20 (s, 9Н, tꢀBu), 1.23 (s, 9Н, tꢀBu), 1.31 (s, 9Н, tꢀBu), 2.08ꢀ2.25 (m, 2Н,
2
2
OСН2СН2СН3), 3.37 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 12.8 Hz), 3.43 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH
11.7 Hz), 3.44 (d, 1Н, ArꢀСН2ꢀeq, 2JHꢀH = 14.0 Hz), 3.45 (d, 1Н, ArꢀСН2ꢀeq, 2JHꢀH = 13.8 Hz),
=
3.86ꢀ3.94 (m, 1Н, OСН2СН2СН3), 3.95ꢀ4.01 (m, 1Н, OСН2СН2OH), 4.02ꢀ4.08 (m, 1Н,
2
OСН2СН2СН3), 4.19 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 13.8 Hz), 4.18ꢀ4.30 (m, 1Н, OСН2СН2OH,
2
2
2Н, OСН2СН2OH), 4.30 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 13.7 Hz), 4.50 (d, 1Н, ArꢀСН2ꢀax, JHꢀH
2
= 12.4 Hz), 4.60 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 12.8 Hz), 5.23ꢀ5.21 (s, br, 1Н, OСН2СН2OH)
6.94 (d, 1Н, ArꢀH, 4JHꢀH = 2.4 Hz), 6.96 (d, 1Н, ArꢀH, 4JHꢀH = 2.4 Hz), 7.08 (d, 1Н, ArꢀH, 4JHꢀ
4
= 2.4 Hz), 7.09ꢀ7.11 (m, 2Н, ArꢀH), 7.12 (d, 1Н, ArꢀH, JHꢀH = 2.4 Hz), 7.13ꢀ7.15 (m, 2Н,
H
ArꢀH), 9.24 (s, 1Н, ОН), 9.66 (s, 1Н, ОН); 13C{1H} NMR (δ (ppm), 125MHz, CDCl3): 10.38
(CH2CH3), 23.15 (CH2CH3), 30.62 (CМe3), 31.22 (C(CH3)3), 31.36 (C(CH3)3), 31.61
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(C(CH3)3), 31.46 (C(CH3)3), 32.73 (CМe3), 32.95 (CМe3), 33.18 (CМe3), 33.90 (ArꢀCH2ꢀAr),
34.97 (ArꢀCH2ꢀAr), 34.12 (ArꢀCH2ꢀAr), 34.13 (ArꢀCH2ꢀAr), 62.24 (HOCH2CH2O), 77.22
(OCH2CH2OH), 78.67 (OCH2CH2), 124.97 (CHAr), 125.46 (CHAr), 125.46 (CHAr), 125.60
(CHAr), 125.80 (CHAr), 126.08 (CHAr), 126.46 (CHAr), 126.59 (CHAr), 126.94 (CArꢀCH2ꢀCAr),
126.95 (CArꢀCH2ꢀCAr), 127.97 (CArꢀCH2ꢀCAr), 128.08 (CArꢀCH2ꢀCAr), 130.11 (CArꢀCH2ꢀCAr),
131.70 (CArꢀCH2ꢀCAr), 133.87 (CArꢀCH2ꢀCAr), 134.04 (CArꢀCH2ꢀCAr), 142.70 (CArꢀtꢀBu),
142.95 (CArꢀtꢀBu), 146.61 (CArꢀtꢀBu), 147.16 (CArꢀtꢀBu), 148.28 (CArꢀOH), 148.94 (CArꢀOH),
150.15 (CArꢀOCH2), 151.21 (CArꢀOCH2); HRМS (ESIꢀTOF) m/z: [M+H]+ Calcd. for
C49H67O5 735.4989; Found 735.4998; mp 85ꢀ89°C; [α]D20 +32.7 (c=1.47, CHCl3).
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(cS)ꢀ5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀchloroethoxyꢀ28ꢀ
propoxycalix[4]arene (cS)ꢀ4.
Alcohol (cS)ꢀ3 (0.59 g, 0.8 mmol) and triphenylphosphine (0.66 g, 2.5 mmol) were
dissolved in a mixture of carbon tetrachloride (4 mL) and THF (15 mL) and refluxed for 5 h.
After completion of the reaction (monitored by TLC), mixture was diluted with THF and
filtered through celite, solvent was removed in vacuo and crude materials was purified by
flashꢀchromatography on silica, using a EtOAc/hexane mixture ( 1/3, v/v) as eluent to yield
product (0.51 g, yield 84%) as a white crystalline solid.
1H NMR (δ (ppm), 400MHz, CDCl3): 0.99 (s, 9Н, tꢀBu), 1.06 (t, 3Н, OСН2СН2СН3,
3JHꢀH = 7.4 Hz), 1.17 (s, 9Н, tꢀBu), 1.21 (s, 18Н, tꢀBu), 1.98ꢀ2.22 (m, 2Н, OСН2СН2СН3),
2
2
3.32 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 12.8 Hz), 3.35 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 14.0 Hz), 3.41 (d,
1Н, ArꢀСН2ꢀeq, 2JHꢀH = 14.4 Hz), 3.46 (d, 1Н, ArꢀСН2ꢀeq, 2JHꢀH = 14.2 Hz), 3.52ꢀ3.63 (m, 1Н,
OСН2СН2Cl), 3.68ꢀ3.80 (m, 1Н, OСН2СН2СН3), 3.80ꢀ3.90 (m, 1Н, OСН2СН2СН3), 4.07ꢀ
4.17 (m, 5Н, 1Н OСН2СН2Cl, 2Н OСН2СН2Cl, 2Н ArꢀСН2ꢀax), 4.40 (d, 1Н, ArꢀСН2ꢀax, 2JHꢀ
H = 13.2 Hz), 4.50 (d, 1Н, ArꢀСН2ꢀax, 2JHꢀH = 12.6 Hz), 6.86 (s, 2Н, ArꢀH), 6.94 (d, 1Н, Arꢀ
H, 4JHꢀH = 2.4 Hz), 6.99 (d, 2Н, ArꢀH, 4JHꢀH = 2.0 Hz), 7.03 (m, 2Н, ArꢀH), 7.09 (d, 1Н, ArꢀH,
4JHꢀH = 2.4 Hz), 8.31 (s, 1Н, ОН), 8.94 (s, 1Н, ОН); 13C{1H} NMR (δ (ppm), 125MHz,
CDCl3): 10.49 (OСН2CH2CH3), 23.32 (OСН2CH2CH3), 30.84 (CМe3), 31.30 (C(CH3)3),
31.44 (C(CH3)3), 31.70 (C(CH3)3), 31.62 (C(CH3)3), 32.65 (CМe3), 32.72 (CМe3), 33.77
(CМe3), 33.97 (ArꢀCH2ꢀAr), 34.04 (ArꢀCH2ꢀAr), 34.07 (ArꢀCH2ꢀAr), 34.27 (ArꢀCH2ꢀAr),
72.18 (ClCH2CH2O), 74.70 (OCH2CH2Cl), 78.14 (OCH2CH2CH3), 124.83 (CHAr), 125.08
(CHAr), 125.19 (CHAr), 125.27 (CHAr), 125.47 (CHAr), 125.67 (CHAr), 126.63 (CHAr), 126.75
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(CHAr), 127.88 (CArꢀCH2ꢀCAr), 127.33 (CArꢀCH2ꢀCAr), 128.56 (CArꢀCH2ꢀCAr), 129.57 (CArꢀ
CH2ꢀCAr), 132.18 (CArꢀCH2ꢀCAr), 133.01 (CArꢀCH2ꢀCAr), 133.03 (CArꢀCH2ꢀCAr), 134.61 (CArꢀ
CH2ꢀCAr), 141.96 (CArꢀtꢀBu), 142.91 (CArꢀtꢀBu), 145.90 (CArꢀtꢀBu), 147.09 (CArꢀtꢀBu), 148.13
(CArꢀOH), 149.69 (CArꢀOH), 150.92 (CArꢀOCH2), 151.27 (CArꢀOCH2); HRМS (ESIꢀTOF) m/z:
[M+H]+ Calcd. for C49H66ClO4 753.4649; Found 753.4661; mp 88ꢀ89°C; [α]D +52.3
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(c=1.35, CHCl3).
(cS)ꢀ5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,26ꢀdihydroxyꢀ27ꢀbromoethoxyꢀ28ꢀ
propoxycalix[4]arene (cS)ꢀ5.
Alcohol (cS)ꢀ3 (0.59 g, 0.8 mmol,) CBr4 (0.40 g, 1.2 mmol) and triphenylphosphine
(0.66 g, 2.5 mmol) were dissolved in THF (20 mL) and refluxed for 5 h. After completion of
the reaction (monitored by TLC), mixture was diluted with THF and filtered through celite,
solvent was removed in vacuo and crude materials was purified by flashꢀchromatography on
silica, using EtOAc/hexane mixture (1/3, v/v) as eluent to yield product (0.56 g, yield 88%) as
a white crystalline solid.
1H NMR (δ (ppm), 400MHz, CDCl3): 1.09 (s, 9Н, tꢀBu), 1.16 (t, 3Н, OСН2СН2СН3,
3JHꢀH = 7.5 Hz), 1.20 (s, 9Н, tꢀBu), 1.25 (s, 9Н, tꢀBu), 1.25 (s, 9Н, tꢀBu), 2.12 (m, 2Н,
2
2
OСН2СН2СН3), 3.35 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 12.7 Hz), 3.43 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH
13.7 Hz), 3.47 (d, 1Н, ArꢀСН2ꢀeq, 2JHꢀH = 14.0 Hz), 3.51 (d, 1Н, ArꢀСН2ꢀeq, 2JHꢀH = 13.8 Hz),
=
3.59 (m, 2Н, OСН2СН2Br), 3.89 (m, 1Н, OСН2СН2СН3), 4.14 (m, 3Н, 1Н OСН2СН2CH3 +
2ꢀax, 2JHꢀH = 13.9 Hz), 4.41 (d, 1Н, ArꢀСН2ꢀax, 2JHꢀH
2Н OСН2СН2Br), 4.14 (d, 2Н, ArꢀСН =
2
13.2 Hz), 4.50 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 12.7 Hz), 6.91 (s, 2Н, ArꢀH), 6.98 (d, 1Н, ArꢀH,
4JHꢀH = 2.4 Hz), 7.02 (m, 2Н, ArꢀH), 7.05 (d, 1Н, ArꢀH, JHꢀH = 2.4 Hz), 7.06 (d, 1Н, ArꢀH,
4JHꢀH = 2.0 Hz), 7.10 (d, 1Н, ArꢀH, JHꢀH = 2.0 Hz), 8.20 (s, 1Н, ОН), 8.68 (bs, 1Н, ОН);
4
4
13C{1H} NMR (δ (ppm), 125MHz, CDCl3): 10.41 (OСН2CH2CH3), 23.25 (OСН2CH2CH3),
29.15 (CМe3), 30.82 (CМe3), 31.19 (C(CH3)3), 31.30 (C(CH3)3), 31.50 (C(CH3)3), 31.58
(C(CH3)3), 32.48 (CМe3), 32.77 (CМe3), 33.85 (ArꢀCH2ꢀAr), 33.92 (ArꢀCH2ꢀAr), 33.96 (Arꢀ
CH2ꢀAr), 34.14 (ArꢀCH2ꢀAr), 74.67 (OCH2CH2Br), 77.21 (OCH2CH2Br), 78.10
(OCH2CH2CH3), 124.92 (CHAr), 125.17 (CHAr), 125.31 (CHAr), 125.40 (CHAr), 125.58
(CHAr), 125.76 (CHAr), 126.42 (CHAr), 126.86 (CHAr), 127.39 (CArꢀCH2ꢀCAr), 127.46 (CArꢀ
CH2ꢀCAr), 128.68 (CArꢀCH2ꢀCAr), 129.65 (CArꢀCH2ꢀCAr), 132.25 (CArꢀCH2ꢀCAr), 133.16 (CArꢀ
CH2ꢀCAr), 133.17 (CArꢀCH2ꢀCAr), 134.66 (CArꢀCH2ꢀCAr), 142.17 (CArꢀtꢀBu), 143.10 (CArꢀtꢀ
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Bu), 146.11 (CArꢀtꢀBu), 147.27 (CArꢀtꢀBu), 148.29 (CArꢀOH), 149.85 (CArꢀOH), 151.13 (CArꢀ
OCH2), 151.42 (CArꢀOCH2); HRМS (ESIꢀTOF) m/z: [M+H]+ Calcd. for C49H66BrO4
797.4144; Found 797.4152; mp. 95ꢀ96°C; [α]D20 +44.4 (c=1.35, CHCl3).
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(
cR)ꢀ5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25,26ꢀdiphosphonyloxyꢀ27ꢀphosphonylethoxyꢀ28ꢀ
propoxycalix[4]arene (cR,pR)ꢀ6.
Calix[4]arene chloride (cS)ꢀ4 (98.0 mg, 0.13 mmol) was dissolved in 2 mL of
triisopropylphosphite. The solution was then refluxed overnight (Tbath = 185°C). After
completion of the reaction (monitored by TLC), solvent was removed in vacuo and the crude
materials were purified by flashꢀchromatography on silica, using chloroform (CHCl3) as
eluent to yield the product (79.4 mg, yield 80%) as a white crystalline solid.
1H NMR (δ (ppm), 400MHz, CDCl3): 0.58 (s, 9Н, tꢀBu), 1.00 (s, 9Н, tꢀBu), 1.11 (t,
3
3Н, OСН2СН2СН3, JHꢀH = 7.4 Hz), 1.34 (s, 9Н, tꢀBu), 1.36 (s, 9Н, tꢀBu), 1.80ꢀ1.96 (m, 2Н,
2
OСН2СН2СН3), 2.50ꢀ2.71 (m, 1Н, OСН2СН2PO), 3.19 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 13.4 Hz),
2
2
3.24 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 13.4 Hz), 3.36 (d, 1Н, ArꢀСН2ꢀeq, JHꢀH = 14.0 Hz), 3.48 (d,
2
1Н, ArꢀСН2ꢀeq, JHꢀH = 15.0 Hz), 3.68ꢀ3.89 (m, 3Н, 2H OСН2СН2СН3, 1H OСН2СН2PO),
2
4.21 (m, 1Н, OСН2СН2PO), 4.30ꢀ4.40 (m, 1Н, OСН2СН2PO), 4.35 (d, 1Н, ArꢀСН2ꢀax, JHꢀH
2
2
= 13.8 Hz), 4.39 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 13.8 Hz), 4.49 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 13.8
2
4
Hz), 4.70 (d, 1Н, ArꢀСН2ꢀax, JHꢀH = 14.9 Hz), 6.15 (d, 1Н, ArꢀH, JHꢀH = 2.2 Hz), 6.26 (d,
1Н, ArꢀH, 4JHꢀH = 2.0 Hz), 6.75 (d, 1Н, ArꢀH), 6.76 (s, 1Н, ArꢀH), 7.12 (d, 1Н, ArꢀH, 4JHꢀH
=
2.0 Hz), 7.20 (m, 2Н, ArꢀH), 7.22 (s, 1Н, ArꢀH); C{1H} NMR (δ (ppm), 125MHz, CDCl3):
11.13 (OСН2CH2CH3), 23.60 (OСН2CH2CH3), 29.70 (CМe3), 29.70 (CМe3), 30.89
(C(CH3)3), 31.07 (C(CH3)3), 31.55 (C(CH3)3), 31.62 (C(CH3)3), 31.40 (CМe3), 32.09 (CМe3),
33.42 (ArꢀCH2ꢀAr), 33.82 (ArꢀCH2ꢀAr), 34.22 (ArꢀCH2ꢀAr), 34.33 (ArꢀCH2ꢀAr), 36.61
(OPCH2CH2O), 64.32 (OCH2CH2PO), 77.05 (OCH2CH2CH3), 124.03 (CHAr), 124.20 (CHAr),
125.05 (CHAr), 125.11 (CHAr), 125.51 (CHAr), 125.58 (CHAr), 125.96 (CHAr), 126.63 (CHAr),
128.33 (CArꢀCH2ꢀCAr), 130.47 (CArꢀCH2ꢀCAr), 130.88 (CArꢀCH2ꢀCAr), 131.88 (CArꢀCH2ꢀCAr),
132.31 (CArꢀCH2ꢀCAr), 133.50 (CArꢀCH2ꢀCAr), 135.31 (CArꢀCH2ꢀCAr), 136.50 (CArꢀCH2ꢀCAr),
144.94 (CArꢀtꢀBu), 146.57 (CArꢀtꢀBu), 146.81 (CArꢀtꢀBu), 147.15 (CArꢀtꢀBu), 146.28 (d, 2JCꢀP
10.4 Hz, CArꢀOP), 147.15 (d, JCꢀP = 10.7 Hz, CArꢀOP), 152.32 (CArꢀOꢀCH2), 153.21 (CArꢀ
OCH2); P{1H} NMR (δ (ppm), 162MHz, CDCl3): 24.10; HRМS (ESIꢀTOF) m/z: [M+H]+
Calcd. for C49H64O5P 763.4491; Found 763.4496; mp 280ꢀ281°C; [α]D20 +8.9 (c=1.7, CHCl3).
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cR)ꢀ5,11,17,23ꢀTetraꢀtertꢀbutylꢀ25ꢀhydroxyꢀ26ꢀphosphonyloxyꢀ27ꢀ
phosphonylethoxyꢀ28ꢀpropoxycalix[4]arene (cR,pR)ꢀ7.
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Calix[4]arene phosphonate (cR,pR)ꢀ6 (40 mg, 0.0524 mmol) was dissolved in
methanol (3 mL) at room temperature. Sodium hydroxide (3 mL of a 2 M water solution) was
added and the resulting mixture was stirred at Tbath = 90°C for 3 h. After cooling back to room
temperature, the mixture was quenched with 2 M hydrochloric acid and extracted with
dichloromethane, washed twice with 25 mL of distilled water, 25 mL of brine and, finally,
dried over Na2SO4. Solvent was removed in vacuo to obtain product (39.2 mg, yield 96%) as
a white crystalline solid.
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1H NMR (δ (ppm), 400MHz, CDCl3): 0.82 (s, 9H, tꢀBu), 0.99 (s, 9H, tꢀBu), 1.13 (t,
3JHꢀH = 7.4 Hz, CH3), 1.36 (s, 9H, tꢀBu), 1.37 (s, 9H, tꢀBu), 1.97 (m, 2H, OCH2CH2CH3), 2.30
2
(m, 1H, OCH2CH2PO), 2.65 (m, 1H, OCH2CH2PO), 3.25 (d, 2H, JHꢀH = 13.2 Hz, ArꢀCH2ꢀ
Ar), 3.29 (d, 1H, 2JHꢀH = 14.5 Hz, ArꢀCH2ꢀAr), 3.49 (d, 1H, 2JHꢀH = 14.0 Hz, ArꢀCH2ꢀAr), 3.85
3
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(t, 2H, JHꢀH = 6.9 Hz, OCH2CH2CH3), 4.04 (d, 1H, JHꢀH = 13.6 Hz, ArꢀCH2ꢀAr), 4.04 (m,
2
2
1H, OCH2CH2PO), 4.24 (d, 1H, JHꢀH = 12.8 Hz, ArꢀCH2ꢀAr), 4.43 (d, 1H, JHꢀH = 13.8 Hz,
ArꢀCH2ꢀAr), 4.59 (m, 1H, OCH2CH2PO), 4.75 (d, 1H, 2JHꢀH = 14.2 Hz, ArꢀCH2ꢀAr), 6.27 (bs,
2H, OH), 6.43 (d, 1H, 4JHꢀH = 2.6 Hz, ArꢀH), 6.53 (d, 1H, 4JHꢀH = 2.5 Hz, ArꢀH), 6.72 (d, 1H,
4
4JHꢀH = 2.4 Hz, ArꢀH), 6.79 (d, 1H, 4JHꢀH = 2.5 Hz, ArꢀH), 7.07 (d, 1H, JHꢀH = 2.4 Hz, ArꢀH),
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7.10 (bs, 3H, ArꢀH); C{1H} NMR (δ (ppm), 125MHz, CDCl3): 10.7 (OCH2CH2CH3), 23.6
(OCH2CH2CH3), 29.7 (CМe3), 30.9 (CМe3), 31.0 (C(CH3)3), 31.1 (C(CH3)3), 31.6 (C(CH3)3),
31.7 (d, J1CꢀP = 39.1 Hz, OCH2CH2PO), 31.8 (C(CH3)3), 33.0 (CМe3), 33.5 (ArꢀCH2ꢀAr), 33.6
(CМe3), 33.9 (ArꢀCH2ꢀAr), 34.0 (ArꢀCH2ꢀAr), 34.2 (ArꢀCH2ꢀAr), 66.5 (d, J2 = 10.0 Hz,
CꢀP
OCH2CH2PO), 78.0 (OCH2CH2CH3), 124.8 (CHAr), 125.3 (CHAr), 125.55 (CHAr), 125.60
(CHAr), 125.62 (CHAr), 125.70 (CHAr), 125.74 (CHAr), 126.5 (CHAr), 126.9 (CArꢀCH2ꢀCAr),
129.1 (CArꢀCH2ꢀCAr), 129.6 (CArꢀCH2ꢀCAr), 130.8 (d, 4JCꢀP = 5.0 Hz, CArꢀOCH2CH2PO), 131.4
(CArꢀCH2ꢀCAr), 132.9 (CArꢀCH2ꢀCAr), 134.8 (CArꢀCH2ꢀCAr), 136.6 (CArꢀCH2ꢀCAr), 141.7 (CArꢀ
2
tꢀBu), 144.6 (CArꢀtꢀBu), 146.03 (d, JCꢀP = 11.1 Hz, CArꢀOP), 146.7 (CArꢀtꢀBu), 146.9 (CArꢀtꢀ
Bu), 150.5 (CArꢀOCH2), 150.6 (CArꢀCH2ꢀCAr), 153.3 (CArꢀOH); 31P{1H} NMR (δ (ppm),
162MHz, CDCl3): 23.04; HRМS (ESIꢀTOF) m/z: [MꢀH]ꢀ Calcd. for C49H64O6P 779.4441;
Found 779.4433; mp 116ꢀ117˚C; [α]D20 +20.6 (c=0.27, CHCl3).
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Xꢀray structural analyses. Single crystal of each compound was mounted under inert
perfluoropolyether at the tip of glass fiber and cooled in the cryostream of a Nonius CAD4
fitted with a Bruker APEXII CCD. The structures were solved by using the integrated spaceꢀ
group and crystal structure determination SHELXt software28 and refined by leastꢀsquares
procedures on F2 using SHELXLꢀ2014.29 All H atoms attached to carbon or oxygen atoms
were introduced in calculation in idealised positions and treated as riding models. In all
compounds disorders were observed affecting some isopropyl group in compound (cS)ꢀ3 and
(cR,pR)ꢀ7 or propyl chain in (cS)ꢀ3 and (cR,pR)ꢀ6 . These disordered parts were treated with
the tools available in SHELXꢀ2014. In (cR,pR)ꢀ7 there are large voids within the unit cell
containing some solvent molecules which were difficult to characterize and modelize. So we
use the SQUEEZE option within PLATON30 to remove the contribution of the disordered
solvent molecules. The absolute configuration for compounds (cR,pR)ꢀ6 and (cR,pR)ꢀ7 has
been determined by refining the Flack’s parameter.31 The drawing of the molecules was
realised with the help of ORTEP32.32,33 Crystal data and refinement parameters are shown in
Table S1.
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Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC 1572943ꢀ1572945.
Copies of the data can be obtained free of charge on application to the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223ꢀ336ꢀ033; eꢀmail:
deposit@ccdc.cam.ac.uk).
Aza Diels–Alder reaction procedure.
In a well dried vial under inert atmosphere, a solution of benzimine (0.25 mmol) and
catalyst (cR,pR)ꢀ7 (9.8 mg, 0.0125 mmol) in dry CH3CN (3.0 mL) was stirred at room
temperature for 30 min. After diene (0.50 mmol) adddition, the mixture was further stirred at
room temperature for 24 h. The resulting mixture was quenched with 2 M HCl aqueous
solution, diluted with saturated water solution of NaHCO3 and then extracted with CH2Cl2.
The organic phase washed twice with 5 mL of distilled water and 5 mL of brine, dried over
Na2SO4. The solution was concentrated under reduced pressure to give pale yellow oil, which
was further purified by flash chromatography using hexane/ethylacetate (3/2, v/v) as eluting
mixture to give the product as a yellow solid. The enantiomeric excess value was determined
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by supercritical fluid chromatography (SFC)ꢀHPLC [Chiralcel OJ column; CO2/iPrOH, 9:1;
flow rate: 5 mL min–1].
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Asymmetric epoxide ring opening reaction procedure.
9
In a well dried vial under inert atmosphere, a solution of benzoic acid (0.75 mmol)
and catalyst (cR,pR)ꢀ7 (39.2 mg, 0.05 mmol) in dry toluene (3.0 mL) was stirred at room
temperature for 30 min. After epoxide (0.50 mmol) was added, the mixture was further stirred
at room temperature for 24 h. The resulting mixture was quenched with 2M water HCl,
diluted with NaHCO3 saturated water solution and then extracted with CH2Cl2. The organic
phase washed twice with 5 mL of distilled water and 5 mL of brine, dried over Na2SO4. The
solution was concentrated under reduced pressure to give pale yellow oil, which was further
purified by flash chromatography using hexane/MTBE (3/2, v/v) as eluting mixture to give
the product as a white solid. Enantiomeric excesses were determined by (SFC)ꢀHPLC
[Chiralpak IA column; CO2/iPrOH, 9:1; flow rate: 2 mL min–1].
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS publication website at
DOI:
Copies of 1H, 13C, 31P NMR and crystallographic data.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmails: andriikarpus@gmail.com (AK); z_voitenko@ukr.net (ZV); vik@ioch.kiev.ua
(VK); eric.manoury@lccꢀtoulouse.fr (EM)
ORCID
Andrii Karpus: 0000ꢀ0002ꢀ5760ꢀ3086
Oleksandr Yesypenko: 0000ꢀ0003ꢀ2290ꢀ4249
Zoia Voitenko: 0000ꢀ0002ꢀ2408ꢀ6991
Vitaly Kalchenko: 0000ꢀ0002ꢀ0325ꢀ7544
Eric Manoury: 0000ꢀ0001ꢀ7991ꢀ8890
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ACKNOWLEDGMENTS
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The work was performed within the framework of the ‘Groupement FrancoꢀUkrainien
en Chimie Moleculaire’ (GDRI) funded by the ‘Centre National de la Recherche Scientifique’
(CNRS, France). AK thanks the French Embassy in Ukraine and the “Institut Universitaire de
France (IUF)” for grant funding.
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