A 'clicked' macrocyclic probe incorporating Binol as the signalling unit for the chiroptical sensing of anions

Article abstract of DOI:10.1016/j.tet.2012.07.038

We describe a macrocyclic chiroptical sensor for the detection of halide anions, with the Binol moiety acting as the CD signalling unit. The macrocycle is conveniently synthesized using CuAAC 'click' reactions in the cyclization step; this methodology ins

Full text of DOI:10.1016/j.tet.2012.07.038

Tetrahedron 68 (2012) 7861e7866
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A ‘clicked’ macrocyclic probe incorporating Binol as the signalling unit for the
chiroptical sensing of anions
,
Marco Caricato a, Alessandro Olmo a, Claudia Gargiulli b, Giuseppe Gattuso b, Dario Pasini a
*
a Department of Chemistry and INSTM Research Unit, University of Pavia, Viale Taramelli 10, 27100 Pavia, Italy
b Department of Organic and Biological Chemistry, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2012
Received in revised form 14 June 2012
Accepted 10 July 2012
Available online 17 July 2012
We describe a macrocyclic chiroptical sensor for the detection of halide anions, with the Binol moiety
acting as the CD signalling unit. The macrocycle is conveniently synthesized using CuAAC ‘click’ reactions
in the cyclization step; this methodology installs 1,2,3-triazole moieties within the macrocyclic back-
bone, able to directionally bind anions by means of CH/Xe hydrogen bonds. 1H NMR complexation
studies in CDCl3 reveal weak binding to halide and aliphatic carboxylate anions. Halide anions, however,
when held into the macrocyclic cavity, are able to trigger a large chiroptical response originating from the
steric interaction with the Binol moiety, which changes its dihedral angle, thus modulating its charac-
teristic CD signature.
Keywords:
Circular dichroism
Macrocycles
Click chemistry
Anion binding
Sensors
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
high-yielding in the macrocyclization step, but it is also efficient in
installing triazole functionalities, in which the acidic CH protons act
Molecular sensors require the presence of a suitable signalling
unit, which usually responds in terms of absorption, emission or
electrochemical changes.1 Circular Dicroism (CD) spectroscopy is
extensively used to conveniently monitor conformational changes
in complex supramolecular systems, given that CD signals, espe-
cially when arising by an exciton-coupled mechanism, can afford
information about ligand conformation or absolute configuration
that cannot be obtained by other means.2a In addition, CD activity
can be sensed orthogonally to isotropic absorption signals or to
other spectroscopic properties, thus becoming a powerful tool for
sensing, especially when the response obtained from isotropic
techniques are particularly weak. It has been possible to devise
receptorsdi.e., chiroptical sensorsdable to detect the binding of
a target analyte by responding with a variation of the CD activity
resulting from the formation of a sensor molecule/analyte ensem-
ble.2b Several examples of chiroptical sensors that provide signifi-
cantly differentiated CD signals upon binding of a metal ion,3 of
neutral guests,4 or chiral polymers5 have been recently reported.
Shape-persistent macrocycles obtained by the CuAAC (Copper
Catalyzed AzideeAlkyne Cycloaddition) reaction have recently
emerged as outstanding candidates for recognition and sensing of
anions in organic solutions. The ‘click’ reaction is not only useful and
as efficient hydrogen-bonding donors in the complexation of anions,
detected using NMR, UV/vis or fluorescence spectroscopies.6 Binol-
based synthons are a robust source of chirality; they are widely
used in asymmetric catalysis, and applications in the fields of sensing
and materials science are being increasingly developed.7,8
We and others have reported how conformational changes,
brought about by variations in the macrocyclic skeletons9a or by
substituents with differing steric demand,9b induce an alteration of
the dihedral angle between the naphthyl planes of the binaphthyl
unit. This alteration can be efficiently signalled by large variations
in the intensity of the exciton-coupled CD signal, the classical sig-
nature of resolved binaphthyl units. These units can therefore be
envisaged as good CD reporters in the design of chiroptical sensors.
In this paper, we describe the design, synthesis and character-
ization of a chiroptical macrocyclic sensing molecule, with embedded
anion-recognizing ‘handles’, in the form of the CH functionalities of
1,2,3-triazole units. These moieties hold the anion in proximity of the
neighbouring binaphthyl moiety, which is the signalling unit (Fig. 1).
2. Results and discussion
2.1. Synthesis
The synthesis of the ‘tweezer-like’ model compound (R)-6 and
of macrocycle (R)-7 is reported in Scheme 1. Preliminary molecular
* Corresponding author. Tel.: þ39 0382 98 7835; fax: þ39 0382 98 7323; e-mail
address: dario.pasini@unipv.it (D. Pasini).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.038

7862
M. Caricato et al. / Tetrahedron 68 (2012) 7861e7866
triazoles are not embedded into a rigid macrocyclic skeleton, yet
they are free to rotate and rearrange, we used classical CuAAC
conditions10 with precursors (R)-3 and commercially-available ar-
omatic terminal alkyne 4, which produced compound (R)-6 in good
yields. Conversely, when the classical CuAAC conditions were ap-
plied to the synthesis of macrocycle (R)-7, even in high dilution
conditions, we could not isolate cyclic material, but rather the
formation of polymeric baseline material was observed.
We therefore used previously reported conditions for CuAAC
macrocyclizations,11 in which the terminal alkyne fragment is
added to a solution of base and Cu(I) catalyst, rather than gener-
ating the Cu(I) catalytic species in situ. By this procedure, the
macrocycle could be isolated in satisfactory yields (31%) after
chromatography, and fully characterized by NMR spectroscopy and
mass spectrometry. Compound (R)-6 and macrocycle (R)-7 showed
the major absorption band centred around 230 nm, typical of the
binaphthyl chromophore, with molar absorption coefficient values
(ε¼70.000e150.000 Mꢀ1 cmꢀ1) within the range of those already
reported for this class of absorbers.8 Other bands, with maxima in
the 250e300 nm range (Fig. S1), are consistent with compounds
containing equivalent conjugated fragments.11 CD spectroscopy of
compounds (R)-3, (R)-6 and (R)-7 showed the exciton-coupled
structure typical of binaphthyl moieties (Fig. S2), corresponding
to the maximum absorption band in the UV/vis spectra. No induced
CD activity could be associated with other chromophores and ab-
sorption bands in the UV/vis spectra.
Macrocycle (R)-7, furthermore, did not show any deviation from
linearity in its LamberteBeer behaviour over a wide range of con-
centrations, both in CH2Cl2 and in nonpolar solvents, such as
n-hexane. In shape-persistent macrocycles, sterically-hindering
tert-butyl groups are frequently introduced within the frame-
work, to improve solubility and to prevent aggregation.12 The ab-
sence of such functionalities in the case of macrocycle 7 could lead
to potential aggregation behaviour by stacking of the extended
aromatic hemicyclic bay of macrocycle 7, which is however not
observed.
Fig. 1. General design of a macrocyclic chiroptical sensor in which the variation of the
CD response of the Binol unit is the key sensing output.
O
Br
OH
2
N3
N3
N3
OMe
OMe
NaH
OMe
OMe
3
THF/DMF
3:1
O
OH
32%
1
N
N
N
O
4
OMe
OMe
3
6
CuSO4, Sodium Ascorbate
EtOH/H2O/toluene 7:3:1
2.2. Complexation studies
O
77%
N
1H NMR titration experiments in CDCl3 showed binding of
a series of anions (Table 1) to both open analogue (R)-6 and mac-
rocycle (R)-7. Maximum complexation-induced shifts (Table S1)
were generally low, but well above the experimental limit of the
instrument and of the analysis method.13 The corresponding as-
sociation constants could be obtained by fitting the data to a 1:1
binding model.
An ascending trend in terms of overall affinity (Table 1) in the
halide series could be observed, going from fluoride to iodide for
both the macrocycle (R)-7 and the open system (R)-6. Anion
binding by neutral receptors in CDCl3 is often very weak as the
receptor has to compete against ion pairing; however, neat CDCl3
was in our case the most suitable solvent given the excellent
N
N
N
N
O
N
H5''
5
OMe
OMe
3
H2'''
N
7
CuI, DBU
toluene dry
O
N
N
31%
Scheme 1. Synthesis of the open analogue (R)-6 and the clicked macrocycle (R)-7.
Table 1
Binding constants (Mꢀ1) for the 1:1 complexes between ‘open analogue’ (R)-6 and
macrocycle (R)-7 and anions in CDCl3
modelling, along with experimental results from our group, sug-
gested that, in order to counterbalance the inherent distortion
brought about by the insertion of the binaphthyl unit into the
macrocyclic framework (Fig. 1), some elements of conformational
flexibility, such as sp3 carbon atoms, imparting a higher confor-
mational freedom with respect to sp or sp2 hybridized carbon
atoms, needed to be introduced. Elaboration of the optically-pure
benzylic diol (R)-1 (Scheme 1) was carried out by means of Wil-
liamson ether synthesis with aromatic azide-containing benzyl
bromide 2, to generate advanced intermediate (R)-3 in good yields.
For the synthesis of model compound (R)-6, in which the two
a
Anion
Compound 6
Macrocycle 7
b
b
Fꢀ
Clꢀ
7.4ꢁ0.3
8.9ꢁ0.0
Brꢀ
10.6ꢁ0.4
12.5ꢁ1.8
18.1ꢁ3.2
15.5ꢁ2.3
14.3ꢁ1.2
8.6ꢁ0.7
Iꢀ
11.4ꢁ0.5
b
CH3COOꢀ
(S)-Mandelate
(R)-Mandelate
b
b
Measured by 1H NMR (500 MHz, 298 K, CDCl3) using tetrabutylammonium salts.
No quantifiable binding was detected.
a
b

M. Caricato et al. / Tetrahedron 68 (2012) 7861e7866
7863
solubility of the hosts and the tetrabutylammonium salts used. We
also tested carboxylate anions, and again weak association con-
stants characterized the binding events in CDCl3; by utilizing chiral
guests (mandelate anions) a moderate degree of enantiodiscrimi-
nation was observed in the case of macrocycle (R)-7.
The similar behaviour shown by the closed and open com-
pounds indicates that size match and preorganizationdwhich de-
termine a ‘best fit’ in correspondence to a certain halide anion in
the case of previously reported shape-persistent macrocyclesdis
not a key issue in the case of compound (R)-7.11 Inspection of the 1H
NMR titrations revealed that the major shift upon complexation is
that observed for the triazole CH hydrogen atoms of the hosts, in-
dicating that the mode of complexation mainly involves, as
expected, these functional groups (Fig. 2).
The inherent UV absorbance of CH2Cl2 or other chlorinated
solvents made the use of the 210e230 nm spectral range not
practical in UV/vis or CD spectroscopies at the low concentrations
(10ꢀ5e10ꢀ6 M) required by the relatively high molar extinction
coefficient values of our Binol-containing receptors in this spectral
region. Seeking to develop the Binol moiety as the CD signalling
unit, we changed the solvent mixture in order to obtain a tradeoff
between solubility of the anions (used as their tetrabutylammo-
nium salts), and optical transparency in the 210e230 nm spectral
range.
Indeed, when titrating macrocycle (R)-7 with Bu4NI in a meth-
ylcyclohexane (MCH)/CH2Cl2 (9/1) solvent mixture, a large varia-
tion of the CD signal could be observed (Fig. 3). Similar titration
profiles could be observed in the presence of halide anions of dif-
fering steric hindrance, such as Brꢀ and Clꢀ, but the effect was not
observed in the presence of fluoride (Fig. 4). This effect was also not
observed in the case of all carboxylate anions tested. For all CD-
active halides (Iꢀ, Brꢀ and Clꢀ), the CD intensity initially de-
creased up to a maximum value and then slightly increased when
the guest concentration exceeded a certain point (after 6e10 equiv
guest, see inset), suggesting that a competition of bridging versus
nonbridging complexations might be in place under excess guest
conditions.14
The open analogue (R)-6, for which complexation with halide
anions has been substantiated by 1H NMR spectroscopy, did not
show any CD response, probably as a result of the innate confor-
mational freedom enjoyed by the open structure, which allows for
a minimization of the steric interaction of the anions with the
binaphthyl unit. Control experiments with Binol precursor (R)-1
excluded any alternative binding mechanism (e.g., anione
p in-
teractions) as the source of the CD output in the investigated sol-
vent system (Fig. 4).15 Even more interestingly, the sensing
macrocyclic molecule is silent upon titration with halide or car-
boxylate anions using UV/vis detection (Fig. S9).
Fig. 2. Aromatic region of the 1H NMR (CDCl3, 500 MHz, 25 ꢂC) spectra of macrocycle
(R)-7 (2.5 mM, bottom) and at the end of the titration with Bu4NI ([(R)-7]¼2.5 mM,
[Bu4NI]¼50 mM, top).
3. Conclusions
We have presented the synthesis and characterization of a novel
macrocycle as a chiroptical sensor for halide anions. The signalling
mechanism is substantially different from previously reported ex-
amples of chiroptical sensor for anions;6b,c in fact, it is not a result of
a specific recognition of the analyte with the CD reporter, the Binol
moiety, but rather a secondary effect. The active anions are held
into the cavity by specific hydrogen-bonding interactions with
triazole CH moieties; they are in close proximity of the Binol moi-
ety, and its conformational change generates strong signalling ex-
clusively when CD spectroscopy is used as the detection tool. The
system shows selectivity towards iodide, bromide and chloride
over fluoride and carboxylate anions.
This report highlights the potential of CD spectroscopy as a sig-
nalling technique that can be used, with suitably designed molec-
ular receptor systems, orthogonally and in a complementary way to
other more direct, isotropic sensing techniques, such as absorbance
or emission spectroscopies. We are currently aiming at more re-
fined, highly specific molecular chiroptical sensors for the detection
of suitable substrates within complex analyte matrices, especially
useful when other, more widely used analytical techniques suffer
interference from competing substrates in the matrices.
Geometry optimization carried out at the semi-empirical (PM3)
level (Figs. S3eS5) on the 1:1 complexes shed light on the binding
mode of anions to the open compound (R)-6 and to macrocycle (R)-
7. In all the cases examined, complexation is driven by the affinity of
the anions to the triazole CH hydrogen atoms. In particular, the
carboxylate anions bind in a bridge-like fashion with the two ox-
ygen atoms pointing towards the two triazole CH groups. In the
case of macrocycle (R)-7, spherical (i.e., halide) anions dock in the
cleft generated by the triazole units and the m-phenylene spacer,6
enjoying an additional interaction with a CH hydrogen atom of
the latter aromatic unit, as confirmed by the complexation-induced
shifts observed during the 1H NMR titrations. On binding halide
anions, the peak belonging to H-2000 (the CH hydrogen atom of the
m-phenylene spacer placed between the triazole units, Scheme 1)
undergoes complexation-induced shifts about three times larger
than those observed upon carboxylate binding. In addition, mo-
lecular modelling clearly indicated, in macrocycle (R)-7/halide
complexes, that the spherical anions sterically interact with the
Binol unit modifying its dihedral angle.
2.3. CD spectroscopy
4. Experimental section
4.1. General
The intensity of the low energy branch of the exciton-coupled
CD signal associated with the Binol moiety can be directly related
to the dihedral angle of the binaphthyl unit.9 It should be stressed
that even large variations in the maximum value of the low energy
component of the couplet correspond to little changes in the di-
hedral binaphthyl angle.
All commercially-available reagents and solvents were used as
received. THF (Na, benzophenone) and CH2Cl2 (CaH2) were dried
and distilled before use. CCl4 (for the NBS bromination) and toluene

7864
M. Caricato et al. / Tetrahedron 68 (2012) 7861e7866
110
200
I-
Br-
0
0
-60
-100
-140
-60
-135
-210
-110
-200
0
3
6
0
3
6
-
-
Eq. Br
Eq. I
220
285
350
220
285
350
λ (nm)
λ (nm)
90
100
50
F-
Cl-
0
0
-50
-100
-150
-90
-110
-130
-50
-100
-150
-90
0
3
6
0
3
6
-
Eq. F
-
Eq. Cl
220
240
260
280
300
320
340
220
285
350
λ (nm)
λ (nm)
Fig. 3. CD titrations of macrocycle (R)-7 with increasing amounts of Bu4NX in MCH/CH2Cl2 9:1 (v/v). Fixed host concentration: 5.2ꢄ10ꢀ6 M; guest concentration: see inset (for inset,
values at 235 nm, for the lowest energy branch of the CD couplet, are plotted vs added guest equivalents).
230e400 mesh). 1H and 13C NMR spectra were recorded in CDCl3 on
200, 300 or 500 MHz spectrometers using the residual solvent peak
or tetramethylsilane as the standard. The UV/vis spectroscopic
studies were recorded using commercially-available spectropho-
tometers. Mass spectra were recorded using an electrospray ioni-
zation instrument. Optical rotations were measured on
80%
a polarimeter with a sodium lamp (
l
¼589 nm) and are reported as
follows: ½a rDt
ꢃ
(c¼g (100 mL)ꢀ1, solvent). CD spectroscopy was per-
formed using a spectropolarimeter; spectra were recorded at 25 ꢂC
at a scanning speed of 20 nm minꢀ1 and were background
corrected.
-20%
4.2. 1H NMR complexation experiments
F-
I-
Br-
Cl-
Fig. 4. Reduction (%) of the lower energy branch of the exciton-coupled CD signal of
the binaphthyl moiety for macrocycle (R)-7 (blue), compound (R)-6 (green) and control
(R)-1 (red) upon complexation with halide anions in MCH/CH2Cl2 9:1 (v/v) (see Fig. 3
and S7eS8).
All spectra were recorded at 500 MHz and at 298 K. Ka values for
the complexation of (R)-6 or (R)-7 with n-Bu4NþXꢀ (Xꢀ¼Fꢀ, Clꢀ,
Brꢀ, Iꢀ, AcOꢀ, (S)-(þ)-PhCH(OH)CO2ꢀ, (R)-(ꢀ)-PhCH(OH)COꢀ2 ) were
assessed by nonlinear treatment of the data obtained from 1H NMR
titration experiments. Samples were prepared by adding to a 0.5 mL
solution of the host (5 mM in CDCl3) successive aliquots of a stock
solution of the guest (62.5 mM in CDCl3) to a final volume of 1.0 mL.
Eight values of dobs for the triazole CH resonances were collected by
keeping the [host] to [guest] ratio in the 1/0.25e1/12.5 interval.
Nonlinear regression analysis of dobs versus [guest], using the
WinEQNMR for Windows software package,19 provided the Ka
value.
16
ꢀ
were dried using 4 A molecular sieves. Compound (R)-1 was
obtained following previously published procedures. Compound
217 was obtained through: (a) diazotization reaction and azide
formation starting from 3-methylaniline;18 (b) NBS bromination.17
Analytical thin layer chromatography was performed on silica gel,
chromophore loaded, commercially-available plates. Flash chro-
ꢀ
matography was carried out using silica gel (pore size 60 A,

M. Caricato et al. / Tetrahedron 68 (2012) 7861e7866
7865
4.3. General procedure for the UV/vis or CD titration
experiments
25 ꢂC)
d
¼8.17 (s, 2H; H500), 8.11 (s, 2H; H4), 7.92 (dt, 2H; J¼8.1,
0.7 Hz, H8), 7.62 (m, 2H; H20), 7.78 (d, 4H; J¼8.0 Hz, H2000), 7.74 (ddd,
2H; J¼7.6, 2.2, 1.4 Hz, H60), 7.53 (part of an ABX system, 2H;
JAB¼7.6 Hz, JAX¼7.6 Hz, H50), 7.50 (part of an ABX2 system, 2H;
JAB¼7.6 Hz, JAX¼1.4 Hz, H40), 7.40 (ddd, 2H; J¼8.1, 6.9, 1.5 Hz, H7),
7.26 (d, 4H; J¼8.0 Hz, H3000), 7.20e7.25 (m, 2H, H6), 7.16e7.19 (m,
2H, H5), 4.94 and 4.88 (AB system, 4H; JAB¼12.4 Hz, BinoleCH2),
4.82 (s, 4H; benzyliceCH2), 3.28 (s, 6H; OCH3), 2.40 (s, 6H; CH3)
Methylcyclohexane (MCH) was purchased as UV/vis spectro-
scopic grade and used as received. An analytical balance (with
a precision of 10ꢀ4 g) was used to weight the samples for the stock
solutions. Aliquots of these stock solutions were then taken via high
precision syringes to prepare the cuvette samples for spectropho-
tometric analyses. Titration experiments. The titration experiments
were conducted as follows: to a stock solution of the host (solution
A) in CH2Cl2 or MCH/CH2Cl2, several aliquots of the guest (the
tetrabutylammonium salt, solution B) were added. Solution B is
formed by the tetrabutylammonium salt at higher concentration
dissolved in solution A, in order to maintain the host always at
a constant concentration.
ppm; 13C NMR (CDCl3, 125 MHz, 25 ꢂC)
d
¼154.7, 140.6, 138.3, 137.3,
134.0, 131.3, 130.5, 129.8 (C50), 129.6 (C3000), 129.2 (C4), 128.1 (C8),
127.8 (C40), 127.4 (Cq), 126.5 (C6), 125.7 (C200), 125.6 (C5), 125.0 (C7),
124.4 (Cq),119.7 (C60),119.6 (C20),117.3 (C500), 72.0 (BinoleCH2), 68.4
(benzyliceCH2), 61.1 (OCH3), 21.3 (CH3). MS (ESI) m/z (%): 891
([MþNa]þ, 23), 869.0 ([MþH]þ, 100).
4.5.3. Macrocycle (R)-7. 1,8-Diazabicyclo[5.4.0]undec-7-ene (742 mg,
4.88 mmol, 20 equiv) was dissolved in dry toluene (100 mL) and N2
was bubbled through the solution for 15 min. The solution was
heated at 70 ꢂC for 30 min and CuI (23 mg, 0.122 mmol, 0.5 equiv) was
added as a solid. A solution of compound (R)-3 (155 mg, 0.244 mmol,
1 equiv) and 1,3-diethynylbenzene 5 (31 mg, 0.244 mmol, 1 equiv) in
dry toluene (40 mL) was added dropwise over a period of 10 h while
keeping the reaction mixture under inert atmosphere. The reaction
was stirred at room temperature for 4 h. H2O (100 mL) was added and
the reaction mixture extracted with CH2Cl2 (3ꢄ100 mL). The product
was purified by flash chromatography (SiO2; hexanes/AcOEt: 9/1 to 7/
3) to afford (R)-6 (58 mg, 31%) as a white solid [found C 75.5, H 5.3.
4.4. Molecular modelling
The conformational analysis of (R)-6 or (R)-7 and their com-
plexes were carried out with the classical molecular mechanics
force field (MMFF) by using the Monte Carlo method to randomly
sample the conformational space. The equilibrium geometry
obtained for the minimum-energy conformer (R)-6 or (R)-7 was
refined at the PM3 semi-empirical level. The equilibrium geometry
of the complexes were calculated using the molecular mechanics
force field from the optimized geometry of the receptor, by placing
the anion(s) at a short distance from the triazole CH hydrogen
atoms and leaving the system free to relax without constraints. The
conformer obtained was further refined by semi-empirical
methods at the PM3 level. All calculations were performed using
Spartan’10 (Wavefunction, Inc., Irvine, CA).20
C48H38N6O4 requires C 75.6, H 5.0%]; ½a D25
ꢀ11.6 (c 0.001 in CH2Cl2).
ꢃ
1H NMR (CDCl3, 500 MHz, 25 ꢂC)
d
¼8.28 (s, 2H; H500), 8.21 (dd, 2H;
J¼7.6, 1.3 Hz, H4000), 8.11 (s, 2H; H4), 7.97 (ddd, 2H; J¼7.9, 2.0, 1.1 Hz,
H40), 7.89 (dd, 2H; J¼8.1, 1.3 Hz, H8), 7.71 (br s, 1H; H2000), 7.62 (br s,
2H; H20), 7.59 (t, 1H; J¼7.6 Hz, H5000), 7.56 (t, 2H; J¼7.9 Hz, H50), 7.50
(dt, 2H; J¼7.9, 1.1 Hz, H60), 7.37 (ddd, 2H; J¼8.1, 6.7, 1.3 Hz, H7), 7.21
(ddd, 2H; J¼8.6, 6.7, 1.3 Hz, H6), 7.15 (dd, 2H; J¼8.6, 1.3 Hz, H5), 4.96
and 4.87 (AB system, 4H; J¼11.6 Hz, benzyliceCH2), 4.85 and 4.79 (AB
system, 4H; J¼12.1 Hz, BinoleCH2), 3.27 (s, 6H; CH3) ppm; 13C NMR
4.5. Synthesis of compounds
4.5.1. Compound (R)-3. Compound (R)-1 (0.303 g, 0.81 mmol,
1 equiv) was added to a solution of NaH (0.088 g, 3.64 mmol,
4.5 equiv) in THF/DMF 3:1 (20 mL). A solution of 2 (0.429 g,
2.02 mmol, 2.5 equiv) in THF (3 mL) was then added. The suspen-
sion was stirred overnight and H2O (5 mL) was added. The THF was
removed in vacuo, then the mixed aqueous layer was extracted
with CH2Cl2 (3ꢄ15 mL). The crude product was purified by flash
chromatography (SiO2; hexanes/AcOEt: 95/5 to 8/2) to afford 3
(164 mg, 32%) as a white solid; [found: C 71.5, H 5.0. C38H32N6O4
(CDCl3, 125 MHz, 25 ꢂC)
d
¼154.8, 147.8, 140.1, 137.1, 134.0, 131.1, 2ꢄ
130.5, 130.2 (2C, C4), 130.1 (3C, C50 and C5000), 130.0, 128.6 (C60), 128.1
(C8),126.6 (C6),126.2 (C4000), 125.6 (C5), 125.1 (C7), 124.5, 123.3 (C2000),
121.0 (CH-40), 119.7 (C20), (C60), 118.3 (C500), 72.6 (BinoleCH2), 68.8
(benzyliceCH2), 61.4 (OCH3). MS (ESI) m/z (%): 785.3 ([MþNa]þ, 100),
1548.1 ([2MþNa]þ, 28).
requires C 71.7, H 5.1%]; ½a D25
ꢃ
ꢀ25.9 (c 0.007, CH2Cl2). 1H NMR
Acknowledgements
(CDCl3, 300 MHz, 25 ꢂC)
d
¼8.13 (s, 2H; H4 binaphthyl), 7.94 (d, 2H;
J¼8.1 Hz, binaphthyl), 7.45e7.18 (m, 12H; binaphthylþAreH), 7.21
(m, 4H; binaphthyl), 7.01 (d, 2H; J¼7.8 Hz, AreH), 4.91 (AB system,
4H; J¼12.4 Hz, CH2), 4.76 (s, 4H; CH2), 3.30 (s, 6H; eOCH3). 13C NMR
Support from the University of Pavia, University of
Messina, MIUR (Programs of National Relevant Interest PRIN
grants 2004-033354 and 2009-A5Y3N9), and, in part, from CAR-
IPLO Foundation (2007e2009) and INSTM-Regione Lombardia
(2010e2012), is gratefully acknowledged.
(CDCl3, 75 MHz, 25 ꢂC)
d
¼154.6 (Cq), 140.4 (Cq), 140.2 (Cq), 133.9
(Cq), 131.4 (Cq), 130.4 (Cq), 129.7 (CH), 128.9 (CH), 128.0 (CH), 126.3
(CH), 125.6 (CH), 124.8 (CH), 124.3 (Cq), 124.1 (CH), 118.2 (CH), 118.1
(CH), 72.2 (CH2), 68.2 (CH2), 61.0 (OCH3). MS (ESI) m/z (%): 659
([MþNa]þ, 100), 1294 ([2MþNa]þ, 6).
Supplementary data
Supplementary data contain additional NMR, UV and CD spec-
tra, titrations and computational details associated with this article.
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.07.038.
4.5.2. Compound (R)-6. Compound (R)-3 (34 mg, 0.053 mmol,
1 equiv) was added to a solution of 4-ethynyltoluene 4 (0.014 mL,
0.106 mmol, 2 equiv), sodium
L-(þ)-ascorbate (2 mg, 0.0106 mmol,
0.2 equiv) and CuSO4 (1 mg, 0.0053 mmol, 0.1 equiv) in EtOH/H2O/
toluene 7:3:1 (1.1 mL). The homogeneous solution was stirred for
48 h at room temperature. The solution was partitioned into two
layers by adding CH2Cl2, and the aqueous layer was extracted with
clean CH2Cl2 (3ꢄ5 mL). The combined organic layers were dried
(Na2SO4), and the product was purified by flash chromatography
(SiO2; hexanes/AcOEt: 9/1 to 7/3) to afford (R)-6 (31 mg, 77%) as
a white solid [found C 77.5, H 5.3. C56H48N6O4 requires C 77.4, H
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