Correlation between conformational equilibria of free host and guest binding affinity in non-preorganized receptors

Article abstract of DOI:10.1021/jo400683j

Positive cooperativity between host conformational equilibria and guest binding has been widely reported in protein receptors. However, reported examples of this kind of cooperativity in synthetic hosts are scarce and largely serendipitous, among other th

Full text of DOI:10.1021/jo400683j

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pubs.acs.org/joc
Correlation between Conformational Equilibria of Free Host and
Guest Binding Affinity in Non-preorganized Receptors
Romen Carrillo,*,† Ezequiel Q. Morales,† Víctor S. Martín,‡ and Tomas Martín*,†,‡
́
†Instituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas, Avda. Astrofísico Francisco
San
́
chez 3, 38206 La Laguna, Tenerife, Spain
‡Instituto Universitario de Bio-Organ
́
ica “Antonio Gonzalez”, Avda. Astrofísico Francisco Sanchez 2, 38206 La Laguna, Tenerife,
́
́
Spain
S
* Supporting Information
ABSTRACT: Positive cooperativity between host conformational
equilibria and guest binding has been widely reported in protein
receptors. However, reported examples of this kind of cooperativity in
synthetic hosts are scarce and largely serendipitous, among other things
because it is hard to envision systems which display this kind of
cooperativity. In order to shed some light on the correlation between
conformational equilibria of free host and guest binding, selected
structural modifications have been performed over a family of
nonpreorganized hosts in order to induce conformational changes and to analyze their effect on the binding affinity. The
conformational effect was evaluated by a theoretical conformational search and correlated with the ability of the receptors. All
data suggest that those receptors that display the best association constants are able to sample folded conformations analogous to
the conformational requirements for the binding of the guests. On the contrary, for those receptors where folded conformers are
scarce, then the association constant and enantioselectivity clearly drop.
study this kind of cooperativity is imperative in order to
facilitate a smart control and further useful application of this
exciting strategy to enhance guest binding.10
INTRODUCTION
■
Conformational landscape induced by the chemical structure is
one of the main factors governing the design and synthesis of
efficient receptors.1 Traditionally, good binding affinities have
been envisioned by conformational control through highly
organized and/or rigid structural features, in order to restrict
the conformational freedom toward the optimal geometry for
binding.2 Recently, though, it has been postulated that
conformational equilibria in a flexible receptor can also enhance
the binding affinity due to positive cooperativity between the
conformational landscape of the receptor and the noncovalent
interactions between host and guest.3,4 Indeed, intrareceptor
noncovalent interactions involved in the conformational
equilibria of free host may induce the same conformational
restrictions on parts of the receptor than guest binding. It has
been proved that conformational rearrangements identical to
those required by guest binding contribute to relieve part of the
adverse binding entropy and therefore to favor complex
stability.5 Consequently, binding is not only mediated by direct
host−guest interactions but also by intrareceptor interactions,
both of which are mutually reinforced. Such positive
cooperative mechanism is fairly frequent in proteins, but
there are just a few precedents reported in synthetic
receptors,6−9 among other reasons because accomplishment
of this kind of cooperativity in synthetic systems represents a
substantial challenge in terms of design. Consequently,
dissection of molecular mechanisms by which conformational
rearrangements of the host reinforce molecular recognition is
highly relevant, and thus the development of simple models to
In this regard, we have recently reported that small synthetic
receptor 1cis (Figure 1)11 displays such a positively cooperative
mechanism, which was proved by isothermal titration
calorimetry (ITC) and by a linear-free energy relationship
(LFER) between the thermodynamic potential and the
activation energy of association.9 Therefore, receptor 1cis may
constitute an excellent model system to gain insight on the
correlation between the performance of the receptor and the
conformational effect of certain structural features. Receptor
1cis has a folded bound state, and a similar folded conformation
is also found in free 1cis (Figure 2a). Preorganization, though,
can be excluded because the system is quickly switching
between two degenerate folded conformations, continuously
unfolding and refolding.9 Herein, we report the modulation of
such conformational landscape through structural modifications
made on receptor 1cis. Conformational equilibria of all
receptors were analyzed through a theoretical conformational
search and correlated to the binding affinity and to the
enantiodiscrimination.
RESULTS AND DISCUSSION
■
The conformational equilibria were tuned through three
variables: the stereochemistry of the tetrahydropyran unit, the
Received: April 1, 2013
© XXXX American Chemical Society
A
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relevant to explore the effect of structural modifications over
the pyridine spacer, particularly on the carbonyl moieties.
Finally, there are two linking points for the spacers with
completely different dynamical properties (spacers A and B in
Figure 1b), with the secondary alcohol less flexible, as it is
directly bonded to the tetrahydropyran ring. Accordingly, the
family of receptors shown in Scheme 1 was synthesized and
analyzed.
Synthesis of all receptors was carried out from the same
starting material for each stereochemical series through a
divergent synthetic strategy (Scheme 2). To carry out the
synthesis of compounds 1cis, 2cis, and 3cis (Scheme 2), the diol
10cis was selectively protected involving 1,3-benzylidene
ketalization followed by DIBAL-H reduction to give the benzyl
ether 11cis. The O-alkylation of the primary alcohol of 11cis
with diethylene glycol ditosylate followed by cleavage of the
benzyl protecting group under hydrogenation conditions
provided the diol 15cis in good yield. The diol 15cis was
used as a common precursor for the synthesis of receptors 1cis,
2cis, and 3cis. The diester 1cis was prepared by reacting 2,6-
pyridinedicarbonyl dichloride with the diol 15cis. The O-
alkylation of the secondary alcohol of diol 15cis with 2,6-
bis(bromomethyl)pyridine provided the receptor 2cis. When
this reaction was carried out using as alkylating reagent
diethylene glycol ditosylate we obtained the receptor 3cis.
To perform the synthesis of the receptors 6cis and 9cis, a
selective protection of primary alcohol of the diol 10cis with
benzyl bromide provided the benzyl ether 12cis. Then, the
same sequence of reactions described above to obtain receptors
2cis and 1cis from alcohol 11cis was applied to alcohol 12cis to
give receptors 6cis and 9cis, respectively. In order to obtain
receptors 4cis, 5cis, and 8cis, it was necessary change the nature
of the protective group. Thus, the diol 10cis was protected, as
the bis-silyl ethers, followed by selective deprotection of the
silyl ether of the primary alcohol to afford compound 17cis,
which was used to obtain the diol 18cis by O-alkylation with
2,6-bis(bromomethyl)pyridine and further deprotection of the
silyl protective groups. Using the same reactions to obtain
receptors 1cis and 2cis from diol 15cis, in the diol 18cis
afforded receptors 4cis and 5cis, respectively. To carry out the
synthesis of receptor 8cis a silyl protective group less prone to
migrate was used. Thus, the diol 10cis was monoprotected as
the triisopropylsilyl ether 19cis, which was used to obtain
receptor 8cis using the same sequence of reactions described to
obtain receptor 4cis. The synthesis of all receptors with
stereochemical trans were performed with identical synthetic
strategy but using as starting material the diol 10trans (Scheme
1S in the Supporting Information). Unfortunately, all attempts
to make both receptors 7 were unfruitful due to the formation
of multiple oligomeric products.
Figure 1. (a) Receptor 1cis. (b) Design for the whole family of
receptors synthesized. (c) Effect of the stereochemistry of the
tetrahydropyran unit: at least one conformer of the cis isomer is
curved whereas trans isomer is completely flat. (d) Conformational
equilibria for 2,6-pyridine diester: there are two cisoid conformers and
two equivalent transoid conformers, all having similar stability. (e)
Spacers employed.
Figure 2. (a) Crystal structure of receptor 1cis.11 (b) Distance taken as
the geometrical parameter to determine the folded geometry of the
receptors.
The association constants (Ka) of the hosts with the methyl
ester of amino acid ammonium picrates (G+Pic−) in CHCl3 at
298 K were determined on the basis of the differential UV
spectrometry at three wavelengths (380, 385, and 390 nm) by
the typical nonlinear least-squares method (1:1 simulation).14
The measured Ka, the enantioselectivity (KD/KL), and the
Gibbs free energy of association (ΔGa) are summarized in
Table 1 except for receptors 3, 7, and 8, both cis and trans, as
they display unsatisfactory association constants (Ka < 100
M−1). On one hand, Table 1 shows the high influence of the
stereochemistry. Undoubtedly, there is a general superior ability
of receptors cis respect to receptors trans. This fact is
particularly notable for receptors 1 and 4. Thus the association
nature and position of the spacers. On one hand, it has been
reported that trans stereochemistry of the tetrahydropyran unit
yields close to flat conformations, whereas cis stereochemistry
induces curvature.12 On the other hand, the 2,6-dicarbonylpyr-
idine spacer is involved in well-known cisoid−transoid
conformational equilibria due to dipole−dipole interactions
between both carbonyl moieties and the pyridine nitrogen,
which are reportedly able to cause relevant shape changes in
receptors.13 As the folded receptor displays a transoid
conformation on the 2,6-dicarbonyl pyridine spacer, it is also
B
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a
Scheme 1. Chemical Structure of the Family of Receptors Studied
a
Key: (a) 2R, 3R; (b) 2R, 3S.
Scheme 2. Synthesis of All-Cis Receptors
constant of 1trans with D-Trp-OMe+ drops almost 6 times
compared to that of 1cis, and the enantiodiscrimination
decreases more than three times, and a similar behavior is
observed for receptors 4cis and 4trans. On the other hand, the
C
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Table 1. Association Constants (Ka), Enantioselectivity (KD/KL), Gibbs Free Energy of Association (ΔGa in kJ mol−1), and
ΔΔGa Calculated from ΔGa for Complexation of the Hosts with Chiral Organic Ammonium Picrates in CHCl3 at 298 K
a
b
,
c
a
b,c
host
guest
Ka (M−1
)
KD/KL
−ΔGa
ΔΔGa
host
guest
Ka (M−1
)
KD/KL
−ΔGa
ΔΔGa
d
1cis
1cis
1cis
1cis
2cis
2cis
2cis
2cis
4cis
4cis
4cis
4cis
5cis
5cis
5cis
5cis
6cis
6cis
6cis
6cis
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
25990
1.80
25.19
23.73
27.85
22.05
13.25
15.08
15.59
14.29
23.57
22.72
25.57
20.52
16.30
15.72
15.08
16.30
18.31
17.24
18.20
17.31
1.46
1trans
1trans
1trans
1trans
2trans
2trans
2trans
2trans
4trans
4trans
4trans
4trans
5trans
5trans
5trans
5trans
6trans
6trans
6trans
6trans
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
D-Ala-OMe+
L-Ala-OMe+
D-Trp-OMe+
L-Trp-OMe+
7350
7370
12770
4090
410
1.00
22.06
22.06
23.43
20.61
14.91
14.13
14.58
15.93
20.19
20.21
21.84
19.76
0.00
d
14410
d
76190
10.39
0.48
1.69
1.41
7.69
1.26
0.61
1.54
1.44
5.80
−1.83
1.30
3.12
1.37
0.58
0.99
2.32
2.82
0.78
d
7330
210
440
300
540
360
−1.35
−0.02
2.08
320
620
13510
9590
30360
3950
720
0.85
3460
3480
6740
2910
e
5.05
0.58
570
440
−1.22
1.07
720
1620
1050
1550
1080
0.89
a
b
Picrate salts were used. The association constants were determined on the basis of differential UV/vis spectroscopy at three wavelengths (380, 385,
c
and 390 nm) by the typical nonlinear least-squares method (1:1 simulation). These values are the average of at least three independent
d
e
measurements. Values obtained from ref 11. Association constant lower than 100 M−1.
nature of the spacers seems to be another fundamental factor
for the ability of the receptor. Accordingly, it is noticeable that
enantioselectivities are low except for 1cis and 4cis, which have
remarkably high ones. In fact, host 1cis presents 2 orders of
magnitude higher association constants and better enantiose-
lectivity than host 2cis. As Table 1 shows, the association
constant of 1cis with D-Trp-OMe+ is 76190 M−1, whereas for
2cis it is 540 M−1 and the enantioselectivity (KD/KL) for the
same substrate is 10.39 and 1.69, respectively. Receptor 4cis is
also much better than 5cis displaying an association constant
with D-Trp-OMe+ almost 70 times higher and much better
enantiodiscrimination. It should be emphasized that the only
difference between host 1cis and 2cis and between 4cis and 5cis
is the presence of the carbonyl groups next to the pyridine.
However, the chemical nature of the spacer is not enough to
generate a good binding and chiral discrimination ability in the
receptor. Indeed, receptors 1cis and 4cis are isomers of 9cis and
8cis, respectively, with the only difference being the way in
which spacers are linked to the tetrahydropyran rings and yet
the effect of that subtle difference is dramatic: receptors 9cis
and 8cis show very low association constant and enantiodis-
crimination. In conclusion, Table 1 shows there are two
essential structural features for a receptor to be good: cis
stereochemistry in the tetrahydropyran unit and 2,6-pyridine
dicarbonyl as spacer A.
among the receptors are observed, but they are better discussed
if a definition of folded geometry in such systems is proposed.
First, a reference system was taken. It is reasonable to
consider the crystal structure of receptor 1cis as the folded
reference of the free receptors (Figure 2a). Second, a good
parameter to follow the folding of the receptors is required.
The distance between the central oxygen of the oxybis-
(ethanediyl) spacer B and the carbon atom in para position of
the pyridine, or equivalent positions in each receptor, defines
quite well the folding degree (Figure 2b), and therefore, it was
considered as the geometrical parameter of folding. Measured
on the reference system it is 5.26 Å. That value was considered
the geometrical reference of folding. Finally, in order to define
what a folded conformer is, a borderline was set at 6 Å which
includes a top margin of almost 15% respect the folding
reference value. Thus, if the distance between those selected
positions is smaller than 6 Å the receptor is considered folded
and it is considered unfolded if the distance is larger. According
to that, there is clearly a prevalence of unfolded conformers on
those receptors lacking carbonyls in spacer A or displaying trans
stereochemistry. Indeed, among the conformers found within a
21 kJ mol−1 range from the global minimum (Figure 3c), 23
out of 50 conformers of receptor 1cis (46%) are folded whereas
they represent only four out of 35 conformers of receptor 2cis
(11.4%) and 33 out of 168 conformers of receptor 1trans
(19.6%). Moreover, while the most stable conformers of
receptor 1cis are folded, exactly the opposite happens to
receptor 2cis which lacks the carbonyls (Figure 3b). Analogous
analyses can be done for receptors 4cis, 5cis, and 4trans.
Another remarkable result extracted from the conformational
search is that the carbonyls do not decrease the number of
conformers by reducing flexibility as it could be expected. On
the contrary, receptor 1cis has more conformers (50) than
receptor 2cis (35) within a 21 kJ mol−1 range from the global
minimum.
To gain insight into the conformational effect of such
structural features, a theoretical conformational analysis was
performed. Conformations were analyzed using the low-mode
search (LMOD),15 a fast and useful method to scan the whole
conformational space of this kind of molecules. Obtained
conformers (up to 10000 steps) were minimized using MMFF
(charges provided by FF and TNGC method) in order to
remove duplicates or conformers with an energy above 21 kJ
mol−1 (5.02 kcal mol−1). Significant conformational differences
D
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Figure 3. (a) Clustering of conformers within 16 kJ mol−1 from the global minimum just for visualization ease only. (b) Most stable conformer. (c)
Representation of all the conformers found within 21 kJ mol−1 from the global minimum vs the geometrical parameter of folding d. The borderline
was set at 6 Å (red line); thus, all of the conformers below that value are considered folded and vice versa. (d) Clustering of conformers within 16 kJ
mol−1, showing the molecular dipole moments. Vector directions are represented from the positive to the negative charge and their lengths are
proportional to the magnitudes of the molecular dipole moments.
A simple NMR experiment can be carried out to verify the
repercussions of the appropriate combination of spacer A and
stereochemistry on the folding as the computational studies
suggested. It consists of comparing equivalent peaks of
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receptors 1cis and 2cis or receptors 4cis and 5cis, since the last
member of both couples lacks the carbonyls in spacer A. The
peaks corresponding to hydrogen 10 and 11 in the pyridine of
spacer B are shifted upfield for receptor 4cis with respect to
receptor 5cis (Figure 4b), indicating that the pyridine ring of
All of the conformational studies above-mentioned suggest
that there is an evident correlation between folded
conformations and an enhanced ability of the receptor. Indeed,
the computational study also shed light on the reason for such
correlation: Most of the folded conformers of 1cis and 4cis have
their molecular dipole moment pointing toward the recognition
cavity, while the unfolded conformers, which are preponderant
in the rest of receptors like 2cis, do not show such an
orientation (Figure 3d). It is well-known that the existence of
permanent dipoles within the host is important to explain the
ability of cation receptors. Indeed, Hay et al. have already
pondered the effect of the orientation of the dipole moments of
every single building block in multidentated hosts.18 In our
case, receptors 1cis and 4cis display a considerable set of folded
conformations which, at the same time, have a convergent
orientation of molecular dipole moments, particularly well
arranged for guest binding, and therefore, those receptors are
understandably the best ones.
CONCLUSION
■
In summary, we have examined the conformational effect of
certain structural features on the binding affinity and chiral
discrimination of a synthetic receptor. All of the data indicate a
high relevance of specific moieties that induce the same
conformational restrictions than guest binding. In particular, a
combination of cis stereochemistry and 2,6-dicarbonylpyridine
as spacer A increase the set of folded conformers analogous to
the complex geometry. It was found that folded conformers
display their molecular dipole toward the recognition cavity
which favors guest binding. As mentioned, it can be stated that
the best receptors sample conformations in the free state that
impose similar local restrictions than guest binding. This causes
a mutual reinforcement of conformational sampling and
binding, or in other words, a reinforced molecular recognition,
which has been already confirmed by other means in receptor
1cis and analogous receptors.8,9 Conformational sampling by
the free receptor is known to play a vital role in the catalytic
activity of enzymes,19 allosteric signaling,20 and ligand binding
in proteins.21 Therefore, it is markedly relevant to understand
the correlation between the conformational landscape induced
by structural modifications and the function that finally
emerges, although this is an extremely challenging task.
Model systems based on synthetic receptors such as those
presented herein are useful for shedding light on the
mechanisms by which the dynamics play a role in the
reinforced molecular recognition and catalysis, which is highly
relevant in a number of important fields, including enzymatic
catalysis and drug development.
Figure 4. Experimental evidence of the increased set of folded
conformers in (a) 1cis and (b) 4cis.
the spacer A is close to the pyridine ring of the spacer B,
therefore suggesting a greater role of folded conformers in
receptor 4cis. Analogously, the peak corresponding to hydrogen
10 in receptor 1cis (Figure 4a) is clearly shifted upfield with
respect to the analogous peak of receptor 2cis, implying that the
pyridine of spacer A is on average closer to the oxybis-
(ethanediyl) spacer (spacer B) in receptor 1cis, therefore
suggesting a more relevant role of folded conformers. Indeed,
the X-ray structure of receptor 1cis (Figure 2a)11 unequivocally
shows a folded structure with the 2,6-pyridine dicarbonyl spacer
(spacer A) in the transoid conformation, which might suggest
some influence of a dipole−dipole interaction between the
carbonyls and the pyridine. An intramolecular CH−π
interaction between hydrogen 10 and the pyridine is also
observed, which is probably assisting the folding.16 It is
noteworthy that crystal packing is usually driven by an
improvement of the noncovalent bonding that restricts
dynamic behavior.3
In addition, a careful geometrical analysis of the 1cis·D-Trp-
OMePic complex structure in CDCl3 by NMR14 shows a folded
structure also for the complex. Intramolecular ROEs were
observed (Figure 5a) between protons in position 10 and 10′
with protons 11 and 11′ of the pyridine and cross peak ROE
between pyridine proton 11′ and axial proton 5′. In
combination with the coupling constants of all peaks, a 3D
structure of the complex could be obtained (Figure 5b).17 The
structure of receptor 1cis upon binding in CDCl3 is quite
similar to some of the conformers found in the conformational
search of free receptor 1cis.
EXPERIMENTAL SECTION
■
Materials and General Methods. 1H NMR spectra were
recorded at 500, 400, or 300 MHz, 13C NMR spectra were recorded
at 75 or 100 MHz, and chemical shifts are reported in ppm and
referenced to the solvent peak. The temperature was calibrated with
methanol and ethylene glycol standards. Melting points were taken on
a capillary melting point apparatus and are uncorrected. Optical
rotations were obtained on a polarimeter at 589 nm at 25 °C using a
10 cm path length and a 1.0 mL volume. Concentration (c) is reported
in g per 100 mL of the solvent specified. Infrared (FT-IR) spectra are
reported in wavenumbers (cm−1). Low- and high-resolution mass
spectra were recorded with dual-focusing sector field analyzer mass
spectrometers by using fast atom bombardment (FAB) mode or with
TOF analyzer mass spectrometers by using electrospray ioniazation
(ESI) mode, as specified in each case. Column chromatography was
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Figure 5. (a) 2D ROESY section showing crucial intra- and intermolecular ROEs for complex 1cis·D-Trp-OMePic in CDCl3 at 223 K. (b) 3D
structure of complex 1cis·D-Trp-OMePic in CDCl3.
performed on silica gel, 60 Å and 0.2−0.5 mm. Compounds were
visualized by use of UV light, 2.5% phosphomolybdic acid in ethanol
or vanillin with acetic and sulfuric acid in ethanol with heating. All
solvents were purified by standard techniques.22 Reactions requiring
anhydrous conditions were performed under nitrogen. Anhydrous
magnesium sulfate was used for drying solutions. Compounds
10cis,12,23 10trans,23 11trans,24 17cis,12 and 17trans25 were prepared
as previously described.
Synthesis of 11cis. To a stirred solution of diol 10cis (2.0 g, 15.1
mmol) in dry CH2Cl2 (50 mL) were sequentially added a catalytic
amount of CSA (175 mg, 0.8 mmol) and benzaldehydedimethyl acetal
(3.4 mL, 22.7 mmol) at room temperature. The reaction mixture was
stirred for 2 h, after which time TLC showed complete conversion to
the benzylidene derivative. Then Et3N was added until pH ≈ 7, and
the mixture was stirred for 5 min, evaporated under reduced pressure,
and purified by silica gel flash-chromatography. To a stirred solution of
the benzylidene derivative in dry CH2Cl2 (150 mL) at 0 °C was added
dropwise DIBAL-H (76 mL, 1 M in hexane, 76 mmol). The reaction
mixture was stirred for 30 min, quenched with water (3 mL), and
allowed to warm to room temperature. The mixture was stirred for 30
min, dried over MgSO4, and filtered through a pad of Celite. The
solvent was evaporated, and the residue was purified by silica gel flash
chromatography, yielding 11cis (3.03 g, 90% overall yield) as an oil:
[α]25D = −58.9 (c 2.1, CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ
= 1.35−1.49 (m, 2H), 1.96−2.15 (m, 2H), 2.34 (bs, 1H), 3.40−3.45
(m, 1H), 3.49 (s, 1H), 3.55 (dd, J = 4.2, 11.5 Hz, 1H), 3.84 (dd, J =
7.1, 11.5 Hz, 1H), 4.03 (m, 1H), 4.37 (d, J = 12.0 Hz, 1H), 4.65 (d, J =
12.0 Hz, 1H), 7.30 (m, 5H); 13C NMR (75 MHz, CDCl3, 298 K) δ =
20.7 (t), 25.8 (t), 63.5 (t), 68.0 (t), 70.6 (t), 71.9 (d), 79.5 (d), 127.7
(d), 127.9 (d), 128.4 (d), 138.2 (s), 170.1 (s); IR (film, NaCl plates)
G
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(cm−1) 3431, 2932, 2945, 2852, 1455, 1209, 1099; LRMS (FAB) m/ z
(relative intensity) 245 [M + Na]+ (16), 223 [M + H]+ (43), 91
(100); HRMS (FAB) m/ z calcd for C13H18O3Na [M+ + Na]
245.1154, found 245.1150.
chromatography on silica gel, to yield the receptor 1cis (72 mg, 45%
1
yield) as an oil: [α]25D = −18.6 (c 1.6, CHCl3); H NMR (300 MHz,
CDCl3, 298 K) δ = 1.50 (d, J = 13.1 Hz, 2H), 1.89 (m, 2H), 2.04 (m,
2H), 2.22 (d, J = 13.6 Hz, 2H), 3.28−3.32 (m, 4H), 3.51−3.74 (m,
12H), 4.05 (d, J = 11.9 Hz, 2H), 5.27 (s, 2H), 7.97 (dd, J = 7.5, 7.5 Hz,
1H), 8.22 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3, 298 K) δ =
21.0 (t), 27.4 (t), 67.6 (t), 69.3 (d), 70.3 (t), 76.6 (d), 127.4 (d), 137.9
(d), 148.8 (s), 164.2 (s); IR (film, NaCl plates) (cm−1) 2950, 2858,
1719, 1451, 1349, 1246, 1145, 1092; LRMS (FAB) m/z (relative
intensity) 488 [M + Na]+ (48), 307 (24), 137 (69), 69 (24); HRMS
(FAB) m/z calcd for C23H31NO9Na [M + Na]+ 488.1897, found
488.1896.
Synthesis of 1trans. The same procedure than the one followed
for the synthesis of 1cis was applied to the diol 15trans (200 mg, 0.6
mmol) to obtain 1trans (128 mg, 46% yield) as a solid: mp 110−112
°C; [α]25D = +51.5 (c 1.7, CHCl3); 1H NMR (300 MHz, CDCl3, 298
K) δ = 1.68−1.84 (m, 6H), 2.35 (m, 2H), 3.34 (m, 4H), 3.45 (ddd, J =
2.3, 11.7, 11.7 Hz, 2H), 3.57 (dd, J = 5.3, 5.3 Hz, 4H), 3.61−3.68 (m,
6H), 4.02 (m, 2H), 5.06 (m, 2H), 7.98 (dd, J = 7.5, 7.5 Hz, 1H), 8.21
(d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 25.2 (t),
29.3 (t), 68.1 (t), 70.6 (t), 71.7 (d), 72.0 (t), 78.1 (d), 127.6 (d), 138.0
(d), 148.7 (s), 163.8 (s); IR (film, NaCl plates) (cm−1) 2949, 2866,
1721, 1454, 1242, 1147, 1099; LRMS (FAB) m/z (relative intensity)
504 [M + K]+ (6), 488 [M + Na]+ (10), 466 [M + H]+ (18), 219 (3),
168 (4); HRMS (FAB) m/z calcd for C23H32NO9 [M + H]+ 466.2077,
found 466.2080.
Synthesis of 2cis. To a solution of diol 15cis (110 mg, 0.33 mmol)
and 2,6-bis(bromomethyl) pyridine (87 mg, 0.33 mmol) in dry THF
(6.6 mL) under nitrogen was added NaH (29 mg, 0.72 mmol, 60% oil
dispersion) at room temperature. The reaction mixture was stirred and
refluxed for 5 h. Then it was diluted with Et2O, washed with an
aqueous saturated NH4Cl solution, dried over MgSO4, and filtered,
and the solvent was removed and purified by silica gel flash
chromatography, yielding receptor 2cis as a white solid (50 mg, 35%
yield): mp 50−52 °C; [α]25D = −95.1 (c 0.8, CHCl3); 1H NMR (300
MHz, CDCl3, 298 K) δ = 1.41 (d, J = 13.4 Hz, 2H), 1.54 (m, 2H),
2.07 (m, 2H), 2.17 (d, J = 13.8 Hz, 2H), 3.47−3.71 (m, 18H), 4.03
(m, 2H), 4.59 (d, J = 13.2 Hz, 2H), 4.82 (d, J = 13.2 Hz, 2H), 7.31 (d,
J = 7.7 Hz, 2H), 7.66 (dd, J = 7.6, 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3, 298 K) δ = 20.9 (t), 26.1 (t), 68.2 (t), 70.4 (t), 70.5 (t), 70.8
(t), 71.0 (d), 71.7 (t), 77.9 (d), 120.9 (d), 158.0 (s); IR (film, NaCl
plates) (cm−1) 2922, 2854, 1592, 1456, 1276, 1101; LRMS (FAB) m/z
(relative intensity) 460 [M + Na]+ (22), 438 [M + H]+ (20), 137 (74),
69 (35); HRMS (FAB) m/z calcd for C23H36NO7 [M + H]+ 438.2496,
found 438.2492.
Synthesis of 13cis. To a stirred solution of the alcohol 11cis (2.0
g, 9.0 mmol) and diethylene glycol ditosylate (1.87 g, 4.5 mmol) in dry
THF (59 mL) under nitrogen was added NaH was added (396 mg, 9.9
mmol, 60% oil dispersion) at room temperature. The mixture was
stirred at reflux for 7 h. Then, the reaction mixture was cooled to room
temperature and diluted with Et2O. The mixture was washed with an
aqueous saturated NH4Cl solution and then dried, filtered,
concentrated, and purified by silica gel flash chromatography, yielding
the benzyl ether 13cis (1.97 g, 85% yield) as an oil: [α]25D = −51.0 (c
1
1.3, CHCl3); H NMR (400 MHz, CDCl3, 298 K) δ = 1.34 (d, J =
13.4 Hz, 2H), 1.44 (m, 2H), 1.97 (m, 2H), 2.08 (d, J = 13.9 Hz, 2H),
3.43−3.62 (m, 18H), 3.98 (m, 2H), 4.39 (d, J = 12.1 Hz, 2H), 4.62 (d,
J = 12.1 Hz, 2H), 7.21−7.32 (m, 10H); 13C NMR (100 MHz, CDCl3,
298 K) δ = 20.6 (t), 25.9 (t), 67.9 (t), 70.3 (t), 70.6 (t), 70.8 (t), 71.3
(d), 71.5 (t), 78.4 (d), 127.4 (d), 127.8 (d), 128.2 (d), 138.5 (s); IR
(film, NaCl plates) (cm−1) 2943, 2858, 1455, 1213, 1100; LRMS
(FAB) m/z (relative intensity) 553 [M + K]+ (7), 537 [M + Na]+
(76), 515 [M + H]+ (40), 91 (100); HRMS (FAB) m/z calcd for
C30H43O7 [M + H]+ 515.3009, found 515.3009.
Synthesis of 13trans. The same procedure as the one followed for
the synthesis of 13cis was applied to 11trans (2.0 g, 9.0 mmol) to
afford 13trans (2.01 g, 87% yield) as an oil: [α]25 = −55.6 (c 1.3,
D
CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ = 1.33−1.49 (m, 2H),
1.56−1.67 (m, 4H), 2.24 (m, 2H), 3.27−3.40 (m, 6H), 3.63 (m, 10H),
3.76 (m, 2H), 3.92 (d, J = 11.3 Hz, 2H), 4.46 (d, J = 11.6 Hz, 2H),
4.60 (d, J = 11.6 Hz, 2H), 7.25−7.36 (m, 10H); 13C NMR (75 MHz,
CDCl3, 298 K) δ = 25.2 (t), 29.4 (t), 67.8 (t), 70.4 (t), 70.8 (t), 70.9
(t), 71.2 (t), 73.4 (d), 80.4 (d), 127.6 (d), 127.7 (d), 128.3 (d), 138.5
(s); IR (film, NaCl plates) (cm−1) 2937, 2862, 1718, 1456, 1272,
1098; LRMS (FAB) m/z (relative intensity) 537 [M + Na]+ (28), 515
[M + H]+ (15), 136 (17), 91 (100); HRMS (FAB) m/z calcd for
C30H43O7 [M + H]+ 515.3009, found 515.3021.
Synthesis of 15cis. A mixture of the benzyl ether 13cis (1.9 g, 3.7
mmol) and Pd(OH)2 (100 mg) in EtOAc (37 mL) was placed under
H2 atmosphere. The reaction mixture was vigorously stirred until TLC
showed complete conversion. The mixture was filtered through a pad
of Celite. The solvent was removed under reduced pressure and the
residue was purified by silica gel flash chromatography affording 15cis
1
(1.23 g, quantitative) as an oil: [α]25 = −1.2 (c 1.2, CHCl3); H
D
NMR (300 MHz, CDCl3, 298 K) δ = 1.32 (d, J = 12.2 Hz, 2H), 1.58
(m, 2H), 1.89−2.06 (m, 4H), 3.32 (s, 2H), 3.42 (dd, J = 5.1, 5.1 Hz,
4H), 3.55−3.69 (m, 12H), 3.84 (m, 2H), 3.98 (m, 2H); 13C NMR (75
MHz, CDCl3, 298 K) δ = 20.2 (t), 30.2 (t), 65.5 (d), 68.6 (t), 70.4 (t),
70.8 (t), 72.3 (t), 77.9 (d); IR (film, NaCl plates) (cm−1) 3440, 2925,
2860, 1444, 1215, 1091; LRMS (FAB) m/z (relative intensity) 357 [M
+ Na]+ (39), 335 [M + H]+ (61), 55 (100); HRMS (FAB) m/z calcd
for C16H 31O7 [M + H]+ 335.2070, found 335.2054.
Synthesis of 2trans. The same procedure as the one followed for
the synthesis of 2cis was applied to the diol 15trans (100 mg, 0.3
mmol) to obtain 2trans (93 mg, 71% yield) as an oil: [α]25 = +94.8
D
(c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ = 1.41 (dddd, J
= 11.6, 11.6, 11.6, 11.6 Hz, 2H), 1.65 (m, 4H), 2.31 (d, J = 9.3 Hz,
2H), 3.24 (d, J = 9.3 Hz, 2H), 3.31 (m, 2H), 3.43−3.51 (m, 8H), 3.64
(m, 6H), 3.91 (d, J = 10.7 Hz, 2H), 4.59 (d, J = 12.9 Hz, 2H), 4.78 (d,
J = 12.9 Hz, 2H), 7.23 (d, J = 7.7 Hz, 2H), 7.65 (dd, J = 7.7, 7.7 Hz,
1H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 25.2 (t), 29.3 (t), 67.8
(t), 70.2 (t), 70.5 (t), 70.8 (t), 71.7 (t), 72.8 (d), 80.5 (d), 120.6 (d),
136.9 (d), 158.0 (s); IR (film, NaCl plates) (cm−1) 2928, 2859, 1593,
1456, 1276, 1095; LRMS (FAB) m/z (relative intensity) 460 [M +
Na]+ (20), 438 [M + H]+ (74), 437 [M]+ (8), 137 (66); HRMS
(FAB) m/z calcd for C23H36NO7 [M + H]+ 438.2492, found 438.2511.
Synthesis of 3cis. To a stirred solution of the diol 15cis (110 mg,
0.33 mmol) and diethylene glycol ditosylate (136 mg, 0.33 mmol) in
dry THF (6.6 mL, 0.05 M), under nitrogen, was added NaH (29 mg,
0.72 mmol, 60% oil dispersion) at room temperature. The mixture was
stirred at reflux for 7 h. Then, the reaction mixture was cooled to room
temperature and was diluted with Et2O. The mixture was washed with
an aqueous saturated NH4Cl solution and then dried, filtered,
concentrated, and purified by silica gel flash chromatography, yielding
the receptor 3cis as a white solid (66 mg, 50% yield): mp 48−50 °C;
[α]25D = −43.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ
= 1.34 (d, J = 13.4 Hz, 2H), 1.48 (m, 2H), 1.93 (m, 2H), 2.06 (d, J =
Synthesis of 15trans. The same procedure as the one followed for
the synthesis of 15cis was applied to 13trans (1.95 g, 3.8 mmol) to
obtain 15trans (1.27 g, quantitative yield) as an oil: [α]25 = −2.3 (c
D
1.6, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ = 1.43 (dddd, J =
12.4, 12.4, 12.4, 4.9 Hz, 2H), 1.60−1.75 (m, 4H), 2.09 (m, 2H), 3.15
(ddd, J = 3.8, 3.8, 8.9 Hz, 2H), 3.33 (ddd, J = 3.4, 11.3, 11.3 Hz, 2H),
3.56−3.73 (m, 12H), 3.83 (dd, J = 3.5, 11.4 Hz, 2H), 3.91 (m, 2H);
13C NMR (100 MHz, CDCl3, 298 K) δ = 25.4 (t), 31.6 (t), 66.9 (d),
68.0 (t), 70.5 (t), 70.6 (t), 71.8 (t), 81.0 (d)); IR (film, NaCl plates)
(cm−1) 3419, 2927, 2858, 1455, 1282, 1092; LRMS (FAB) m/ z
(relative intensity) 357 [M + Na]+ (38), 335 [M + H]+ (71), 137 (69),
97 (35); HRMS (FAB) m/z calcd for C16H30O 7Na [M + Na]+
357.1889, found 357.1891.
Synthesis of 1cis. To a solution of the diol 15cis (115 mg, 0.34
mmol) in dry CH2Cl2 (7 mL) under nitrogen were added 2,6-
pyridinedicarbonyl dichloride (70 mg, 0.34 mmol) and DMAP (85
mg, 0.69 mmol) at 0 °C. The mixture was stirred for 10 min at 0 °C,
and the reaction was allowed to warm to room temperature. The
solvent was removed under vacuum, and the residue was purified by
H
dx.doi.org/10.1021/jo400683j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
13.9 Hz, 2H), 3.50−3.76 (m, 26H), 3.98 (m, 2H); 13C NMR (100
MHz, CDCl3, 298 K) δ = 20.7 (t), 25.9 (t), 68.1 (t), 68.3 (t), 70.3 (t),
70.6 (t), 71.0 (t), 71.9 (d), 78.0 (d); IR (film, NaCl plates) (cm−1)
2922, 2859, 1461, 1214, 1099; LRMS (FAB) m/z (relative intensity)
427 [M + Na]+ (38), 405 [M + H]+ (44), 91 (100); HRMS (FAB) m/
z calcd for C20H36O8Na [M + Na]+ 427.2308, found 427.2316.
Synthesis of 3trans. The same procedure as the one followed for
the synthesis of 3cis was applied to the diol 15trans (120 mg, 0.36
mmol) to obtain 3trans (78 mg, 54% yield) as an oil: [α]25D = +54.0 (c
1099; LRMS (FAB) m/z (relative intensity) 515.1 [M + H]+ (6);
HRMS (FAB) m/z calcd for C30H43O7 [M + H]+ 515.3009, found
515.2997.
Synthesis of 6cis. A mixture of the benzyl ether 14cis (200 mg,
0.39 mmol) and Pd(OH)2 (15 mg) in EtOAc (37 mL) was placed
under H2 atmosphere. The reaction mixture was vigorously stirred
until TLC showed complete conversion. The mixture was filtered
through a pad of Celite. The solvent was removed under vacuum, and
the crude of the diol 16cis was used in the next step without further
purification. Then a solution of the diol 16cis was treated under the
same conditions as described to obtain receptor 2cis affording receptor
1
1.3, CHCl3); H NMR (400 MHz, CDCl3, 298 K) δ = 1.36 (m, 2H),
1.67 (m, 4H), 2.24 (m, 2H), 3.24 (m, 2H), 3.38 (m, 4H), 3.60−3.78
(m, 20H), 3.94 (m, 2H); 13C NMR (100 MHz, CDCl3, 298 K) δ =
25.3 (t), 29.4 (t), 68.0 (t), 68.7 (t), 70.5 (t), 70.8 (t), 71.0 (t), 73.7
(d), 80.5 (d); IR (film, NaCl plates) (cm−1) 2929, 2863, 1457, 1276,
1097; LRMS (FAB) m/z (relative intensity) 427 [M + Na]+ (17), 405
[M + H]+ (39), 137 (69), 97 (41); HRMS (FAB) m/z calcd for
C20H36O8 [M]+ 404.2410, found 404.2392.
Synthesis of 12cis. To a solution of diol 10cis (27.8 g, 210.6
mmol) in toluene (420 mL, 0.5 M) was added Bu2SnO (68 g, 273.8
mmol) and the solution refluxed in a Dean−Stark overnight. The
reaction mixture was cooled, Bu4NI (101 g, 273.8 mmol) and benzyl
bromide (32.6 mL, 273.8 mmol) were added, and the mixture was
refluxed 4 h. The mixture was cooled to room temperature and filtered
through Celite, the solvent was removed under vacuum, and it was
6cis as a colorless oil (63 mg, 37% yield): [α]25 = −13.5 (c 1.3,
D
CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ = 1.24−1.52 (m, 4H),
1.83−2.04 (m, 4H), 3.27−3.69 (m, 18H), 3.97−4.01 (m, 2H), 4.57 (d,
J = 13.1 Hz, 2H), 4.75 (d, J = 13.1 Hz, 2H), 7.32 (d, J = 7.7 Hz, 2H),
7.69 (dd, J = 7.7, 7.7 Hz, 1 H); 13C NMR (75 MHz, CDCl3, 298 K) δ
= 20.7 (t), 26.0 (t), 68.1 (t), 68.3 (t), 69.7 (t), 70.2 (t), 72.3 (d), 74.3
(t), 78.1 (d), 121.3 (d), 137.2 (d), 157.5 (s); IR (film, NaCl plates)
(cm−1) 2924, 2856, 1724, 1593, 1458, 1213, 1098; LRMS (FAB) m/z
(relative intensity) 460.06 [M + Na]+ (15), 438.1 [M + H]+ (17);
HRMS (FAB) m/z calcd for C23H36NO7 [M + H]+ 438.2496, found
438.2500.
Synthesis of 6trans. The same methodology used to obtain 6cis
was applied to benzyl ether 14trans (180 mg, 0.35 mmol) to obtain
6trans (66 mg, 43% yield as an oil): [α]25D = +15.1 (c 1.3, CHCl3); 1H
NMR (300 MHz, CDCl3, 298 K) δ = 1.25−1.32 (m, 2H), 1.60 (m,
4H), 2.11−2.15 (m, 2H), 3.19−3.71 (m, 18H), 3.85−3.91 (m, 2H),
4.54 (d, J = 13.6 Hz, 2H), 4.66 (d, J = 13.6 Hz, 2H), 7.30 (d, J = 7.8
Hz, 2H), 7.64 (dd, J = 7.5, 7.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3,
298 K) δ = 25.1 (t), 29.2 (t), 67.9 (t), 68.2 (t), 68.6 (t), 69.6 (t), 70.7
(t), 73.9 (d), 74.2 (t), 80.1 (d), 121.1 (d), 136.9 (d), 157.8 (s); IR
(film, NaCl plates) (cm−1) 2933, 2861, 1592, 1459, 1095; LRMS
(FAB) m/z (relative intensity) 438.3 [M + H]+ (6); HRMS (FAB) m/
z calcd for C23H36NO7 [M + H]+ 438.2492, found 438.2540.
Synthesis of 9cis. A solution of the benzyl ether 14cis (190 mg,
0.37 mmol) was treated under the same conditions as described to
purified by silica gel flash chromatography to afford 12cis (27.3 g, 58%
1
yield as an oil): [α]25 = +54.0 (c 1.3, CHCl3); H NMR (300 MHz,
D
CDCl3, 298 K) δ = 1.35−1.40 (m, 1H), 1.62−1.66 (m, 1H), 1.91−
2.02 (m, 2H), 2.77 (s, 1H), 3.46−3.52 (m, 2H), 3.64 (d, J = 4.9 Hz,
2H), 3.83 (s, 1H), 4.03 (ddd, J = 1.8, 3.0, 11.3 Hz, 1H), 4.56 (s, 2H),
7.25−7.38 (m, 5H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 20.0 (t),
30.2 (t), 66.0 (d), 68.6 (t), 71.4 (t), 73.7 (t), 78.2 (d), 127.7 (d), 127.8
(d), 128.3 (d), 137.6 (s); IR (film, NaCl plates) (cm−1) 2929, 2863,
1457, 1276, 1097; LRMS (FAB) m/z (relative intensity) 223.1 [M +
Na]+ (40), 245.1 [M + H]+ (10); HRMS (FAB) m/z calcd for
C13H19O3 [M + H]+ 223.1334, found: 223.1338.
Synthesis of 12trans. The same procedure as the one followed for
the synthesis of 12cis was applied to the diol 10trans (5.0 g, 38.0
obtain receptor 1cis to afford receptor 9cis (69 mg, 40% yield) as a
mmol) to obtain 12trans (8.1 g, 96% yield) as an oil: [α]25 = −80.8
1
colorless oil: [α]25 = −18.6 (c 1.6, CHCl3); H NMR (300 MHz,
D
D
1
(c 1.1, CHCl3); H NMR (400 MHz, CDCl3, 298 K) δ = 1.41 (m,
CDCl3, 298 K) δ = 1.36−1.58 (m, 4H), 1.92−2.10 (m, 4H), 3.48−
4.03 (m, 2H), 4.34 (dd, J = 10.0, 10.0 Hz, 2H), 4.77 (dd, J = 4.6, 9.9
Hz, 2H), 7.99 (dd, J = 7.7, 7.7 Hz, 1H), 8.29 (d, J = 7.7 Hz, 2 H); 13C
NMR (75 MHz, CDCl3, 298 K) δ = 20.8 (t), 25.8 (t), 62.8 (t), 68.1
(t), 68.4 (t), 69.7 (t), 70.8 (d), 75.4 (d), 128.0 (d), 138.0 (d), 148.3
(s), 165.0 (s); IR (film, NaCl plates) (cm−1) 2924, 2853, 1723, 1641,
1343, 1142, 1095; LRMS (FAB) m/z (relative intensity) 504.09 [M +
K]+ (6), 488.15 [M + Na]+ (7), 466.2 [M + H]+ (9); HRMS (FAB)
m/z calcd for C23H32NO9 [M + H]+ 466.2077, found 466.2068.
Synthesis of 9trans. The same methodology used to obtain 9cis
was applied to the benzyl ether 14trans (180 mg, 0.35 mmol) to
1H), 1.67 (m, 2H), 2.11 (m, 1H), 2.77 (s, 1H), 2.85 (d, J = 3.0 Hz,
1H), 3.27 (m, 1H), 3.35 (m, 1H), 3.56 (m, 1H), 3.67 (dd, J = 5.5, 9.8
Hz, 1H), 3.72 (dd, J = 5.0, 9.8 Hz, 1H), 3.92 (m, 1H), 4.57 (d, J = 12.1
Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 7.25−7.39 (m, 5H); 13C NMR
(100 MHz, CDCl3, 298 K) δ = 25.5 (t), 32.5 (t), 68.1 (t), 69.5 (d),
72.2 (t), 74.1 (t), 80.2 (d), 128.2 (d), 128.9 (d), 138.1 (s); LRMS
(FAB) m/z (relative intensity) 223.1 [M + H]+ (11), 136.0 (91), 91.1
(44); HRMS (FAB) m/z calcd for C13H19O3 [M + H]+ 223.1334,
found 223.1344.
Synthesis of 14cis. The same procedure as the one followed for
obtain 9trans (70 mg, 43% yield) as a solid: [α]25 = +12.7 (c 0.9,
the synthesis of 13cis was applied to alcohol 12cis (2.0 g, 9.0 mmol) to
D
obtain 14cis (1.88 g, 81% yield) as an oil: [α]25 = −51.0 (c 1.3,
CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ = 1.32−1.42 (m, 2H),
1.64−1.68 (m, 4H), 2.25−2.29 (m, 2H), 3.34−3.43 (m, 4H), 3.49−
3.56 (m, 2H), 3.59−3.71 (m, 6H), 3.77−3.82 (m, 2H), 3.92 (m, 1H),
3.95 (m, 1H), 4.58 (dd, J = 2.7, 11.7 Hz, 2H), 4.84 (dd, J = 2.7, 11.7
Hz, 2H), 7.97 (dd, J = 7.8, 7.8 Hz, 1H), 8.25 (d, J = 7.8 Hz, 2 H); 13C
NMR (400 MHz, CDCl3, 298 K) δ = 25.1 (t), 29.2 (t), 64.8 (t), 68.0
(t), 68.2 (t), 70.0 (t), 73.8 (d), 79.2 (d), 104.2 (s), 116.4 (s), 127.6
(d), 137.8 (d); IR (film, NaCl plates) (cm−1) 1725, 1601, 1322, 1144,
1100; HRMS (ESI) m/z calcd for C23H31NO9Na [M + Na]+
488.1897, found 488.1902.
D
CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ = 1.31−1.46 (m, 4H),
2.03−2.09 (m, 4H), 3.41−3.67 (m, 18H), 3.98 (m, 2H), 4.49 (dd, J =
3.0, 12.1 Hz, 2H), 4.60 (dd, J = 3.0, 12.1 Hz, 2H), 7.25−7.33 (m,
10H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 20.7 (t), 26.2 (t), 68.0
(t), 68.6 (t), 70.4 (t), 70.7 (t), 72.9 (d), 73.4 (t), 78.4 (d), 127.5 (d),
127.7 (d), 128.3 (d), 138.3 (s); IR (film, NaCl plates) (cm−1) 2928,
2858, 1720, 1274, 1095; LRMS (FAB) m/z (relative intensity) 537.3
[M + Na]+ (27), 515.3 [M + H]+ (13); HRMS (FAB) m/z calcd for
C30H43O7 [M + H]+ 515.3009, found 515.3009.
Synthesis of 14trans. The same methodology used to obtain
Synthesis of 18cis. Alcohol 17cis (1.2 g, 4.87 mmol) was
dissolved in dry THF (45 mL, 0.1 M). 2,6-Bis(bromomethyl)pyridine
(430 mg, 1.62 mmol) was added along with a catalytic amount of
NBu4I. The reaction mixture was stirred and cooled to 0 °C. NaH
(60%, 215 mg, 5.35 mmol) was then added.The mixture was allowed
to sit at room temperature overnight. Water was added and the
mixture extracted with AcOEt (3 × 30 mL). The organic phases were
collected and dried over MgSO4, the solvent was removed under
vacuum, and the crude was used in the next step without further
purification. To a solution of the mentioned crude in dry THF (8 mL,
14cis was applied to alcohol 12trans (2.0 g, 9.0 mmol) to obtain
14trans (1.92 g, 83% yield) as an oil: [α]25 = +23.7 (c 1.3, CHCl3);
D
1H NMR (300 MHz, CDCl3, 298 K) δ = 1.25−1.43 (m, 2H), 1.65−
1.69 (m, 4H), 2.03−2.07 (m, 2H), 3.25−3.48 (m, 12H), 3.64−3.73
(m, 6H), 3.92−3.96 (m, 2H), 4.54 (dd, J = 2.3, 12.3 Hz, 2H), 4.61
(dd, J = 2.3, 12.3 Hz, 2H), 7.22−7.36 (m, 10H); 13C NMR (75 MHz,
CDCl3, 298 K) δ = 25.2 (t), 29.4 (t), 67.8 (t), 68.3 (t), 69.9 (t), 70.7
(t), 73.5 (t), 74.3 (d), 80.4 (d), 127.4 (d), 127.8 (d), 128.2 (d), 138.4
(s); IR (film, NaCl plates) (cm−1) 2936, 2861, 1721, 1454, 1278,
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0.2 M) was added NBu4F (1 M in THF, 2.1 mL, 2.1 mmol). After 5 h,
water was added (10 mL) and the mixture extracted with AcOEt (3 ×
5 mL). The combined organic phases were dried over MgSO4, the
solvent was removed under vacuum, and the residue was purified by
(d, J = 13.4 Hz, 4H), 7.04 (d, J = 7.7 Hz, 2H), 7.09 (d, J = 7.7 Hz,
2H), 7.44 (dd, J = 7.7, 7.7 Hz, 1H), 7.54 (dd, J = 7.7, 7.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3, 298 K) δ = 20.7 (t), 25.8 (t), 68.2 (t), 69.1
(t), 70.6 (d), 71.5 (t), 73.8 (t), 77.9 (d), 120.6 (d), 120.6 (d), 136.4
(d), 136.7 (d), 157.5 (s), 157.6 (s); IR (film, NaCl plates) (cm−1)
2925, 2854, 1594, 1452, 1102; LRMS (FAB) m/z (relative intensity)
493 [M + Na]+ (54), 471 [M + H]+ (100), 307 (7.5), 137 (37), 69
(41.3); HRMS (FAB) m/z calcd for C26H35N2O6 [M + H]+ 471.2495,
found 471.2513.
silica gel flash chromatography to afford 18cis (506 mg, 85% overall
1
yield) as an oil: [α]25 = +1.6 (c 0.9, CHCl3); H NMR (300 MHz,
D
CDCl3, 298 K) δ = 1.36−1.46 (m, 2H), 1.54−1.64 (m, 4H), 1.90−
1.97 (m, 2H), 3.27−3.30 (m, 2H), 3.48−3.52 (m, 2H), 3.63−3.68 (m,
4H), 3.85 (s, 2H), 3.97 (dd, J = 3.4, 8.4 Hz 2H), 4.59 (d, J = 13.6 Hz,
1H), 4.64 (d, J = 13.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.64 (dd, J =
7.6, 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 24.1 (t),
30.1 (t), 65.2 (d), 68.5 (t), 71.6 (t) 73.6 (t), 78.0 (d), 120.5 (d), 137.5
(d), 157.4 (s); IR (film, NaCl plates) (cm−1) 3372, 2941, 2874, 1461,
1881; LRMS (FAB) m/z (relative intensity) 368 [M + H]+ (5.3), 242
(100), 184 (8.4), 142 (12.9); HRMS (FAB) m/z calcd for C19H30NO6
[M + H]+ 368.2073, found 368.2068.
Synthesis of 5trans. The same methodology used to obtain 5cis
was applied to diol 18trans (190 mg, 0.52 mmol) to obtain 5trans (73
1
mg, 30% yield) as an oil: [α]25 = −10.7 (c 0.9, CHCl3); H NMR
D
(300 MHz, CDCl3, 298 K) δ = 1.36−1.49 (m, 2H), 1.68−1.70 (m,
4H), 2.32−2.37 (m, 2H), 3.32 (ddd, J = 2.7, 9.3, 9.3 Hz, 2H), 3.37−
3.43 (m, 2H), 3.51 (ddd, J = 4.5, 9.3, 9.3 Hz, 2H), 3.70 (d, J = 2.7 Hz,
4H), 3.98 (d, J = 10,6 Hz, 2H), 4.36 (d, J = 12.8 Hz, 2H), 4.41 (d, J =
12.8 Hz, 2H), 4.66 (dd, J = 11.0, 11.0 Hz, 4H), 6.99 (d, J = 7.7 Hz,
2H), 7.13 (d, J = 7.7 Hz, 2H), 7.48 (dd, J = 7.6, 7.6 Hz, 1H), 7.53 (dd,
J = 7.6, 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 25.2 (t),
29.1 (t), 68.2 (t), 69.2 (t), 71.2 (t), 72.4 (d), 73.9 (t), 80.1 (d), 120.5
(d), 120.7 (d), 136.7 (d), 157.5 (s), 157.6 (s); IR (film, NaCl plates)
(cm−1) 2932, 2868, 1634, 1076; LRMS (FAB) m/z (relative intensity)
493 [M + Na]+ (11.2), 471 [M + H]+ (80.16), 307 (44.2), 136 (70.5),
69 (51.9); HRMS (FAB) m/z calcd for C26H35N2O6 [M + H]+
471.2495, found 471.2513.
Synthesis of 18trans. The same methodology used to obtain
18cis was applied to alcohol 17trans (2.0 g, 8.1 mmol) to obtain
18trans (0.9 g, 60% overall yield) as an oil: [α]25 = −11.2 (c 1.1,
D
CHCl3); 1H NMR (300 MHz, CDCl3, 298 K) δ = 1.47 (dddd, J = 5.1,
11.7, 11.7, 11.7 Hz, 2H), 1.63−1.69 (m, 4H), 2.07−2.13 (m, 2H),
3.17−3.21 (m, 2H), 3.36 (ddd, J = 3.5, 10.1, 10.1 Hz, 2H), 3.72−3.82
(m, 4H), 3.89−3.94 (m, 2H), 4.02 (dd, J = 3.1, 10.1, 10.1 Hz, 2H),
4.67 (d, J = 13.2 Hz, 4H), 7.20 (d, J = 7.7 Hz, 2H), 7.68 (dd, J = 7.7,
7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3, 298 K) δ = 25.6 (t), 31.5
(t), 66.0 (d), 68.3 (t), 71.2 (t), 72.3 (t), 81.7 (d), 121.7 (d), 138.1 (d),
151.7 (s); IR (film, NaCl plates) (cm−1) 3428, 2939, 2860, 1643,
1039; LRMS (FAB) m/z (relative intensity) 390 [M + Na]+ (80.3),
368 [M + H]+ (100), 242 (35.5), 186 (12.7), 133 (6.8); HRMS (FAB)
m/z calcd for C19H30NO6 [M + H]+ 368.2073, found 368.2056.
Synthesis of 4cis. Starting from the diol 18cis (200 mg, 0.54
mmol), the same methodology used to obtain receptor 1cis was
employed to yield receptor 4cis as a colorless oil (95 mg, 35% yield):
[α]25D = −25.0 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ
= 1.49−1.52 (m, 2H), 1.83−1.90 (m, 2H), 2.00−2.15 (m, 4H), 3.58−
3.77 (m, 8H), 4.10−4.13 (m, 2H), 4.43 (d, J = 12.9 Hz, 2H), 4.52 (d, J
= 12.9 Hz, 2H), 6.85 (d, J = 7.7 Hz, 2H), 7.01 (dd, J = 7.8, 7.8 Hz,
1H), 7.91 (dd, J = 7.8, 7.8 Hz, 1 H), 8.2 (d, J = 7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 298 K) δ = 20.9 (t), 27.6 (t), 68.1 (t), 68.9 (d),
69.1 (t), 74.0 (t), 76.4 (d), 120.0 (d), 127.7 (d), 136.1 (d), 137.6 (d),
148.1 (s), 156.5 (s), 163.4 (s); LRMS (FAB) m/z (relative intensity)
536.91 [M + K]+ (18), 521 [M + Na]+ (18), 499.04 [M + H]+ (100);
HRMS (FAB) m/z calcd for C26H31N2O8 [M + H]+ 499.2080, found
499.2104.
Synthesis of 8cis. Diol 10cis (460 mg, 3.5 mmol) was dissolved in
dry CH2Cl2 (20 mL, 0.175 M), and imidazole (476 mg, 7 mmol) and
triisopropylsilyl chloride (0.82 mL, 3.8 mmol) were added. The
reaction mixture was evaporated onto silica gel and passed through a
short pad of silica using a mixture of 20% hexane in ethyl acetate as
eluent to yield quantitatively (1.02 g) the protected diol 19cis, which
was subsequently dissolved in dry THF (70 mL, 0.05M). Then 2,6-
bis(bromomethyl) pyridine (470 mg, 1.77 mmol) and a catalytic
amount of tetrabutylammonium iodide (129 mg, 0.35 mmol) were
added. Finally, NaH (280 mg, 7 mmol, 60% oil dispersion) was added
and the reaction mixture allowed to stir overnight. Water was added
and the mixture extracted with AcOEt (3 × 30 mL). The organic
phases were collected and dried over MgSO4, the solvent was removed
under vacuum, and the crude was used in the next step without further
purification. To a solution of the mentioned crude in dry THF (18
mL, 0.1 M) was added NBu4F (1 M in THF, 3.9 mL, 2.1 mmol).
Water was added after 5 h (10 mL) and the mixture extracted with
AcOEt (3 × 5 mL). The combined organic phases were dried over
MgSO4,and the solvent was removed under vacuum and the mixture
purified by silica gel flash chromatography affording 20cis (570 mg,
89% overall yield). Then starting from the diol 20cis (200 mg, 0.54
mmol), the same methodology used to obtain receptor 1cis was
employed to yield receptor 8cis as a colorless oil (113 mg, 42% yield):
[α]25D = +42.3 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ
= 1.41−1.51 (m, 2H), 1.56−1.61 (m, 2H), 1.95−2.01 (m, 2H), 2.18−
2.22 (m, 2H), 3.51 (ddd, J = 2.4, 14.0, 14.0 Hz, 2H), 3.59−3.63 (m,
2H), 3.63−3.66 (m, 2H), 4.03−4.07 (m, 2H), 4.24−4.26 (m, 4H),
4.50 (d, J = 13.0, 2H), 4.75 (d, J = 13.0 Hz, 2H), 7.29 (m, 2H), 7. 39−
7.41 (m, 3H), 7.71 (dd, J = 7.0, 7.0 Hz, 1H) ; 13C NMR (100 MHz,
CDCl3, 298 K) δ = 20.1 (t), 20.6 (t), 25.2 (t), 26.1 (t), 52.3 (t), 63.5
(t), 67.3 (t), 68.1 (t), 68.2 (t), 68.5 (t), 73.5 (d), 76.0 (d), 123.8 (d),
128.1 (d), 138.5 (d), 144.1 (d), 147.8 (s), 154.4 (s), 164.2 (s); IR
(film, NaCl plates) (cm−1) 2941, 2874, 1724, 1594, 1459, 1342, 1317,
1243, 1142, 1097; HRMS (ESI) m/z calcd for C26H30N2O8Na [M +
Na]+ 521.1900, found 521.1888.
Synthesis of 4trans. The same methodology used to obtain 4cis
was applied to diol 18trans (200 mg, 0.54 mmol) to obtain 4trans
1
(100 mg, 37% yield) as an oil: [α]25 = +16.9 (c 1.1, CHCl3); H
D
NMR (400 MHz, CDCl3, 298 K) δ = 1.66−1.90 (m, 6H), 2.26−2.30
(m, 2H), 3.46 (ddd, J = 2.2, 11.7, 11.7 Hz, 2H), 3.58−3.63 (m, 4H),
3.72−3.76 (m, 2H), 4.01−4.05 (m, 2H), 4.44 (d, J = 13.0 Hz, 2H),
4.56 (d, J = 13.0 Hz, 2H), 5.12 (m, 2H), 6.74 (m, 3H), 7.92 (dd, J =
7.8, 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3, 298 K) δ = 25.2 (t), 29.3 (t), 68.2 (t), 70.0 (t), 70.96 (d), 73.9
(t), 78.0 (d), 119.7 (d), 127.6 (d), 135.8 (d), 137.5 (d), 148.3 (s),
156.8 (s), 163.1 (s); IR (film, NaCl plates) (cm−1) 2924, 2853, 1727,
1712, 1367, 1168; HRMS (ESI) m/z calcd for C26H30N2O8Na [M +
Na]+ 521.1900, found 521.1909.
Synthesis of 5cis. Diol 18cis (67 mg, 0.18 mmol) was dissolved in
dry THF (3.6 mL, 0.05M), and 2,6-bis(bromomethyl)pyridine (48
mg, 0.18 mmol) was added along with a catalytic amount of NBu4I.
The reaction mixture was cooled to 0 °C, and NaH (60%, 18 mg, 0.45
mmol) was added. The mixture was allowed to sit overnight at room
temperature, water was added (5 mL), and the mixture was extracted
with AcOEt (3 × 5 mL). The combined organic phase were dried over
MgSO4, and the solvent was removed under vacuum and purified by
silica gel flash chromatography to afford the receptor 5cis (26 mg, 30%
Synthesis of 8trans. Starting from alcohol 10trans (500 mg, 3.8
mmol), the same methodology used to obtain 8cis was employed to
yield receptor 8trans (72 mg, 38% overall yield) as an oil: [α]25
=
D
+57.8 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K) δ = 1.40−
1.45 (m, 2H), 1.68−1.72 (m, 4H), 2.03−2.05 (m, 2H), 3.37−3.41 (m,
2H), 3.54−3.56 (m, 2H), 3.61−3.65 (m, 2H), 3.92−4.01 (m, 2H),
4.48 (dd, J = 3.6, 11.6 Hz, 2H), 4.68 (d, J = 13.2 Hz, 2H), 4.75 (d, J =
13.2 Hz, 2H), 4.79 (dd, J = 3.6, 11.6 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H),
7.25 (dd, J = 8.0, 8.0 Hz, 1H), 7.85 (dd, J = 8.0, 8.0 Hz, 1H), 8.07 (d, J
= 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, 298 K) δ = 25.1 (t), 25.3
yield) as a colorless oil: [α]25 = +1.6 (c 0.9, CHCl3); 1H NMR (400
D
MHz, CDCl3, 298 K) δ = 1.38 (d, J = 13.4 Hz, 2H), 1.49−1.57 (m,
2H), 1.98−2.05 (m, 2H), 2.16 (d, J = 13.9 Hz, 2H), 3.49−3.62 (m,
10H), 4.02 (dd, J = 3.3, 8.4 Hz, 2H), 4.37 (d, J = 13.4 Hz, 4H), 4.66
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(t), 32.0 (t), 66.2 (t), 67.4 (t), 67.9 (t), 76.7 (d), 79.7 (d), 128.3 (d),
138.6 (d), 147.7 (s), 147.8 (s), 163.9 (s); IR (film, NaCl plates)
(cm−1) 2939, 2877, 1726, 1595, 1341.9, 1243.4, 1143, 1099; HRMS
(ESI) m/z calcd for C26H30N2O8Na [M + Na]+ 521.1900, found
521.1888.
(6) (a) Schneider, H.-J.; Guttes, D.; Schneider, U. J. Am. Chem. Soc.
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1988, 110, 6449−6454. (b) Timmerman, P.; Verboom, W.;
Reinhoudt, D. N. Tetrahedron 1996, 52, 2663−2704. (c) Botta, B.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
(8) Carrillo, R.; Feher-Voelger, A.; Martín, T. Angew. Chem., Int. Ed.
2011, 50, 10616−10620.
1H and 13C NMR spectra, UV titration parameters, bidimen-
sional NMR experiments, and computational details are given.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Carrillo, R.; Morales, E. Q.; Martín, V. S.; Martín, T. Chem.Eur.
J. 2013, 19, 7042−7048.
(10) Williams, D. H.; Stephens, E.; Zhou, M. Chem. Commun. 2003,
1973−1976.
́
(11) Carrillo, R.; Lopez-Rodríguez, M.; Martín, V. S.; Martín, T.
AUTHOR INFORMATION
Corresponding Author
*E-mail: (R.C.) rcarrillo@ipna.csic.es, (T.M.) tmartin@ipna.
csic.es.
■
Angew. Chem., Int. Ed. 2009, 48, 7803−7808.
(12) (a) Carrillo, R.; Martín, V. S.; Martín, T. Tetrahedron Lett. 2004,
45, 5215−5219. (b) Carrillo, R.; Martín, V. S.; Lop
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Tetrahedron 2005, 61, 8177−8191.
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792−795. (b) Geib, S. J.; Hirst, S. C.; Vincent, C.; Hamilton, A. D. J.
Chem. Soc., Chem. Commun. 1991, 1283−1285.
Notes
The authors declare no competing financial interest.
(14) See the Supporting Information.
ACKNOWLEDGMENTS
■
(15) Kolossvar
5019.
́
y, I.; Guida, W. C. J. Am. Chem. Soc. 1996, 118, 5011−
This research was supported by the Spanish MINECO,
cofinanced by the European Regional Development Fund
(ERDF) (CTQ2011-22653 and CTQ2011-28417-C02-01).
(16) (a) Takahashi, O.; Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110,
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(17) For a more detailed NMR analysis see ref 11.
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