Cyclotriveratrylene-BINOL-Based Host Compounds: Synthesis, Absolute Configuration Assignment, and Recognition Properties

Article abstract of DOI:10.1021/acs.joc.6b00159

New host compounds combining a cyclotriveratrylene (CTV) unit and three binaphthol moieties have been synthesized enantiomerically and diastereomerically pure. The use of a chemical correlation allows for the assignment of their absolute configuration. The energy barrier of epimerization was measured, suggesting that no intramolecular hydrogen bonding occurs between the hydroxyl groups of the binaphthols. These open-shell host compounds were then tested in the recognition of carbohydrates; a preferential binding of mannose toward glucose was observed, and good diastereoselectivities were reached (up to 1:10). This recognition of sugar derivatives by open-shell CTV-based host compounds is unprecedented and opens up the way for a wider use of this easily accessible class of molecules as chiral sensors.

Full text of DOI:10.1021/acs.joc.6b00159

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Article
Cyclotriveratrylene-BINOL based host compounds: synthesis,
absolute configuration assignment and recognition properties
Sara Lefevre, Alexandre Héloin, Delphine Pitrat, Jean-Christophe Mulatier, Nicolas
Vanthuyne, Marion Jean, Jean-Pierre Dutasta, Laure Guy, and Alexandre Martinez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00159 • Publication Date (Web): 24 Mar 2016
Downloaded from http://pubs.acs.org on March 28, 2016
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Cyclotriveratrylene-BINOL based host compounds: synthesis, absolute
configuration assignment and recognition properties
‡
‡
‡
‡
Sara Lefevre , Alexandre Héloin , Delphine Pitrat , Jean-Christophe Mulatier , Nicolas
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†
†
,‡
,‡
,†
Vanthuyne , Marion Jean , Jean-Pierre Dutasta* , Laure Guy* and Alexandre Martinez*
†
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313
13397, Marseille, France
Eꢀmail: alexandre.martinez@centraleꢀmarseille.fr
‡
Laboratoire de Chimie
École Normale Supérieure de Lyon, CNRS, UCBL
4
6, Allée d'Italie, Fꢀ69364 Lyon, France
Laure.guy@ensꢀlyon.fr, jeanꢀpierre.dutasta@ensꢀlyon.fr
ꢀε
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4
2
00
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CTVBINOHRdia1
P-RRR-1
Selective
M SS-1
CTVB-SINOHSdia1
complexation
1
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λ (nm)
-
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400
Abstract. New host compounds combining a cyclotriveratrylene (CTV) unit and three binaphthol
moieties have been synthesized enantiomerically and diastereomerically pure. The use of a chemical
correlation allows for the assignment of their absolute configuration. The energy barrier of
epimerization was measured, suggesting that no intramolecular hydrogen bonding occurs between the
hydroxyl groups of the binaphthols. These openꢀshell host compounds were then tested in the
recognition of carbohydrates; a preferential binding of mannose toward glucose was observed and
good diastereoselectivities were reached (up to 1:10). This recognition of sugar derivatives by openꢀ
shell CTVꢀbased host compounds is unprecedented and opens up the way for a wider use of this easy
accessible class of molecules as chiral sensors.
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Introduction
The design of chiral molecular hosts is very attractive, since they can be used for the stereoselective
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recognition of chiral guest molecules or in asymmetric catalysis. Two main approaches have been
chosen to obtain chiral receptors: (i) the introduction of chiral units or (ii) the inherent chirality of the
host due to its bowl shape scaffold. Among the cage compounds presenting inherent chirality, those
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based on the cyclotriveratrylene (CTV) unit have recently received a growing interest.
They are
composed of two main classes: the cryptophanes and the hemicryptophanes. Cryptophanes containing
two CTV units have found applications in the chiral discrimination of racemic mixtures of small
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molecules like epoxides or the small halogenoalkane CHFClBr.
combine a CTV moiety with another C symmetrical unit and display chiral recognition properties
towards molecules of biological interest like neurotransmitters and carbohydrates.
The related hemicryptophanes
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Although the
efficiency and selectivity of these two classes of cage compounds were demonstrated, their quite
complex and low yield syntheses raise the question about the potential applications of such
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sophisticated structures.
Thus, we decided to investigate the chiral recognition properties of “openꢀ
shell” enantiopure CTV units: their synthesis avoids the macrocyclization step, and therefore should
be easier and shorter. However, such hosts are expected to be more flexible and less preꢀorganized
than their cage counterparts and thus supposed to be less efficient and selective. Indeed openꢀshell
CTV based host compound have been reported to complex ionic molecules such as choline, but with
low binding constant and moderate selectivity; furthermore, the complexation of neutral molecules in
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solution has been rarely described with this kind of molecules.
Thus, in order to maintain both a
good affinity and selectivity in the recognition processes we decided to balance this lack of rigidity
and preꢀorganization by combining in a unique molecule the axial chirality of a binaphthol unit with
the helicity of the CTV. We anticipate that the unprecedented association of these two chiral units will
compensate the lower efficiency and selectivity expected from an open structure, when compared to
the closed one. Here, we report on the synthesis of openꢀshell host molecules containing both a CTV
unit and three binaphthol moieties. These compounds were obtained enantiomerically and
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diastereomerically pure and their absolute configurations were assigned thanks to a chemical
correlation. The new host molecules exhibit selective recognition toward carbohydrates.
Results and discussion
Synthesis
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Figure 1. Structure of hemicryptophanes MꢀSSSꢀ1, PꢀRRRꢀ1, MꢀRRRꢀ1 and PꢀSSSꢀ1
The strategy used to synthesize compounds MꢀSSSꢀ1, PꢀRRRꢀ1, MꢀRRRꢀ1 and PꢀSSSꢀ1 presented in
Figure 1 is based on the CTV precursor 3 (Scheme 1). Compound 3 was prepared according to a
previously reported two steps procedure: reaction between vanillic alcohol and dibromoethane affords
compound 2 and the subsequent cyclization with scandium triflate in CH CN gives CTV racꢀ3 in 18
3
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2
% overall yield. Monoꢀprotection of the enantiopure Sꢀbinaphthol by an allyl group provides
compound Sꢀ4, which then reacts with CTV racꢀ3 to give a mixture of the two diastereomers MꢀSSSꢀ5
and PꢀSSSꢀ5 (the two stereoisomers MꢀRRRꢀ5, PꢀRRRꢀ5, were similarly obtained starting from Rꢀ
binaphthol). Their separation reveals difficult and we were not able to isolate stereoisomerically pure
compounds. Thus we decided to first deprotect the allyl group using triphenylphosphine and palladium
acetate, and then to separate the resulting diastereomers MꢀSSSꢀ1 and PꢀSSSꢀ1 (Scheme 1). This
strategy turned out to be successful, leading to an easier separation of the two diastereomers by
f
column chromatography on silica gel (ꢀR = 0.2) and providing hundreds of milligrams of each
diastereomers. Similarly, the MꢀRRRꢀ5 and PꢀRRRꢀ5 isomers were deprotected and subsequent
separation by column chromatography afforded the two other diasteromers MꢀRRRꢀ1 and PꢀRRRꢀ1.
The four isomers were thus obtained in five steps, starting from the commercially available vanillyl
alcohol with an overall yield of 3% each.
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Scheme 1. Synthesis of enantiopure hosts MꢀSSSꢀ1 and PꢀSSSꢀ1.
1
The H NMR spectra of MꢀRRRꢀ1 and PꢀRRRꢀ1 in CHCl
3
indicate that these molecules are on average
of C symmetry. They display the expected signals for the CTV unit (Figure 2): two singlets for the
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aromatic protons, and the characteristic AB system for the ArCH bridges. The aromatic protons of the
binaphthol units appear as a complex pattern and the OH protons give a singlet between 5.5 and 6.0
ppm.
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Figure 2. H NMR spectra (500 MHz, CDCl ) of PꢀRRRꢀ1 and MꢀRRRꢀ1.
3
Assignment of the absolute configuration
ꢀε
ꢀε
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P-RRR-1
CTVBINOHRdia1
CT
M
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λ (nm)
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Figure 3. Experimental ECD spectra (CH CN, 298 K, c = 2.10 mol.L ) of the stereoisomers of 1 (left: first
3
eluted compounds; right: second eluted compounds.
Electronic circular dichroism (ECD) spectra of the four enantiopure receptors were recorded in
3
CH CN at 298 K (Figure 3). Each spectrum presents a similar behaviour that consists of one main
exciton pattern centred on 230 nm. The absolute configurations of hemicryptophanes are usually
1
determined by comparing the sign of the bands of the experimental ECD spectrum around the L
A
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transition (240 nm) with those of the calculated ECD spectrum. However, in compound 1 the signal
of the CTV unit is fully hidden by that related to the three binaphthol units. Indeed, MꢀSSSꢀ1 and Pꢀ
SSSꢀ1 diastereomers exhibit almost the same ECD spectrum. The overlap of the signals of these two
units and the much stronger intensity of the signal induced by the binaphthol moieties, prompted us to
investigate another method for the assignment of the absolute configuration. We decided to focus on
the use of chemical correlation to determine unambiguously the absolute configuration of these new
compounds. Thus, CTV racꢀ3 was resolved using chiral HPLC, according to our previous published
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procedure. The ECD spectra of the two enantiomers were recorded in CH CN at 293 K allowing the
assignment of the absolute configuration of Pꢀ3 (first eluted) and Mꢀ3 (last eluted). Then each
following steps of the synthesis of the open cages has to be performed at low temperature with
reaction time no longer than two days. Indeed, the energy barrier for racemization of 3 is around 114ꢀ
ꢀ1
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15 kJ.mol , which corresponds to a halfꢀlife time of 6 months at 293 K. Therefore, the deprotection
step of the allyl groups of MꢀSSSꢀ5 and PꢀSSSꢀ5, which required heating at high temperature (80°C)
for one night should be avoided, and a new procedure to access to the isomers of 1 has been developed
(
Scheme 2). Enantiopure Mꢀ3 or Pꢀ3 was first reacted with compound Sꢀ6 at room temperature for two
days, providing enantiomerically and diastereomerically pure MꢀSSSꢀ7 or PꢀSSSꢀ7. In each case, the
NMR spectrum of the crude product shows only one set of signals, demonstrating that the inversion of
the stereochemistry of the CTV unit, which should lead to the diastereomer PꢀSSSꢀ7 (respectively Mꢀ
SSSꢀ7), can be neglected during this step. In parallel, reaction between MꢀSSSꢀ1 or PꢀSSSꢀ1 (Scheme
1
) and iodomethane was performed in DMF at room temperature, affording enantiomerically and
diastereomerically pure MꢀSSSꢀ7 or PꢀSSSꢀ7, respectively. Again, no isomerization of the CTV was
observed. Thus, compounds MꢀSSSꢀ7 and PꢀSSSꢀ7 were obtained by two different pathways, allowing
the assignment of the absolute configuration of MꢀSSSꢀ1 (first eluted) or PꢀSSSꢀ1 (last eluted) by a
simple comparison of the NMR spectra. This unique chemical correlation also allows the direct
determination of the absolute configuration of MꢀRRRꢀ1 (last eluted) and PꢀRRRꢀ1 (first eluted).
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Scheme 2. Synthetic pathway allowing the determination of the absolute configuration of the stereoisomers of 1
.
Energy barrier
We then wondered if the OH groups of the binaphthol units in host 1 are connected together by
intramolecular hydrogen bonding ꢀ therefore closing the cavity thanks to these interactions ꢀ or if this
host presents an open concave cavity. To address this issue, we decided to compare the energy barriers
of racemization of MꢀSSSꢀ1 or PꢀSSSꢀ1 with those of MꢀSSSꢀ7 or PꢀSSSꢀ7, which bear methoxy groups
instead of OH groups, in two different solvents (Table 1). If intramolecular hydrogen bonding is
occurring in MꢀSSSꢀ1 or PꢀSSSꢀ1, hence (i) a much higher energy barrier of racemization are expected
for MꢀSSSꢀ1 or PꢀSSSꢀ1 than for MꢀSSSꢀ7 or PꢀSSSꢀ7 and (ii) the effect should be less pronounced in a
polar solvent (DMSO), which should be able to break such hydrogen bonding, than in an apolar
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solvent (toluene). The energy barriers for stereoconversion were determined from H NMR
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experiments: diastereomerically pure samples of 1 or 7 were dissolved in DMSOꢀd or tolueneꢀd , and
1
equilibration was monitored by H NMR spectroscopy: the changes in concentrations of the two
diastereomers with time, allowed the measurement of the rate constants of epimerization which then
gave access to the energy barriers (more details can be found in the supporting information). Similar
values, also comparable to the energy barrier measured for compound 3, were obtained for both
compounds and no solvent effect was evidenced, suggesting that no intramolecular hydrogen bonding
between the OH groups takes place in solution (Table 1). Interestingly, it appears that the
diastereomers MꢀSSSꢀ1 and PꢀSSSꢀ1 are slightly more stable than their epimer counterparts, with a K
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Table 1. Energy barriers at 80°C for the epimerization process of 1 and 7.
Energy barrier (kJ.mol )
ꢀ
1
DMSO
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Toluene
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MꢀSSSꢀ1/PꢀRRRꢀ1
MꢀRRRꢀ1/PꢀSSSꢀ1
MꢀSSSꢀ7/PꢀRRRꢀ7
MꢀRRRꢀ7/PꢀSSSꢀ7
Recognition properties
The free OH groups of the binaphthol units may be of prime importance for the recognition of guest
molecules capable of interacting through Hꢀbond. Herein, we investigate the ability of these hosts to
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discriminate closely related carbohydrate guests.
The two nꢀoctylpyranoside anomers of glucose
(
OctαGlc and OctβGlc) and mannose (OctαMan and OctβMan) were chosen as guest molecules (Table
1
2
). Measurement of the binding constants was performed thanks to H NMR titration experiments in
CDCl
3
at 298 K. In all cases only one set of signals was observed for the complex and for the free
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receptor, showing that hostꢀguest exchange is fast on the NMR time scale. Since a Job’s plot
experiment performed with MꢀRRRꢀ1 and OctαMan evidences a 1:1 stoichiometry, the same
stoichiometry is then assumed for all the other complexes (Figure Sꢀ1 in the SI). Complexation
induced shifts of the OH groups of the host were plotted as a function of the guest/host ratio and these
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curves were fitted with the HypNMR2008 software using a 1:1 model (see Figure Sꢀ2 in the SI), and
allowing the determination of the binding constants (Table 2). Interestingly, the aromatic protons of
the binaphthol units also display significant shift during the titration experiment suggesting that these
units play an important role in the recognition process.
–
1
Table 2. Binding constants Ka (M ) for the 1:1 complexes formed between the different isomers of host 1 and
a
the carbohydrate guests.
Guest
PꢀRRRꢀ1
MꢀRRRꢀ1
MꢀSSSꢀ1
177
122
161
359
457
403
334
616
1174
393
204
375
288
197
PꢀSSSꢀ1
98
749
a
1
47
K
a determined by fitting H NMR titration curves (CDCl
3
, 500 MHz, 298 K) on OH protons with HypNMR2008;
estimated error 10%.
These open shell hosts display interesting features when compared to hemicryptophane cage
complexes. Firstly they show binding constants in the same range of magnitude as hemicryptophane
3
ꢀ1
cage complexes (up to 10 M , Table 2). Secondly, for a given carbohydrate guest molecule, some
previously reported hemicryptophanes showed almost identical binding constants whatever its
stereochemistry, while host 1 exhibits association constants that depend on the configuration of its
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different components. For instance, with OctαMan, MꢀRRRꢀ1 displays higher binding constants than
all its stereoisomer counterparts. Furthermore, another trend slightly differs from that observed with
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parent hemicryptophanes: the selectivity towards the different guests follows this order: OctαMan >
OctβGlc > OctβMan > OctαGlc. This order is partially consistent with the ability of these
carbohydrates to be involved in intermolecular hydrogen bonds emphasizing the crucial role played by
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this interaction in the recognition process.
It can also be noticed that selfꢀassociation of alkylꢀ
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7
8
9
0
glycosides in solution might occurs at the end of the titration experiment, slightly affecting the
5
0a
accuracy of the binding constants. Further insight into the key role of hydrogen bonding was also
provided thanks to the direct comparison of the recognition properties of hosts 1 and 7. Indeed, no
binding between OctαMan and host 7 was observed, demonstrating that once the acidic protons of the
host 1 are removed, the association constant dramatically drops. Secondly, depending on the chirality
of the CTV, different level of selectivity can be reached. In particular hosts with a MꢀCTV unit,
discriminate more efficiently OctαMan from OctαGlc when compared to their P counterparts (a 1:10
and 1:3 diastereoselectivity can be obtained with host MꢀRRRꢀ1 and PꢀRRRꢀ1 respectively). Thus
these hosts belong to the very limited class of artificial receptors able to recognize selectively mannose
50ꢀ56
and its derivatives versus other glucoses.
Conclusion
In conclusion, we have described the synthesis of new enantiopure host compounds based on the
combination of CTV and binaphthol units. The assignment of their absolute configuration was realized
by chemical correlation. The determination of the energy barrier for the interconversion process in 1
and 7 indicates that this epimerization is slow when compared to the time of a titration experiment.
The lack of intramolecular hydrogen bonds between binaphthol moieties, closing the cavity, is in
accord with these results and was further evidenced by recognition experiments with carbohydrate
guests. Binding constants, similar to that obtained with covalently closed hemicryptophanes were
measured, and interesting selectivities were reached. This recognition of sugar molecules by openꢀ
shell CTVꢀbased host compounds is unprecedented, paving the way for a new and wider use of such
structures as easy accessible and highly selective hosts for chiral recognition.
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Experimental section
Methods and Materials.
All reactions were carried out under argon by means of an inert gas/vacuum double manifold and
standard Schlenk techniques. Dichloromethane was dried and degassed on a solvent station by passage
through an activated alumina column followed by an argon flush. Other solvents were dried prior to
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60
1
13
use over molecular sieves. H and C spectra were recorded at 500.1 MHz and 125.7 MHz
1
13
respectively, and are reported relative to the residual protonated solvent signal ( H, C). The HRMSꢀ
ESI mass spectra were recorded in positiveꢀion mode (or negative) on a hybrid quadrupole timeꢀofꢀ
flight mass spectrometer with an Electrospray Ionization (ESI) ion source.
Synthesis of R-4 and S-4.
2 3
A solution of P (or M) binaphthol (20.9 mmol, 1 eq) and K CO (27 mmol, 1.3 eq) in 50 mL of
acetone was stirred during 1h. Then allyl bromide (23 mmol, 1.1 eq) was added and the mixture was
stirred at 50°C overnight. The mixture was filtered and the solvent was removed under vacuum. The
2 2
crude product was purified by column chromatography on silica gel using a 30:70 mixture of CH Cl
and petroleum ether and then a 60:40 mixture of the same solvents as eluent to give a monoprotected
1
binaphthol Pꢀ4 (or M-4) with 76% yield (15.9 mmol). H NMR (CDCl , 298 K, 500.1 MHz) δ 7.94 (d,
3
1
H, J = 8.8 Hz); 7.81ꢀ7.83 (m, 2H); 7.78 (d, 1H, J = 8.1 Hz); 7.36 (d, 1H, J = 8.8 Hz); 7.26ꢀ7.31 (m,
H); 7.19ꢀ7.24 (m, 2H); 7.11ꢀ7.15 (m, 2H); 7.98 (d, 1H, J = 8.1 Hz); 5.64ꢀ5.72 (m, 1H); 4.99 (dd, 1H,
2
13
J = 7.5 Hz and 1.4 Hz); 4.85 (s, 1H); 4.44ꢀ4.51 (m, 2H). C NMR (CDCl , 298 K, 125.7 MHz) δ
3
154.9; 151.24; 134.0; 133.8; 133.1; 130.8; 128.8; 129.6; 129.1; 128.2; 128.1; 127.3; 126.3; 125.0;
+
124.9; 124.3; 123.2; 117.5; 117.2; 116.5; 115.8; 115.1; 70.0. ESIꢀMS m/z: 327.1375 [M+H]
ꢁ
ꢂ
ꢁꢂ
(calculated 327.1380 for C23
.100; CH Cl
H
19
O
2
2 2
ꢀ
). Rꢀ4: [∝] = ꢀ12.4 (c = 0.109; CH Cl ); Sꢀ4: [∝] = +15.3 (c =
ꢀ
0
2
2
)
Synthesis of RRR-5 or SSS-5.
A solution of S (or Rꢀ4) (2.11 mmol, 3 eq), CTV racꢀ3 (0.705 mmol, 1 eq) and Cs
2 3
CO (803.9 mmol,
3.5 eq) in 10 mL of DMF was stirred overnight at 40°C under argon atmosphere. Then 75 mL of
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2
2
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2
2
2
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6
AcOEt and 100 mL of 10% aqueous NaOH10% was added. The organic layer was separated and the
aqueous phase was extracted with AcOEt (2×50 mL). The combined organic layers were washed with
aqueous NaOH 10% (2x50 mL), dried over Na SO and the organic solvent was removed under
2
4
vacuum. The crude product was purified by column chromatography on silica gel with CH
2 2
Cl then a
0
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4
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6
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0
1
2
3
4
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9
0
95:5 mixture of CH Cl and AcOEt solvents as eluent to give SSSꢀ5 (or RRR-5) as a mixture of two
2
2
1
diastereomers PSSSꢀ5 and MSSSꢀ5 with 85% yield (0.602 mmol). H NMR (CDCl , 298 K, 500.1
3
MHz), mixtures of the two diastereomers, δ 7.84ꢀ7.98 (m, 12H); 7.52 (dd, 3H, J = 9 Hz and 1.5 Hz);
7
5
3
.36ꢀ7.41 (m, 6H); 7.24ꢀ7.30 (m, 6H); 7.15ꢀ7.19 (m, 9H); 6.50ꢀ6.57 (m, 6H); 5.69ꢀ5.74 (m, 3H); 4.94ꢀ
.02 (m, 6H); 4.59ꢀ4.64 (m, 3H); 4.48ꢀ4.51 (m, 6H); 4.27ꢀ4.34 (m, 6H); 3.88ꢀ4.00 (m, 6H); 3.46 and
13
3
.38 (s and s, 9H), 3.29ꢀ3.37 (m, 3H). C NMR (CDCl , 298 K, 125.7 MHz), mixtures of the two
diastereomers, δ 154.2; 154.1; 154.1; 154.0; 148.3; 148.2; 146.7; 146.6; 134.1; 134.0; 134.0; 133.7;
1
1
1
5
33.6; 132.6; 132.2; 131.7; 129.6; 129.4; 129.4; 129.3; 129.3; 129.2; 129.1; 127.9; 127.8; 126.3;
26.3; 126.2; 125.6; 125.5; 125.4; 125.3; 123.8; 123.7; 123.6; 121.0; 120.9; 120.3; 120.1; 116.5;
16.5; 116.4; 116.4; 116.3; 116.1; 115.8; 115.7; 113.9; 133.7; 70.0; 68.2; 68.1; 67.8; 60.4; 56.1; 55.9;
+
3.1; 44.3; 36.2; 36.2. ESIꢀMS m/z: 1465.6015 [M+H] (calculated 1465.6036 for C99
H
85
O12). RRRꢀ5:
ꢁꢂ
ꢁꢂ
[
∝] = +26.4 (c = 0.074; CH Cl ); SSSꢀ5: [∝] = ꢀ29.1 (c = 0.079; CH Cl ).
ꢀ
2
2
ꢀ
2
2
Synthesis of P-RRR-1, M-SSS-1, P-SSS-1 and M-RRR-1
2 3
Rꢀ5 (or Sꢀ5) (0.546 mmol, 1 eq), Pd(OAc) (0.033 mmol, 0.06 eq), PPh (0.11 mmol, 0.2 eq) and
NHEt (25.1 mmol, 46 eq) 2 mL of H O and 8 mL of THF was stirred at 80°C under argon atmosphere
2
2
during 4h. Then the mixture was cooled at room temperature and solvents was removed under
vacuum. 10 mL of AcOEt was added and removed under vacuum, twice. 10 mL of AcOEt and 10 mL
of H O was added. The organic layer was separated and the aqueous phase was extracted with AcOEt
2
(
2×10 mL). The combined organic layers were dried over Na
removed under vacuum. The solid was washed with Et O. The 2 diastereomers was separated by
column chromatography on silica gel with a 95:5 mixture of CH Cl /EtOAc solvents as eluent to give
2 4
SO and the organic solvent was
2
2
2
PꢀRRRꢀ1 (or PꢀSSSꢀ1) with 25% yield (0.137 mmol) and MꢀRRRꢀ1 (or MꢀSSS-1) with 24% (0.133
mmol) yield.
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3
PꢀRRR-1 / MꢀSSSꢀ1: H NMR (CDCl , 298 K, 500.1 MHz) δ 7.77 (d, 3H, J = 8.9 Hz); 7.73 (d, 3H, J =
8.1 Hz); 7.66 (d, 3H, J = 8.3 Hz); 7.50 (d, 3H, J = 9.1 Hz); 7.21ꢀ7.24 (m, 6H); 7.14ꢀ7.17 (m, 6H);
7.08ꢀ7.11 (m, 6H); 7.04ꢀ7.07 (m, 3H); 6.94 (d, 3H, J = 8.3 Hz); 6.54 (s, 3H); 6.42 (s, 3H); 5.74 (s,
3H); 4.57 (d, 3H, J = 13.7 Hz); 4.35ꢀ4.40 (m, 3H); 4.11ꢀ4.15 (m, 3H); 4.00ꢀ4.02 (m, 6H); 3.30 (d, 3H,
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34
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38
39
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48
49
50
51
52
53
54
55
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58
59
60
1
3
3
J = 13.7 Hz); 3.08 (s, 9H); C NMR (CDCl , 298 K, 125.7 MHz) δ 155.2; 151.6; 148.0; 145.8; 134.0;
133.9; 132.9; 131.9; 130.4; 129.9; 129.6; 129.0; 128.1; 128.0; 127.0; 126.3; 125.2; 124.8; 124.3;
123.1; 118.1; 117.8; 116.7; 115.7; 115.4; 113.4; 68.3; 67.4; 55.4; 36.3. ESIꢀMS m/z: 1345.5073
+
ꢁꢂ
[
M+H] (calculated 1345.5097 for C90
H
73
O
2 2
12). PꢀRRRꢀ1: [∝] = +109.4 (c = 0.103; CH Cl ); MꢀSSSꢀ
ꢀ
ꢁꢂ
1: [∝] = ꢀ104.8 (c = 0.111; CH Cl )
ꢀ
2
2
1
PꢀSSS-1 / MꢀRRR-1: H NMR (CDCl
3
, 298 K, 500.1 MHz) δ 7.83 (d, 3H, J = 9.1 Hz); 7.79 (d, 3H, J =
8
3
3
4
.1 Hz); 7.76 (d, 3H, J = 8.9 Hz); 7.74 (d, 3H, J = 8.1 Hz); 7.32 (d, 3H, J = 9.1 Hz); 7.27ꢀ7.29 (m,
H); 7.21 (d, 3H, J = 8.9 Hz); 7.15ꢀ7.17 (m, 3H); 7.11 (d, 3H, J = 8.3 Hz); 7.06ꢀ7.09 (m, 3H); 6.97 (d,
H, J = 8.1 Hz); 6.46 (s, 3H); 6.43 (s, 3H); 5.51 (s, 3H); 4.54 (d, 3H, J = 13.7 Hz); 4.24ꢀ4.29 (m, 3H);
13
.13ꢀ4.17 (m, 3H); 3.92ꢀ3.96 (m, 3H); 3.83ꢀ3.87 (m, 3H); 3.29 (d, 3H, J = 13.7 Hz); 3.20 (s, 9H). C
NMR (CDCl3, 298 K, 125.7 MHz) δ 155.3; 151.6; 148.2; 146.1; 134.0; 133.8; 132.7; 131.7; 130.6;
1
29.9; 129.7; 129.0; 128.1; 128.0; 127.0; 126.3; 125.2; 124.9; 124.4; 123.1; 117.9; 117.7; 116.7;
+
1
15.8; 115.3; 113.6; 68.2; 68.0; 55.7; 36.3. ESIꢀMS m/z: 1345.5073 [M+H] (calculated 1345.5097 for
ꢁ
ꢂ
ꢁꢂ
C
90
H
73
O
2 2
ꢀ
12). PꢀSSS-1: [∝] = ꢀ121.7 (c = 0.105; CH Cl ); MꢀRRR-1: [∝] = +121.0 (c = 0.099;
ꢀ
CH
2
Cl )
2
Synthesis of P-RRR-7, M-SSS-7, P-SSS-7 and M-RRR-7
A solution of PꢀRRRꢀ1 (37.2 ꢁmol, 1 eq), MeI (743 ꢁmol, 60 eq) and Cs
mL of DMF was stirred 2 days at 25°C under argon atmosphere. Then 15 mL of AcOEt and 15 mL of
O was added. The organic layer was separated and the aqueous phase was extracted with AcOEt
2×10 mL). The combined organic layers were washed with H O (2x10 mL), dried over Na SO and
2 3
CO (148 ꢁmol, 4 eq) in 4
H
2
(
2
2
4
the organic solvent was removed under vacuum. The crude product was purified by column
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2 2 2
chromatography on silica gel with a 98:2 mixture of CH Cl and Et O solvents as eluent to give Pꢀ
PPRꢀ7 with 83% yield (31 ꢁmol).
1
PꢀRRR-7 / MꢀSSS-7: H NMR (CDCl , 298 K, 500.1 MHz) δ 7.96 (t, 6H); 7.91 (d, 3H, J =8.1 Hz);
3
7
.86 (d, 3H, J =8.1 Hz); 7.52 (d, 3H, J = 9.1 Hz); 7.40 (d, 3H, J = 9.1 Hz); 7.37 (d, 3H, J = 7.8 Hz);
.24ꢀ7.30 (m, 6H); 7.12ꢀ7.19 (m, 9H); 6.55 (s, 3H); 6.47 (s, 3H); 4.61 (d, 3H, J = 13.5 Hz); 4.25ꢀ4.34
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1
3
(
m, 6H); 3.90ꢀ3.99 (m, 6H); 3.70 (s, 9H); 3.35 (s, 9H); 3.30 (d, 3H, J = 13.5 Hz). C NMR (CDCl ,
3
298 K, 125.7 MHz) δ 154.9; 154.1; 148.4; 146.5; 134.1; 134.0; 132.7; 131.6; 129.7; 129.4; 129.3;
129.0; 128.0; 127.9; 126.4; 126.3; 125.5; 125.2; 123.9; 123.4; 121.1; 119.2; 116.6; 116.4; 113.8;
+
113.5; 68.3; 68.2; 56.5; 55.8; 36.1. ESIꢀMS m/z: 1387.5544 [M+H] (calculated 1387.5566 for
93 79 12
C H O )
1
3
PꢀSSS-7 / MꢀRRR-7: H NMR (CDCl , 298 K, 500.1 MHz) δ 7.86 (d, 3H, J = 5.4 Hz); 7.85 (d, 3H, J =
5.4 Hz); 7.78 (d, 3H, J =8.1 Hz); 7.74 (d, 3H, J = 8.1 Hz); 7.40 (d, 3H, J = 9.1 Hz); 7.31 (d, 3H, J =
9.1 Hz); 7.24ꢀ7.27 (m, 3H); 7.11ꢀ7.17 (m, 6H); 7.00ꢀ7.07 (m, 9H); 6.44 (d, 6H, J = 5.1 Hz); 4.52 (d,
3H, J = 13.8 Hz); 4.19 (t, 6H); 3.74ꢀ3.84 (m, 6H); 3.61 (s, 9H); 3.33 (s, 9H); 3.23 (d, 3H, J = 13.8 Hz).
13
3
C NMR (CDCl , 298 K, 125.7 MHz) δ 154.9; 154.1; 148.3; 146.7; 134.1; 134.0; 132.6; 131.8; 129.7;
129.5; 129.4; 129.1; 128.0; 127.9; 127.8; 126.3; 125.4; 125.3; 123.9; 123.5; 121.1; 119.4; 116.7;
+
116.0; 114.1; 114.0; 68.4; 68.0; 56.7; 54.1; 36.2. ESIꢀMS m/z: 1387.5544 [M+H] (calculated
ꢁ
ꢂ
ꢁꢂ
1
387.5566 for C93
.105; CH Cl
H
79
O
12). MꢀRRR-7: [∝] = +116 (c = 0.0965; CH
2
Cl
2
); PꢀSSS-7: [∝] = ꢀ122 (c =
ꢀ
ꢀ
0
2
2
)
Synthesis of P-SSS-7 (second method)
A solution of P-3 (0.14 mmol, 1 eq), S-6 (0.41 mmol, 3 eq) and Cs
2
CO
3
(0.48 mmol, 3.5 eq) in 2 mL
of DMF was stirred 1 day at 25°C under argon atmosphere. Then 10 mL of AcOEt and 10 mL of
aqueous NaOH10% was added. The organic layer was separated and the aqueous phase was extracted
with AcOEt (2×10 mL). The combined organic layers were washed with aqueous NaOH 10% (2x10
mL), dried over Na SO and the organic solvent was removed under vacuum. The crude product was
2
4
2 2 2
purified by column chromatography on silica gel with a 98:2 mixture of CH Cl and Et O solvents as
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eluent to give PꢀSSSꢀ7 with 70% yield (0.098 mmol). The characterizations are identical to those
obtained with the first method described above.
Complexation of octyl-D-gluco-, and manno-pyranosides by hemicryptophanes 1.
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Solutions of hosts (1.0 mM in CDCl , 500
µ
L) were titrated in NMR tubes with small aliquots of
). Complexation induced shifts ꢂδ of the aromatic protons or the
protons of the host were measured after each addition and plotted as a function of the guest/host
3
solutions of guests (20 mM in CDCl
3
OCH
3
ratio. The resulting curves were fitted with HypNMR 2008 software, providing the reported binding
constants.
Kinetic of epimerization of 1 and 7
Compounds 1 or 7 were heated in toluene or DMSO at 80°C. The evolution of the ratio of the two
1
diastereoisomers was followed by H NMMR, allowing the determination of the energy barrier.
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: alexandre.martinez@ensꢀlyon.fr
Notes The authors declare no competing financial interest.
ASSOCIATED CONTENTS
Supporting Information
1
13
H, C NMR spectra, CD and mass spectra of compounds 1, 4, 5, 7; Job plot andtitration experiments;
kinetic of epimerization.
REFERENCES
(
(
1) Raynal, M.; Ballester, P.; VisalꢀFerran A.; Van Leeuwen, P. W. N. M. Chem. Rev. 2014, 43, 1734.
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10) Hermann, K.; Ruan, Y.; Hardin, A. M.; Hadad C. M.; Badjić J. D. Chem. Soc. Rev. 2015, 44
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(
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(
(
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(
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