Enantiopure C1-Cyclotriveratrylene with a Reversed Spatial Arrangement of the Substituents

Article abstract of DOI:10.1021/acs.orglett.8b03621

Cyclotriveratrylene (CTV) is a macrocyclic cyclophane presenting a bowl-shaped conformation, used as building block to construct cryptophane and hemicryptophane capsules. A method to synthesize new enantiopure CTV derivatives with an unprecedented spatial

Full text of DOI:10.1021/acs.orglett.8b03621

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantiopure C ‑Cyclotriveratrylene with a Reversed Spatial
1
Arrangement of the Substituents
†
†
†
†
†
‡
Augustin Long, Cedric Colomban, Marion Jean, Muriel Albalat, Nicolas Vanthuyne, Michel Giorgi,
Lorenzo Di Bari,§ Marcin Gor
ecki, Jean-Pierre Dutasta, and Alexandre Martinez*
⊥
⌉
,†
́
†
‡
§
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
Aix Marseille Universite, CNRS, Centrale Marseille, FSCM, Spectropole, Marseille, France
di Pisa, via Moruzzi 13, 56124 Pisa, Italy
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
́
Dipartimento di Chimica e Chimica Industriale, Universita
̀
⊥
⌉
́
Laboratoire de Chimie, Ecole Normale Super
́
ieure de Lyon, CNRS, UCBL, 46 Allee
́
d’Italie, F-69364 Lyon, France
*
S Supporting Information
ABSTRACT: Cyclotriveratrylene (CTV) is a macrocyclic cyclophane presenting a bowl-
shaped conformation, used as building block to construct cryptophane and hemi-
cryptophane capsules. A method to synthesize new enantiopure CTV derivatives with an
unprecedented spatial arrangement of their substituents, exhibiting C symmetry, is
1
described. The absolute configuration was assigned by ECD spectroscopy coupled with
modeling. A statistical model has allowed for optimization of the proportion of C CTV,
1
and the modularity of this approach is also highlighted.
4
yclotriveratrylene (CTV) 1 is a macrocyclic trimer of
veratrole presenting a bowl-shaped conformation (Figure
a). The first synthesis of the CTV was achieved
resulting racemic mixture can be resolved. Members of the
CTV family have attracted considerable attention due to their
C
1
5
1
usefulness for versatile applications ranging from separations,
sensing, gels, and dendrimers to liquids crystals. Moreover,
they have been also used as building blocks for the
construction of supramolecular assemblies such as polymers,
cubes, pseudorotaxanes, catenanes and capsules.
6
7
8
9
10
11
12
13
1,14
In
particular, the combination of two CTV derivatives, linked
14,15
together, gives molecular capsules, named cryptophanes,
which present remarkable recognitions properties toward small
1
6,17
molecules like epoxydes and methane,
cations like choline
18,19
and cesium, and anions.
They were also found to complex
Xe atom, leading to promising tools for bioimaging. When
20
21
the CTV moiety is connected with another C symmetrical
3
22
Figure 1. (a) Structure of the cyclotriveratylene 1. (b) General
structure of chiral CTV derivatives 2 with C symmetry (R ≠ R ). (c)
unit, it gives rise to hemicryptophanes. These chiral covalent
cages can act as receptors for neurotransmitters and
3
1
2
23,24
25
Classical approach to obtain C CTV derivatives. (d) Strategy of
1
carbohydrates,
molecular switches, and supramolecular
27d
Becker et al. (e) Our approach.
26
catalysts.
While most CTV or CTV-based hosts reported so far
present a C symmetry, few C -symmetrical CTVs have been
described in the literature. This change of the symmetry
3
1
independently by Ewins and Robinson in 1909 and 1915,
respectively. In 1965, Lindsey, Erdtman, and Goldup
27
2
results from the introduction of an R group, different from R
3
1
proposed a revised structure describing a macrocryclic trimer
3
and R , on one of the aromatic rings, for instance, by
2
of aromatic rings. Since then, various CTV analogues have
been obtained by changing the nature of the R /R
substituents at their side arms (2, Figure 1b). When R
1
2
1
Received: November 14, 2018
1
differs from R , the CTV derivatives are chiral, and the
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
monodemethylation of the CTV unit (compound 3, Figure 1c)
(Figures S26 and S28). For instance, the characteristic signals
corresponding to the H protons of the AB systems of the CH
2
27b,c
or by monoiodation of a C CTV derivative.
Becker et al.
3
a
have recently reported the synthesis of the C CTV-lactam 4
bridges in 5 appear as the superposition of three doublets at
4.71 ppm, with an expected coupling constant around 13.6 Hz,
and the aromatic protons of the three CTV units give six
singlets between 6.85 and 6.95 ppm.
1
through the original functionalization of one of the apical
2
7d
position of the CTV moiety (Figure 1d).
However,
compound 4 turns out to be more flexible than the “classical”
CTV moiety, leading to a lower energy barrier of racemization
and avoiding their resolution by chiral HPLC. To the best of
The chiroptical properties of the two enantiomers of 5 were
then studied. Their optical rotations, measured in CH Cl at
2
2
our knowledge, the straightforward synthesis of C -symmetrical
589 nm, correspond to a third of that of their C parents (±5
3
2
1
−1
CTV derivatives, where the loss of symmetry arises from the
permutation of the substituents R and R (Figure 1e) on one
and ±15 deg cm g , respectively (see the Supporting
Information)). Similarly, their electronic circular dichroism
(ECD) spectra, recorded in MeCN at 25 °C (Figures 2 and
1
2
2
7e
of the aromatic ring is currently rather uncommon.
Importantly, such an approach will lead to C -derivatives
1
with an original spatial arrangement of their substituents,
which will be highly valuable in order to access to
cryptophanes and hemicryptophanes with shapes and sizes of
their cavity that cannot be achieved by the existing methods.
Herein, we propose a new C CTV structure where the loss
1
of symmetry is due to an inverted arrangement of one aromatic
ring. The unmodified CH bridges, found in this structure, aim
2
at maintaining its conformational rigidity, allowing for its
resolution; meanwhile the specific arrangement of the
substituents could afford a new chiral cyclophane building
block, with a bowl-shaped conformation. We therefore report
the synthesis of a CTV derivative, where the sequential
distribution of the R /R substituents is reversed on one of the
1
2
aromatic ring (Figure 1e). To favor the formation of the C1
over the C CTV, we optimized the reaction conditions by
3
Figure 2. Experimental ECD spectra of the enantiomers of 5: the first
mean of a statistical model. The racemic mixture was resolved
by chiral HPLC and the assignment of the absolute
configuration was achieved by ECD spectroscopy. Other
eluted enantiomer is represented with a green solid line (0.404 mmol
−1
L
L
in CH Cl ) and the second one by a red dotted line (0.442 mmol
2 2
−1
in CH Cl ) together with TDDFT calculations performed for M-
2
2
related C CTVs were prepared to highlight the modularity of
our approach and X-ray diffraction analyses confirm the
proposed structures.
C1 CTV 5 bearing allyl and bromoethyl substituents was
synthesized by mixing the two regio-isomers 6 and 7 in a 4:1
ratio in acetonitrile using scandium triflate as Lewis acid
5. Calculations were carried out at the CAM-B3LYP/SVP/PCM-
(MeCN) level of theory; spectrum red-shifted by 33 nm, Gaussian
bandwidth 0.23 eV, similarity factor assigned by means of SpecDis
1
30
ver. 1.70 for the second peak = 0.833, while for the first one = 0.008.
Figures S94 and S95), also exhibit a decrease of the intensities
for the observed transitions by two-thirds compared to their C3
counterparts. The inverted position of one of the aromatic
rings probably induces two excitons coupling of the same sign
and one of the opposite and could account for this
experimental result. The assignment of the absolute config-
uration of the C1 CTV was then achieved. First, the
stereodescriptor was chosen according to the method
catalyst (Scheme 1). A mixture of C - and C -symmetric CTVs
3
1
a
Scheme 1. Synthesis of C CTV 5
1
28
described by Prelog. However, because of the lack of the
C axis, the conformations around the six CH −Ar single
3
2
bonds are no more equivalent. The priority of one pair can be
determined according to CIP rules, and the procedure of
Prelog can be applied, giving a M descriptor, if R > R , for the
1
2
enantiomer drawn in Figure 1e (see the Supporting
28
a
Information for more details). Second, this stereodescriptor
was linked with a chiroptical property so that their electronic
circular dichroism (ECD) spectra were thus used to achieve
A mixture of four stereoisomers is obtained: (+)-8, (−)-8, (+)-5, and
−)-5.
(
this goal. Indeed, the spectra exhibit two exciton patterns
1
8
and 5, respectively, was obtained in 52% yield after removal
centered on the isotropic absorption of the L
a
(∼240 nm) and
1
of the byproducts of the reaction (oligomers and polymers) by
L (∼290 nm) transitions, as usually observed for CTV
b
analogues. Collet et al. have demonstrated that the sign of the
column chromatography. The four isomers (+)-8, (−)-8,
1
(
+)-5, and (−)-5 were separated on chiral HPLC (see Figures
bands of the experimental ECD spectrum around the L ∼
a
S76 and 77), allowing isolation of each enantiomer of the CTV
on a gram scale. Both compounds 8 and 5 display identical
240 nm is poorly sensitive to the nature of CTV derivatives
substituents. Therefore, the determination of their absolute
configuration was achieved by means of comparison to the
5
1
mass spectra (Figures S56−S57); however the H NMR
spectrum of enantiopure CTV 8 confirms the C symmetry,
whereas that of enantiopure 5 exhibits a more complex pattern
29
calculated ECD spectra of a reference CTV. On the basis of
these previous works, the second and third eluted compounds
3
B
DOI: 10.1021/acs.orglett.8b03621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
(+)-5 and (−)-5, respectively) correspond to the P and M
Letter
(
are reached when an equimolar mixture of both isomers is
configurations, whereas the first and fourth eluted compounds
used, leading to a maximum yield of 75% of C CTV.
1
(
(+)-8 and (−)-8, respectively) correspond to the P and M
We then examined if other C CTV derivatives, presenting
1
configurations of the C CTV. To confirm this stereochemical
an inverted arrangement of one of their aromatic rings, could
be obtained following our method. Using the same procedure
and starting from the 1:1 mixture of the two regioisomers 11
and 12, a mixture of C and C CTV 9 was obtained in 46%
3
assignment, ECD spectra were calculated for an arbitrary
chosen M-5 by using the TDDFT method. In order to
guarantee the quality of the obtained data, two hybrid
functionals (CAM-B3LYP, ωB97X-D) with the SVP basis set
and PCM model for MeCN were tested. The results are
completely in agreement. This confirms the aforementioned
assignment; i.e., the second eluted peak is M-5, while the first
one is P-5 (Figure 2).
3
1
yield, with a C /C ratio of 25/75 in agreement with the
3
1
previously established statistical model. The subsequent
deprotection of the allyl groups then affords the C and C
3
1
CTV 10 in 90% yield (Scheme 2). Resolution of CTVs 9 and
We then focused our attention on the improvement of the
C /C ratio (5/8 ratio) by varying the initial proportions of the
Scheme 2. Synthesis of C CTV-9 and -10
1
1
3
starting regioisomers 6 and 7. The proportions of C and C
3
1
CTV derivatives can be explained by a simple statistical model,
assuming (i) a kinetic model for the reaction, (ii) that both
isomers 6 and 7 have the same reactivity, and (iii) that the
racemization of the CTVs C and C occurs frequently during
1
3
the reaction time (see the Supporting Information). This latter
hypothesis was assessed by measuring the energy barrier of the
C1 enantiomer. A value of 112.1 kJ mol− was found, similar to
1
that of its C parent, which corresponds to a half-life time of 24
3
min at 82 °C (Figures S100 and S101). With this model for the
cyclization, the probabilities are given by the polynomial law
with Newton’s binomial coefficients
10 was performed on chiral HPLC (see the Supporting
Information). As previously observed with CTV-5, the
chiroptical properties of the C CTVs 9 and 10 are one-third
1
of those of their C parents. The absolute configurations of
3
i3y
i3y
j z
0
3−0
j z
3
3−3
P (x) = j zx (1 − x)
+ j zx (1 − x)
= 1 − 3x(1 − x)
these C CTVs were assigned using the same strategy as that
C3
j z
j z
1
0
3
k {
k {
described for C CTV 5. Furthermore, it should be noted that
1
various functional groups can be easily grafted on the phenol
i3y
i3y
j z 1
3−1
j z
2
3−2
P (x) = j zx (1 − x)
+ j zx (1 − x)
= 3x(1 − x)
function of C CTV 10, allowing for a straightforward tuning of
1
C
1
1
2
k {
k {
its properties and making it a promising cyclophane building
block. Single crystals suitable for X-ray diffraction studies of C1
where x is the proportion of regioisomer and P (x) and P (x)
the probabilities to obtain the C and C CTV, respectively.
Thus, from these equations we find that the maximum of the
function PC1 is reached for an equimolar mixture of each
C
1
C
3
CTV-9 and C CTV-10 were obtained by slow diffusion of
1
1
3
pentane and ether, respectively, in chloroform solutions
(
Figure 4 and Figures S104 and 105). These compounds
regioisomer (x = 0.5) and yields a maximum of 75% of C1
derivative and 25% of C derivative. To confirm this model,
3
several cyclizations were performed under the same conditions
with different proportions x of the starting regioisomer 7. The
1
proportions PC1 and PC3 were both determined by H NMR
and HPLC (Figures S65−S74). The statistical model was
found to be in excellent agreement with the experiments,
confirming our hypothesis (Figure 3). Moreover, it supports
Figure 4. (a) X-ray crystal structure of (−)-P−C CTV-9. (b) Angles
1
that the optimal conditions for the synthesis of C derivative
1
between the bulky linkers.
display the expected bowl-shaped structure, with the
permutation of the spatial arrangement of the substituents
on one of the aromatic rings. The angles formed between the
oxygen atoms bearing the bulky substituents and their
barycenter are reported in Figure 4b, highlighting the
difference between the three intervals, induced by the
desymmetrization.
We have thus described the unprecedented synthesis of
enantiopure C -symmetrical CTVs. The C symmetry,
1
3
classically observed with CTV derivatives, was successfully
broken following a novel approach based on the inversion of
the position of the two alkoxy groups of one of the aromatic
rings. This leads to original enantiopure bowl-shaped cyclo-
phanes with novel structural and optical properties. Impor-
Figure 3. Proportion of C CTV-8 (in red) and C CTV-5 (in blue)
3
1
obtained with different initial proportions x of isomer 7 for the
cyclization. Triangles represent the experimental proportions, and the
line represents the binomial statistical model.
tantly, the C CTV scaffold obtained following this approach
1
C
DOI: 10.1021/acs.orglett.8b03621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
represents a new tool for the construction of molecular cages
with three apertures of different sizes. In addition, this is a
promising strategy for the fine-tuning of the in/out kinetics of
guest encapsulation inside the cryptophane cavity, while
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(
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retaining high affinity. As the C CTVs precursors can be
1
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Zhao, X.; Jiang, X.-K.; Li, Z.-T. Hydrogen Bonding-Directed
Quantitative Self-Assembly of Cyclotriveratrylene Capsules and
easily obtained in a gram scale, we envision that library of such
challenging building blocks can be rapidly built.
3
1
13
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03621.
Their Encapsulation of C60 and C . J. Org. Chem. 2011, 76, 3531−
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Synthetic procedures, 1H, 13C NMR, mass, and ECD
spectra, HPLC separation, and X-ray structure of CTV
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Mendoza, J. de. Tripodal ExTTF-CTV Hosts for Fullerenes. J. Am.
Chem. Soc. 2010, 132, 5351−5353. (e) Lijanova, I. V.; Maturano, J. F.;
10 (PDF)
Chavez, J. G. D.; Montes, K. E. S.; Ortega, S. H.; Klimova, T.;
́
Martínez-García, M. Synthesis of Cyclotriveratrylene Dendrimers and
Accession Codes
Their Supramolecular Complexes with Fullerene C . Supramol.
6
0
CCDC 1876355−1876356 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Chem. 2009, 21, 24−34.
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Chierici, S.; Pinet, S.; Gosse, I.; Baraille, I.; Brown, R. Selective, Direct
Detection of Acetylcholine in PBS Solution, with Self-Assembled
Fluorescent Nano-Particles: Experiment and Modelling. Phys. Chem.
Chem. Phys. 2015, 17, 4168−4174. (b) Sarsah, S. R. S.; Lutz, M. R.;
Zeller, M.; Crumrine, D. S.; Becker, D. P. Rearrangement of
Cyclotriveratrylene (CTV) Diketone: 9,10-Diarylanthracenes with
OLED Applications. J. Org. Chem. 2013, 78, 2051−2058. (c) Peyrard,
L.; Dumartin, M.-L.; Chierici, S.; Pinet, S.; Jonusauskas, G.; Meyrand,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: alexandre.martinez@centrale-marseille.fr.
ORCID
(7) (a) Westcott, A.; Sumby, C. J.; Walshaw, R. D.; Hardie, M. J.
Lorenzo Di Bari: 0000-0003-2347-2150
Jean-Pierre Dutasta: 0000-0003-0948-6097
Alexandre Martinez: 0000-0002-6745-5734
Metallo-Gels and Organo-Gels with Tripodal Cyclotriveratrylene-
Type and 1,3,5-Substituted Benzene-Type Ligands. New J. Chem.
2
009, 33, 902−912. (b) Bardelang, D.; Camerel, F.; Ziessel, R.;
Notes
Schmutz, M.; Hannon, M. J. New Organogelators Based on
Cyclotriveratrylene Platforms Bearing 2-Dimethylacetal-5-Carbon-
ylpyridine Fragments. J. Mater. Chem. 2008, 18, 489−494.
The authors declare no competing financial interest.
(
8) Percec, V.; Imam, M. R.; Peterca, M.; Wilson, D. A.; Heiney, P.
ACKNOWLEDGMENTS
A. Self-Assembly of Dendritic Crowns into Chiral Supramolecular
■
Spheres. J. Am. Chem. Soc. 2009, 131, 1294−1304.
We thank Pr. K. Travis Holman from the Department of
Chemistry, Georgetown University, Washington D.C., for
fruitful discussions about his recent results on C1 CTV
derivatives. A.M. and C.C. thank ANR MEUH (ANR-14-
OHRI-0015-01) for funding.
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Z. Mesomorphism, Isomerization, and Dynamics in a New Series of
Pyramidic Liquid Crystals. J. Am. Chem. Soc. 2002, 124, 15286−
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Smectic and Columnar Liquid Crystalline Phases by Cyclotrivera-
trylene (CTV) and Cyclotetraveratrylene (CTTV) Derivatives
Incorporating Calamitic Structural Units. J. Mater. Chem. 1997, 7,
2001−2011.
(10) (a) Thorp-Greenwood, F. L.; Ronson, T. K.; Hardie, M. J.
Copper Coordination Polymers from Cavitand Ligands: Hierarchical
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