A hemicryptophane with a triple-stranded helical structure

Article abstract of DOI:10.3762/bjoc.14.162

A hemicryptophane cage bearing amine and amide functions in its three linkers was synthesized in five steps. The X-ray molecular structure of the cage shows a triple-stranded helical arrangement of the linkers stabilized by intramolecular hydrogen bonds b

Full text of DOI:10.3762/bjoc.14.162

A hemicryptophane with a triple-stranded helical structure
Augustin Long1, Olivier Perraud2, Erwann Jeanneau3, Christophe Aronica3,
Jean-Pierre Dutasta2 and Alexandre Martinez*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1885–1889.
1Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille,
France, 2Laboratoire de Chimie École Normale Supérieure de Lyon,
CNRS, UCBL46, Allée d'Italie, F-69364 Lyon, France and 3LMI-UMR
5615 CNRS / UCBL, Université Claude Bernard Lyon 1, 6 rue victor
Grignard, 69622 Villeurbanne cedex, France
doi:10.3762/bjoc.14.162
Received: 15 April 2018
Accepted: 29 June 2018
Published: 24 July 2018
Email:
This article is part of the thematic issue "Macrocyclic and supramolecular
chemistry".
Alexandre Martinez* - alexandre.martinez@centrale-marseille.fr
* Corresponding author
Guest Editor: M.-X. Wang
Keywords:
© 2018 Long et al.; licensee Beilstein-Institut.
License and terms: see end of document.
CTV; hemicryptophanes; organic cages; triple helical structure
Abstract
A hemicryptophane cage bearing amine and amide functions in its three linkers was synthesized in five steps. The X-ray molecular
structure of the cage shows a triple-stranded helical arrangement of the linkers stabilized by intramolecular hydrogen bonds be-
tween amide and amine groups. The chirality of the cyclotriveratrylene unit controls the propeller arrangement of the three aromat-
ic rings in the opposite part of the cage. 1H NMR studies suggest that this structure is retained in solution.
Introduction
Among the remarkable architectures found in biological from artificial collagenous biomaterials to peptides for thera-
systems, those presenting a triple helical arrangement are of peutic uses [3-5].
particular interest. Beside its classical double strand structure
formed by Watson–Crick base pairing, DNA can also organize Recently, molecular cages presenting a triple helical structure
in a triple helical fashion [1]. These three-stranded structures of have aroused a considerable interest [6-8]: for instance, Malik et
DNA naturally occur and play important roles in regulating al. described the synthesis and recognition properties of an
gene function and DNA metabolism. Collagen, the most abun- organic cage including three helicene moieties in its arms [9].
dant protein in animals, also adopts a triple helical structure: This cage presents a triple stranded helical structure with the
three parallel peptide chains coil about each other in a triple framework fully twisted due to the arrangement of the three
stranded left-handed helical structure. Its high thermal and me- helicene units in a propeller fashion. Other recent examples are
chanical stability results mainly from the numerous hydrogen the triple-stranded phenylene cages presenting a helical rod-like
bonds found in the triple helix framework [2]. Bioinspired shape synthesized by Kirsche et al. [10].
structures, based on peptide backbones, have been built,
allowing a better understanding of the properties of this biologi- Hemicryptophanes are chiral covalent cages combining a
cal system and giving rise to numerous applications ranging cyclotriveratrylene (CTV, north part) unit with another C3 sym-
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Beilstein J. Org. Chem. 2018, 14, 1885–1889.
metrical moiety (south part). They display recognition proper- to a triple helical arrangement of the linkers. The CTV unit is
ties toward neurotransmitters and carbohydrates, and can act as also found to strongly control the chirality of this triple helices
molecular switches and supramolecular catalysts [11]. Their C3 since the CTV with a P (respectively M) configuration induces
symmetry makes them promising candidates to build molecular a Δ (respectively Λ) chirality of the propeller-like arrangement
cages displaying a triple helical arrangement of the linkers. of the linkers.
Furthermore, we have previously reported that the chirality unit
Results and Discussion
in the south part and the chirality of the CTV unit in the north
part influence each other, suggesting that the chirality of the Synthesis of cage 1
CTV moiety could control the helical arrangement of the linkers According to the synthetic pathway shown in Scheme 1,
[12,13].
hemicryptophane host 1 was obtained in five steps [14,15].
Alkylation of vanillyl alcohol by chloroacetic acid in ethanol
We herein report the synthesis of the hemicryptophane 1 bear- under reflux afforded 2 in 73% yield. The CTV triester was ob-
ing both amide and amine functions in its three likers. In solu- tained by adding first one equivalent of HCl and then a catalyt-
tion, the 1H NMR spectrum shows a C3 symmetrical cage, ic amount of para-toluenesulfonic acid in methanol to com-
which is also observed in the solid state by X-ray crystallogra- pound 2. Then, compound 3 was reacted with ethylenediamine,
phy. Moreover, in the solid, amide and amine functional groups providing 4 in 48% yield. The reaction between 1,3,5-
of different linkers interact through hydrogen bonding, leading tris(bromomethyl)benzene and 2-hydroxybenzaldehyde provi-
Scheme 1: Synthesis of 1.
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Beilstein J. Org. Chem. 2018, 14, 1885–1889.
ded the precursor of the south unit 5 in 78% yield. Finally, a spectively. The signals of the aromatic protons of the linkers
[1 + 1] macrocyclization between 4 and 5 was achieved by a re- give two doublets and two triplets between 6.75 and 7.2 ppm,
ductive amination in a 1:1 CHCl3/MeOH mixture. A remark- whereas the diastereotopic aliphatic protons exhibit expected
able yield of 92% was obtained for this last step. As this kind of broad multiplets between 1.50 ppm and 2.36 ppm. The
reductive amination has been proved to be under thermo- Ar–CH2–NH diastereotopic protons appear as two doublets at
dynamic control, the resulting intermediate cage bearing three 3.87 and 3.49 ppm.
imine functions is highly sable [12,13]. Hydrogen bonds be-
tween the amide group and the formed imine function could Structure of cage 1
account for the high stability of this intermediate, shifting the Slow evaporation of a solution of cage 1 in a 1:1 mixture of
equilibrium between the different oligomers and the cage in CHCl3/MeOH affords crystals suitable for X-ray diffraction. In
favor of this latter (vide infra).
the solid, the hemicryptophane cage presents a perfect C3
symmetry (Figure 2). Further examination of the crystal struc-
ture reveals that 1 adopts a chiral conformation where the three
1H NMR of cage 1
The 1H NMR spectrum of hemicryptophane 1 in CDCl3 shows linkers are twisted into a triple helix with the lone pair of the
that this host presents, on average, a C3 symmetry in solution amines and the amide hydrogen atoms oriented toward the
(Figure 1). The characteristic signals of the CTV unit can be ob- cavity, while the amide oxygen atoms are oriented outwards.
served: one signal for the OMe group at 3.94 ppm, two singlets Intramolecular hydrogen bonding between the nitrogen of the
for the aromatic protons at 6.58 and 6.75 ppm and the expected amine function of one linker with the N–H of the amide group
AB systems for the CH2 bridges at 4.67 and 3.44 ppm. The aro- of another arm can account for this helical structure
matic protons of the benzene ring in the south part of the cage (Namine···Namide distances of 2.97 Å). This structure sheds light
and the corresponding diastereotopic CH2 bridges displays a on the excellent yield achieved in the last step of the synthesis.
singlet at 7.46 ppm and two doublets at 5.11 and 4.92 ppm, re- Indeed, such intramolecular hydrogen bonding probably also
Figure 1: 1H NMR spectrum of 1 (400 MHz, CDCl3).
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Beilstein J. Org. Chem. 2018, 14, 1885–1889.
Figure 2: X-ray molecular structure of 1. Hydrogen atoms are omitted for clarity; dashed lines represent hydrogen bonds.
occurred in the imine precursor, accounting for its high thermo- the propeller shape of the three aromatic rings in the south part
dynamic stability compared to oligomers that could also be of the hemicryptophane. This remote control of the helicity of
formed during the reaction between 4 and 5.
the southern part by that of the northern CTV unit, through nine
bonds, is allowed by this specific triple stranded helical struc-
Interestingly, one can also see that the CTV with the P configu- ture, which induces a strong twist of the whole framework.
ration (respectively M) imposes a Δ (respectively Λ) propeller-
like arrangement of the lateral arms, with a 120° turn around the This helical arrangement probably also occurred in solution.
C3 axis of the molecule (Figure 2). This also underlines how the Indeed, the south part of cage 1 is similar to that of cage 6
chirality of the CTV unit propagates along the linkers to induce (Figure 3) and the comparison between the signals of the
Figure 3: (a) Structure of compound 6. (b) 1H NMR of 6 (CDCl3, 400 MHz). (c) 1H NMR of 1 (CDCl3, 400 MHz).
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Beilstein J. Org. Chem. 2018, 14, 1885–1889.
7. Yamakado, R.; Mikami, K.; Takagi, K.; Azumaya, I.; Sugimoto, S.;
Matsuoka, S.-i.; Suzuki, M.; Katagiri, K.; Uchiyama, M.; Muranaka, A.
Chem. – Eur. J. 2013, 19, 11853–11857. doi:10.1002/chem.201301198
8. Ikeda, A.; Udzu, H.; Zhong, Z.; Shinkai, S.; Sakamoto, S.;
Yamaguchi, K. J. Am. Chem. Soc. 2001, 123, 3872–3877.
doi:10.1021/ja003269r
CH2–NH and Ar–O–CH2–Ar protons of cage 6 with those of
cage 1 shows respectively downfield and highfield shifts of
around −0.2 ppm and more than +0.8 ppm, respectively [16].
Moreover, the chemical shift differences of the two diastereo-
topic protons of the two AB systems are much greater for 1 than
for 6 with Δδ = 0.38 ppm for the CH2NH and of Δδ = 0.19 ppm
for the Ar–O–CH2–Ar of 1, compared to 0.07 ppm and
0.05 ppm for 6, respectively (Figure 3). This is consistent with a
more rigid structure of cage 1 in solution, as suggested by the
solid-state structure.
9. Malik, A. U.; Gan, F.; Shen, C.; Yu, N.; Wang, R.; Crassous, J.;
Shu, M.; Qiu, H. J. Am. Chem. Soc. 2018, 140, 2769–2772.
doi:10.1021/jacs.7b13512
10.Sato, H.; Bender, J. A.; Roberts, S. T.; Krische, M. J.
J. Am. Chem. Soc. 2018, 140, 2455–2459. doi:10.1021/jacs.8b00131
11.Zhang, D.; Martinez, A.; Dutasta, J.-P. Chem. Rev. 2017, 117,
4900–4942. doi:10.1021/acs.chemrev.6b00847
12.Chatelet, B.; Joucla, L.; Padula, D.; Di Bari, L.; Pilet, G.; Robert, V.;
Dufaud, V.; Dutasta, J.-P.; Martinez, A. Org. Lett. 2015, 17, 500–503.
doi:10.1021/ol5035194
Conclusion
In summary, we have described the synthesis of a new
hemicryptophane organic cage, which adopts a triple helical
structure because of the propeller-like arrangement of its three
linkers. The chirality of the CTV was shown to control that of
the whole helical cage structure, since only P-Δ and M-Λ enan-
tiomers were observed in solid state. NMR studies suggest that
this propeller-like arrangement also occurs in solution. Further
investigations are in progress in order to propagate the chirality
of the CTV to even more remote opposite sites through the for-
mation of such triple helical structures.
13.Gosse, I.; Robeyns, K.; Bougault, C.; Martinez, A.; Tinant, B.;
Dutasta, J.-P. Inorg. Chem. 2016, 55, 1011–1013.
doi:10.1021/acs.inorgchem.5b02750
14.Vériot, G.; Dutasta, J.-P.; Matouzenko, G.; Collet, A. Tetrahedron 1995,
51, 389–400. doi:10.1016/0040-4020(94)00904-9
15.Perraud, O.; Robert, V.; Gornitzka, H.; Martinez, A.; Dutasta, J.-P.
Angew. Chem., Int. Ed. 2012, 51, 504–508.
doi:10.1002/anie.201106934
16.Long, A.; Perraud, O.; Albalat, M.; Robert, V.; Dutasta, J.-P.;
Martinez, A. J. Org. Chem. 2018, 83, 6301–6306.
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Supporting Information
License and Terms
Supporting Information File 1
Procedures for the synthesis of compounds 1–5;
1H, 13C NMR, spectra mass spectra of compound 1 and
crystallographic data.
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ORCID® iDs
Christophe Aronica - https://orcid.org/0000-0001-7098-7355
(https://www.beilstein-journals.org/bjoc)
Jean-Pierre Dutasta - https://orcid.org/0000-0003-0948-6097
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