Shorter and modular synthesis of hemicryptophane-tren derivatives

Article abstract of DOI:10.1021/ol201355t

Hemicryptophanes are host molecules with many applications as supramolecular catalysts or in ion selective recognition. A very convenient and efficient modular approach for the synthesis of hemicryptophane-tren (tren, tris(2-aminoethyl)-amine) derivatives

Full text of DOI:10.1021/ol201355t

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3706–3709
Shorter and Modular Synthesis of
Hemicryptophane-tren Derivatives
Bastien Chatelet, Elina Payet, Olivier Perraud, Pascal Dimitrov-Raytchev,
ꢀ
Laure-Lise Chapellet, Veronique Dufaud, Alexandre Martinez,* and Jean-Pierre Dutasta*
ꢀ
Laboratoire de Chimie, CNRS, Ecole Normale Superieure de Lyon, 46 Allee d’Italie,
ꢀ
ꢀ
F-69364 Lyon, France
alexandre.martinez@ens-lyon.fr; jean-pierre.dutasta@ens-lyon.fr
Received May 19, 2011
ABSTRACT
Hemicryptophanes are host molecules with many applications as supramolecular catalysts or in ion selective recognition. A very convenient and
efficient modular approach for the synthesis of hemicryptophane-tren (tren, tris(2-aminoethyl)-amine) derivatives has been developed. For
instance, hemicryptophane 1 was synthesized at the gram scale in four steps from vanillyl alcohol compared to the previous seven-step
procedure. The size, shape, and functionalities of the molecular cavity were also easily modified.
The efficient and versatile synthesis of molecular con-
tainers is one of the key aspects of supramolecular
chemistry.1 The cryptophane hosts, which are constructed
from two cyclotriveratrylene (CTV) units, can encapsulate
a wide variety of guests and have remarkable binding
properties toward neutral or charged guests and efficient
chiral recognition properties.2 Recently improved syn-
thetic routes for cryptophanes, involving fewer steps and
higher yields, have been reported. In particular Rousseau
et al.3 and Dmochowski et al.4 developed respectively a
scalable synthesis of cryptophane-111 and a shorter synth-
esis of tribsubstituted cryptophane-A derivatives. The
hemicryptophanes5 are ditopic host molecules and were
found to be a novel class of efficient supramolecular
catalysts,6 selective hosts for ammonium,5a ion pairs,7
C60 fullerene,8 and enantioselective carbohydrate receptors.9
They led to the design of novel molecular mechanical com-
ponents as propellers10 or gyroscopes.11 We have previously
described the synthesis of hemicryptophane 1 (Scheme 1),
which contains a CTV unit, providing a rigid scaffold with a
lipophilic cavity, and a C3-symmetrical ligand derived from
tris(2-aminoethyl)-amine (tren).12 Supramolecular ligands
combining these two features have been used to complex
(6) Martinez, A.; Dutasta, J.-P. J. Catal. 2009, 267, 188–192.
(7) (a) Le Gac, S.; Jabin, I. Chem.;Eur. J. 2008, 14, 548–557. (b)
Perraud, O.; Robert, V.; Martinez, A.; Dutasta, J.-P. Chem.;Eur. J.
2011, 17, 4177–4182.
(8) Wang, L.; Wang, G.-T.; Zhao, X.; Jiang, X.-K.; Li, Z.-T. J. Org.
Chem. 2011, 76, 3531–3535.
(1) (a) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 707–724.
(b) Sanders, J. K. M. Chem.;Eur. J. 1998, 4, 1378–1383. (c) Lehn, J.-M.
Rep. Prog. Phys. 2004, 67, 245–249. (d) Yoshizawa, M.; Klosterman,
J. K.; Fujita, M. Angew. Chem., Int. Ed. 2009, 48, 3418–3438.
(2) Brotin, T.; Dutasta, J.-P. Chem. Rev. 2009, 109, 88–130.
(9) Perraud, O.; Martinez, A.; Dutasta, J.-P. Chem. Commun. 2011,
47, 5861–5863.
(10) (a) Martinez, A.; Robert, V.; Gornitzka, H.; Dutasta, J.-P.
Chem.;Eur. J. 2010, 16, 520–527. (b) Martinez, A.; Guy, L.; Dutasta,
J.-P. J. Am. Chem. Soc. 2010, 132, 16733–16734.
(11) Khan, N. S.; Perez-Aguilar, J. M.; Kaufmann, T.; Hill, P. A.;
Taratula, O.; Lee, O.-S.; Carroll, P. J.; Saven, J. G.; Dmochowski, I. J.
J. Org. Chem. 2011, 76, 1418–1424.
(12) Dimitrov Raytchev, P.; Perraud, O.; Aronica, C.; Martinez, A.;
Dutasta, J.-P. J. Org. Chem. 2010, 75, 2099–2102.
ꢀ
(3) Traore, T.; Delacour, L.; Garcia-Argote, S.; Berthault, P.;
Cintrat, J.-C.; Rousseau, B. Org. Lett. 2010, 12, 960–962.
(4) Taratula, O.; Hill, P. A.; Bai, Y.; Khan, N. S.; Dmochowski, I. J.
Org. Lett. 2011, 13, 1414–1417.
(5) (a) Canceill, J.; Collet, A.; Gabard, J.; Kotzyba-Hibert, F.; Lehn,
J.-M. Helv. Chim. Acta 1982, 65, 1894–1897. (b) Smeets, J. W. H.;
Coolen, H. K. A. C.; Zwikker, J. W.; Nolte, R. J. M. Recl. Trav. Chim.
Pays-Bas 1989, 108, 215–218. (c) Rapenne, G.; Crassous, J.; Collet, A.;
Echegoyen, L.; Diederich, F. Chem. Commun. 1999, 1121–1122. (d)
Gosse, I.; Dutasta, J.-P.; Perrin, M.; Thozet, A. New J. Chem. 1999, 23,
545–548. (e) Gautier, A.; Mulatier, J.-C.; Crassous, J.; Dutasta, J.-P.
Org. Lett. 2005, 7, 1207–1210.
(13) Makita, Y.; Sugimoto, K.; Furuyoshi, K.; Ikeda, K.; Fujiwara,
S.; Shin-ike, T.; Ogawa, A. Inorg. Chem. 2010, 49, 7220–7222.
r
10.1021/ol201355t
Published on Web 06/10/2011
2011 American Chemical Society

zinc13 and phosphorus14 leading to original compounds
with unexpected reactivities. Host 1 was also found to be
an efficient ammonium receptor, providing high associa-
tion constants for the dopamine neurotransmitter.15
Nevertheless, its synthesis involved seven steps with a 3%
overall yield and a final time-consuming reduction step.
Herein, we wish to report a shorter four-step synthesis of
host 1 from commercially available vanillyl alcohol. The
modular character of the synthesis provides an easy way to
access variable molecular cavity sizes and to change the
functional groups present in the linkers.
we opted to vary the linkers to prepare different analogues
of hemicryptphane 1 starting from the same alkyl-bromi-
nated CTV precursor 3. This should allow synthetic devel-
opment of new hosts with different shapes and functions
and variation in the volume of the inner molecular cavity,
while retaining the tren and CTV key moieties. We first
envisioned modifying the cavity size by changing the
relative position of the aldehyde and the hydroxy groups
on the aromatic linker. The corresponding hemicrypto-
phanes 5 and 6 were preparedinrespectively 50% and 49%
overall yields from precursor 3 via the two-step sequence
that involved nucleophilic substitution followed by reduc-
tive amination (Figure 2bÀc). Single crystals of host 5
suitable for X-ray diffraction analysis were obtained by
slow evaporation from a CH2Cl2/diethyl ether solution.
Scheme 1. Four-Step Synthesis of Hemicryptophane 1
Figure 1. X-ray molecular structure of host 5.
We investigated the new synthetic pathway for hemi-
cryptophane 1 as shown in Scheme 1. Starting from the
commercially available vanillyl alcohol and 1,2-dibro-
moethane reagents to give compound 2, the alkyl-bromi-
nated CTV 3 was synthesized in two steps according to the
procedure described by Dmochowski et al.4 The prepara-
tion of the hemicryptophane precursor 4 was then con-
ducted under standard conditions by reacting 3 with
4-hydroxybenzaldehyde in DMF in the presence of
Cs2CO3. Compound 4 was isolated with excellent yields
without theneedfor column chromatography purification.
The condensation of 4 with tris(2-aminoethyl)-amine di-
luted ina CHCl3/CH3OHmixture, followedby a reduction
step with sodium borohydride, afforded 1 in 77% yield.
Hemicryptophane 1 has thus been obtained in 8% overall
yield via a four-step synthetic route, which improves our
seven-step procedure previously published (3% overall
yield). Moreover, this pathway was applied to larger
quantities of starting materials allowing the production
of host 1 at the gram scale. This strategy also avoids the
time-consuming reduction step, which required nearly one
week of reaction time.
The molecule adopts a compact structure with the
molecular cavity occupied by one of the linkers so that
the tren moiety is significantly deviated from the inner
cavity (Figure 1). This is an unexpected form of the
molecular host, which generally exists as solvate with an
encapsulated guest solvent inside the cavity. For instance,
the crystal structure of molecule 1, previously published,
has revealed the C3-symmetry of the host and the presence
of a well-preorganized cavity imprisoning a molecule of n-
pentane.12 This highlights the significantly different behavior
in the solid state of these two compounds, since both the
cavity size and its shape are remarkably affected by the
nature of the linkers. Second, an electron-donating group
was incorporated in the aromatic part of the linker at
different positions, leading to hosts 7 and 8 (Figure 2dÀe).
Interestingly, compound 8 presents a cavity including six
methoxy groups, thus closer to that of cryptophane-A than 1.
Therefore, it could combine the complexation properties of
cryptophanes toward small neutral molecules and the cata-
lytic activities of hemicryptophane complexes. Third, the
chlorine electron-withdrawing group was also successfully
integrated in the host’s aromatic walls to give compound 9
(Figure 2f). Nevertheless, the cyclization steps failed when
fluorine or nitro groups were present in the hemicryptophane
precursors (17 and 18, respectively) (Figure 2gÀh). The
introduction of these strong electron-withdrawing substitu-
ents on the benzaldehyde moiety can lead to more stable
Given the potential of this synthetic pathway, we in-
vestigated the possible functions within this structure, and
(14) Dimitrov Raytchev, P.; Martinez, A.; Gornitzka, H.; Dutasta,
J.-P. J. Am. Chem. Soc. 2011, 133, 2157–2159.
(15) Perraud, O.; Lefevre, S.; Robert, V.; Martinez, A.; Dutasta,
J.-P. Unpublished results.
Org. Lett., Vol. 13, No. 14, 2011
3707

Figure 2. Hemicryptophanes and precursors synthesized from the alkyl-brominated CTV 3 and the corresponding starting compounds aÀj.
imine bonds,16 preventing the reversibility of the imine bonds
formation, thus avoiding the thermodynamic control of the
reaction which could account for the unsuccessful results.
Fourthly, hemicryptophanes with larger aromatic walls
were obtained when naphthyl moieties were included in the
linkers, and compounds10and 11weresynthesizedin29%
and 47% overall yields from the brominated CTV 3
(Figure 2iÀj). Note that these hosts could lead to optical
chemosensors by giving a fluorescence response when
bound to a suitable guest.17
(16) Godoy-Alcantar, C.; Yatsimirsky, A. K.; Lehn, J.-M. J. Phys.
Org. Chem. 2005, 18, 979–985.
(17) Bell, T. W.; Hext, N. M. Chem. Soc. Rev. 2004, 33, 589–598.
Org. Lett., Vol. 13, No. 14, 2011
3708

In summary, a short synthesis of hemicryptophane 1 has
been developed. Improvement of the overall yield was also
achieved allowing the isolation of host 1 on the gram scale.
Moreover, the size, shape, and function in the aromatic
walls of the cavity can be modified through this synthetic
pathway, whereas the key CTV and tren moieties are
maintained in the host structure. Therefore, seven new
hemicryptophane hosts have been prepared. This proce-
dure should conceivably allow synthesis of a large number
of CTV-based hemicryptophane-tren molecules with var-
ious functionalities and an inner cavity of modulable size.
Acknowledgment. Support from the French Ministry
of Research (Project ANR-2010JCJC 711 1 [(Sup)3Base]) is
acknowledged. The authors greatly thank Dr. Erwann
ꢀ
Jeanneau from the Centre de Diffractometrie Henri
Longchambon (CDHL, Institute of Chemistry, Lyon)
for X-ray analysis and X-ray facilities access.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data; X-ray diffraction
analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
3709