Cryptophanols, new versatile compounds for the synthesis of functionalized cryptophanes and polycryptophanes

Article abstract of DOI:10.1039/b109301k

After deprotection with a palladium catalyst, mono-allylated cryptophane-A (1, 2) and cryptophane-E (3) gave the new cryptophanols 4, 5 and 6, respectively, which are important key compounds for the preparation of monofunctionalized cryptophanes as well a

Full text of DOI:10.1039/b109301k

Cryptophanols, new versatile compounds for the synthesis of
functionalized cryptophanes and polycryptophanes†
Magali Darzac,a Thierry Brotin,*a Denis Bouchub and Jean-Pierre Dutasta*a
a Stéréochimie et Interactions Moléculaires, École Normale Supérieure de Lyon (UMR CNRS 5532), 46
Allée d'Italie, F-69364 Lyon Cedex 07, France. E-mail: dutasta@ens-lyon.fr; Fax: 33(0)472728483
b Centre de Spectrométrie de Masse, Université Claude Bernard Lyon I, 43 Boulevard du 11 Novembre
1918, F-69622 Villeurbanne Cedex, France
Received (in Cambridge, UK) 11th October 2001, Accepted 14th November 2001
First published as an Advance Article on the web 14th December 2001
After deprotection with a palladium catalyst, mono-ally-
lated cryptophane-A (1, 2) and cryptophane-E (3) gave the
new cryptophanols 4, 5 and 6, respectively, which are
important key compounds for the preparation of mono-
functionalized cryptophanes as well as for the design of large
supramolecular hosts such as the bis-cryptophanes 7 and
8.‡
Cryptophanes are fascinating molecules and represent an
important class of supramolecular hosts known to form stable
inclusion complexes with neutral and cationic molecules.1,2
This was recently enlightened with the exceptionally large
stable under acidic condition as the last step of the synthesis is
affinity of cryptophane-A for xenon in tetrachloroethane
usually performed in formic acid, and secondly, it has to be
solution (K ≈ 3000 M21 at 293 K).3 They are therefore of
easily cleaved. In addition this group has to be of small size as
potential interest for the development of new chemical sensors
previous work has shown that bulky substituents attached to the
in the field of molecular recognition and especially for
cryptophane precursors, such as long alkyl chains, prevent the
formation of the cryptophanes in the final cyclization step. This
results in a rather limited number of available efficient
protecting groups, even though the protection of phenol has
been widely described in the literature.5
applications of xenon NMR in biological systems.4 This
requires however the design of complex molecular receptors
using cryptophanes as the host. So far, little effort has been
made to develop the chemistry of cryptophanes exhibiting
specific functionality and bio-compatibility, or to build large
supramolecular systems with e.g. polymeric or dendritic
structures. The present work reports the synthesis of mono-
functionalized cryptophanes 1–3 bearing a single allyl group,
The choice of an adequate protecting group was thus
suggested and facilitated by our recent investigations on the
formation of cryptophanes from their precursors by mass
spectrometry. The behaviour of cryptophane precursors under
the LSIMS conditions showed some similarities with chemistry
in solution, and it was demonstrated that both the allyl and
benzyl moieties could be used as potential protecting groups
without altering the last cyclization step.6 In addition these
groups are easily cleaved by various methods.
The attachment of a single substituent requires a modification
of the strategy used for cryptophanes with C3 or D3 symmetry.
For this purpose we followed our procedure recently described
for the preparation of deuterium labelled cryptophanes.7 This
method based on a multistep synthesis involves the formation of
the two cyclotriveratrylene units at two different stages of the
preparation as depicted for 4 in Scheme 1.
Cyclotriveratrylene 9 was prepared according to a known
procedure8 and was allowed to react with the mono-protected
benzyl alcohol 10 in the presence of caesium carbonate as a base
to give compound 11 in 25–30% yield. This low yield was
mainly due to the formation of the di- and tri-substituted
derivatives. Reaction of 11 with 12 under similar conditions
gave the precursor 13 in good yields (60–80%). The use of the
tetrahydropyranyl (THP) ether function made the purification
easier of the desired material by column chromatography on
silica gel. A similar strategy was applied for the preparation of
cryptophanes 2 and 3 to give the corresponding precursors with
yields ranging from 60 to 80%.
The key step in this synthesis is the trimerization of the
benzyl alcohol groups of the precursors to give cryptophanes
1–3. Attempts to use classical reagents such as perchloric acid
in methanol or pure formic acid were unsuccessful and led to
non-isolable compounds. However, a mixture of chloroform
and formic acid as solvent (50+50) at 55 °C was found to be
effective for leaving the protecting group unreacted and led to
the formation of the desired compounds 1–3 in 35–40% yields.§
which are easily converted to the mono-hydroxylated com-
pounds 4–6. Hosts 4–6 are very attractive and important key
compounds for the synthesis of original substituted crypto-
phanes, such as chiral precursors and bio-compatible ligands for
molecular recognition, as well as for the generation of large
supramolecular systems. As an example we report the synthesis
of symmetrical (7) and unsymmetrical (8) bis-cryptophanes,
which have been fully characterized by usual analytical
techniques.
The substitution of only one protecting group in place of a
methoxy peripheral substituent in the cryptophane molecules
requires some restrictions. Firstly, this group has to be very
† Electronic supplementary information (ESI) available: experimental
details for compounds 4, 5, 6, 7, 8 and 14. See http://www.rsc.org/suppdata/
cc/b1/b109301k/
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CHEM. COMMUN., 2002, 48–49
This journal is © The Royal Society of Chemistry 2002

Fig. 1 MALDI spectrum of 8.
In summary, we report here the preparation of the new
cryptophanols 4–6 containing a single hydroxy function. The
strategy described herein provides the basis for a general
method for preparing functionalized cryptophanes. These new
molecules are believed to be key compounds for the elaboration
of large supramolecular systems, as suggested by the synthesis
of compounds 7, 8 and 14. Monofunctionalized cryptophanes
provide an original tool for the optical resolution of new
diastereoisomeric derivatives via the reaction of molecules 4–6
with a chiral substrate.10 We now focus our work on the
synthesis of selectively multiprotected cryptophanes for the
design of new elaborate structures such as hosts of biological
relevant interest, water-soluble cryptophanes and xenon@cryp-
tophane complexes.
Scheme 1 Reagents and conditions: i, Cs2CO3, DMF, 80 °C, 18 h; ii,
CHCl3, HCO2H (50+50), 55 °C, 2 h 30 min; iii, Pd(OAc)2, PPh3, THF,
NHEt2, H2O, 4 h.
We thank J.-C. Mulatier for skilful experimental assistance.
These yields are however significantly lower than that obtained
with cryptophane-A under the same experimental conditions.2
The difficulties encountered in the preparation of these new
derivatives led us to the conclusion that new routes using milder
conditions should also be examined. For instance it has been
reported that scandium triflate promotes calixarene formation in
moderate yields under mild conditions leaving unreacted allyl
groups.9 In the light of these results, attempts were made to
reproduce these experiments with cryptophane precursors. The
results appeared promising as, for instance, reaction of 13 with
scandium triflate (0.6 equiv.) in acetonitrile gave 1 in 10% yield
after purification. Finally, removal of the allyl group was
achieved by the use of a palladium catalyst in the presence of
diethylamine and water to give the unprotected cryptophanes
4–6 in 80–85% yields.§ These new cryptophanes have been
isolated as their anti chiral isomer and are of large potential
interest in the design of new supramolecular hosts.
Notes and references
‡ Presented at the 6th International Conference on Calixarenes, May
29–June 2, 2001, Twente (NL).
§ The cryptophanes described herein were purified by column chromatog-
raphy on silica gel and recrystallized in a chloroform–ethanol mixture. All
new compounds were fully characterized by 1H and 13C NMR spectroscopy
and by HRMS. The detailed synthesis of 4–8 and 14 will be presented in a
forthcoming full paper.
1 L. Garel, B. Lozach, J.-P. Dutasta and A. Collet, J. Am. Chem. Soc.,
1993, 115, 11652; L. Garel, J.-P. Dutasta and A. Collet, Angew. Chem.,
Int. Ed. Engl., 1993, 32, 1169; A. Collet, in Comprehensive Supramo-
lecular Chemistry, Pergamon, New York, 1996, vol. 2, p. 325.
2 A. Collet, J.-P. Dutasta, B. Lozach and J. Canceill, Topics in Current
Chemistry, 1993, 165, 103; A. Collet, J.-P. Dutatsa and B. Lozach, Bull.
Soc. Chim. Belg., 1990, 99, 617.
3 K. Bartik, M. Luhmer, J.-P. Dutasta, A. Collet and J. Reisse, J. Am.
Chem. Soc., 1998, 120, 784.
Hosts 7 and 8 were designed for the study of the guest
exchange processes between cryptophanes and exemplify the
potentialities of cryptophanols 4–6. Compounds 7 and 8 are
similar except that one cryptophane in molecule 8 has been
replaced by its partially deuterated congener. Both compounds
have been obtained by a Williamson synthesis using caesium
carbonate as base and 1,10-diiododecane as alkylating agent.
Compound 7 was obtained in 30% yield in DMF from two
equivalents of 4 and one equivalent of 1,10-diiododecane. The
unsymmetrical molecule 8 required the synthesis of compound
14, which was obtained by treating 4 with an excess of
1,10-diiododecane. The reaction of 14 and cryptophanol 5 under
similar conditions, afforded compound 8.§ Bis-cryptophanes 7
4 C. Dybowski and N. Bansal, Annu. Rev. Phys. Chem., 1991, 42, 433; P.
J. Barrie, J. Klinowski and D. Raftery, Prog. Nucl. Magn. Reson.
Spectros., 1992, 91; M. Luhmer, B. M. Goodson, Y. Q. Song, D. D.
Laws, L. Kaiser, M. C. Cyrier and A. Pines, J. Am. Chem. Soc., 1998,
120, 3502.
5 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, 2nd edn., 1991.
6 T. Brotin, M. Darzac, D. Forest, M. Becchi and J.-P. Dutasta, J. Mass
Spectrom., 2001, 36, 1092.
7 T. Brotin, A. Lesage, L. Emsley and A. Collet, J. Am. Chem. Soc., 2000,
122, 1171; T. Brotin, T. Devic, A. Lesage, L. Emsley and A. Collet,
Chem. Eur. J., 2001, 7, 1561.
8 J. Canceill, A. Collet and G. Gottarelli, J. Am. Chem. Soc., 1984, 106,
5997.
and 8 have been isolated as a mixture of stereoisomers. 1H, 13
C
9 H. Konishi, H. Sakakibara, K. Kobayashi and O. Morikawa, J. Chem.
Soc., Perkin Trans. 1, 1999, 2583.
10 T. Brotin, M. Darzac, R. Barbe and J.-P. Dutasta, unpublished results.
NMR and MALDI mass spectrometry were used to ascertain the
structures of molecules 7 and 8 (Fig. 1).
CHEM. COMMUN., 2002, 48–49
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