holds great potential, particularly when combined with
combinatorial chemistry. Dynamic combinatorial libraries
(DCLs) of noncovalent capsules or cages4 have been previ-
ously realized by others.5 We now report the first example
of a DCL containing covalent cages.
Scheme 1. Synthesis of Trithiol Building Block 59-12
In dynamic combinatorial chemistry,6 a mixture of com-
pounds is generated by linking building blocks together
through a reversible reaction. Reversibility ensures that the
DCL is in thermodynamic equilibrium and responsive to
external influences. Upon exposure of a DCL to a molecular
target, those library members that bind to the target are
stabilized; the equilibrium shifts and strong binders are
amplified at the expense of poor binders in the library.7 After
the exchange of building blocks has been turned off, the
amplified compound(s) can be isolated directly from the
frozen library. Thus, dynamic combinatorial chemistry not
only is a method of selection but also provides a synthetic
route for the selected compounds.
Following our successful work on DCLs of linear and
macrocyclic receptors starting from mono and dithiols,8 we
have started to explore the use of trithiols to generate DCLs
of cage-like structures. We now report the first results of
these studies, based on cysteine-derived trithiol building
block 5.
The synthesis of trithiol 5 is shown in Scheme 1. We have
chosen to protect the thiol and carboxylate groups of the
cysteine subunits with acid labile protecting groups (trityl
and tert-butyl, respectively). The protected cysteine 3 should
allow straightforward coupling to any suitable carboxylic-
acid derived scaffold after which the thiol moiety (for
disulfide formation and exchange) and carboxylic acid (for
water solubility) can be liberated in a single clean depro-
tection step.
In this case, the protected cysteine 3 was coupled to 1,3,5-
benzenetricarbonyl chloride to produce the protected trithiol
4. Finally, removal of the tert-butyl and trityl protecting
groups to yield 5 was achieved using trifluoroacetic acid and
triethylsilane. In addition, ethanethiol had to be added to
prevent migration of the tert-butyl group to the cysteine thiol.
We have prepared and analyzed DCLs made from trithiol
building block 5 and two dithiol building blocks 6 and 7,
which should allow access to mixed cages (Figure 1).
(4) As the term “capsules” is associated with structures that have receptor
characteristics, we use the term “cages” to describe the macrobicyclic
structures in our libraries. Others have used this term before to describe
structures that do not necessarily have receptor characteristics (see ref 2d).
(5) For a review, see: (a) Otto, S.; Sanders, J. K. M. In Supramolecular
Libraries, Encyclopedia of Supramolecular Chemistry; Atwood, J., Steed,
J., Eds.; Marcel Dekker: New York, 2004; pp 1427-1433. For examples
using hydrogen bonding, see: (b) Crego-Calama, M.; Hulst, R.; Fokkens,
R.; Nibbering, N. M. M.; Timmerman, P.; Reinhoudt, D. N. Chem. Commun.
1998, 1021. (c) Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.
Angew. Chem., Int. Ed. 2000, 39, 755. (d) Hof, F.; Nuckolls, C.; Rebek, J.,
Jr. J. Am. Chem. Soc. 2000, 122, 4251. For examples using metal-ligand
coordination, see: (e) Albrecht, M.; Blau, O.; Frolich, R. Chem. Eur. J.
1999, 5, 48. (f) Kusukawa, T.; Fujita, M. J. Am. Chem. Soc. 1999, 121,
1397. (g) Hiraoka, S.; Fujita, M. J. Am. Chem. Soc. 1999, 121, 10239. (h)
Hiraoka, S.; Fujita, M. Chem. Commun. 2000, 1509. (i) Ziegler, M.;
Miranda, J. J.; Andersen, U. N.; Johnson, D. W.; Leary, J. A.; Raymond,
K. N. Angew. Chem., Int. Ed. 2001, 40, 733. (j) Kubota, Y.; Sakamoto, S.;
Yamaguchi, K.; Fujita, M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4854.
(k) Albrecht, M.; Janser, I.; Runsick, J.; Raabe, G.; Weis, P.; Fro¨lich, R.
Angew. Chem., Int. Ed. 2004, 43, 6662.
(6) For reviews, see: (a) Karan, C.; Miller, B. L. Drug DiscoV. Today
2000, 5, 67. (b) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J.
K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898. (c) Ramstro¨m,
O.; Bunyapaiboonsri, T.; Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta
2002, 1572, 178. (d) Otto, S. Curr. Opin. Drug DiscoV. DeV. 2003, 6, 509.
(7) Exceptions can occur under certain conditions: (a) Grote, Z.;
Scopelliti, R.; Severin, K. Angew. Chem., Int. Ed. 2003, 42, 3821. (b)
Severin, K. Chem. Eur. J. 2004, 10, 2565. (c) Corbett, P. T.; Otto, S.;
Sanders, J. K. M. Chem. Eur. J. 2004, 10, 3139. (d) Saur, I.; Severin, K.
Chem Commun. 2005, 1471.
Figure 1. Trithiol and dithiol building blocks used in DCLs.
(8) (a) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. J. Am. Chem. Soc.
2000, 122, 12063. (b) Otto, S. Furlan, R. L. E.; Sanders, J. K. M. Science
2002, 297, 590. (c) Brisig, B.; Sanders J. K. M.; Otto, S. Angew. Chem.,
Int. Ed. 2003, 42, 1270. (d) Otto, S.; Kubik, S. J. Am. Chem. Soc. 2003,
125, 7804.
Disulfide formation occurs readily by oxidation of an
aqueous solution of the thiols upon exposure to air. Exchange
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Org. Lett., Vol. 7, No. 13, 2005