ORGANIC
LETTERS
2012
Vol. 14, No. 23
5816–5819
Two-Stage Amplification of Receptors
Using a Multilevel Orthogonal/Simultaneous
Dynamic Combinatorial Library
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Andrea M. Escalante, A. Gaston Orrillo, Ignacio Cabezudo, and Ricardo L. E. Furlan*
´
ꢀ
Farmacognosia, Facultad de Ciencias Bioquımicas y Farmaceuticas, Universidad
Nacional de Rosario, Rosario, Argentina
Received August 6, 2012
ABSTRACT
Sequential activation of different reversible exchange reactions in a dynamic combinatorial library allows directed exploration of the chemical
space: initially a macrocyclic scaffold is selected by the template and finally side chain and conformational constrains are introduced into such a
scaffold.
In the past decade, Dynamic Combinatorial Chemistry1
has proven invaluable for the identification of novel binders
for a variety of targets, impacting several fields such us
materials science,2 drug and fragrance delivery,3 two phase
transport,4 biosensing,5 and systems chemistry.6
Dynamic combinatorial libraries (DCLs) have become a
powerful source of high affinity receptors with complex
and, sometimes unexpected, structures.7
Most of the DCLs prepared to date have involved only
one reversible exchange process; however, there are some
examples where two exchange reactions are combined
in the same system. Depending on the relative functional
state of the exchange processes (activated/inactivated), the
systems can be simultaneous or orthogonal. In simulta-
neous DCLs, both exchange reactions occur at the same
time, as observed in the dynamic system based in thioesters
and disulfides reported by Otto et al.8 In orthogonal
DCLs, each reversible reaction used can be activated under
different conditions allowing their manipulation in a se-
quential order.9 In previous work the groups of Otto,10
Miller,11 and ourselves12 have described the combination
of hydrazones and disulfides to prepare orthogonal DCLs.
(1) (a) Cougnon, F. B. L.; Sanders, J. K. M. Acc. Chem. Res. 2012,
ASAP article DOI 10.1021/ar200240m. (b) Corbett, P. T.; Leclaire, J.;
Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem.
Rev. 2006, 106, 3652.
(2) (a) aMoulin, E.; Cormos, G.; Giuseppone, N. Chem. Soc. Rev. 2012,
41, 1031. (b) Hirsch, A. K. H; Buhler, E.; Lehn, J.-M. J. Am. Chem. Soc.
2012, 134, 4177. (c) Folmer-Andersen, J. F.; Lehn, J.-M. J. Am. Chem. Soc.
2011, 133, 10966. (d) Ruff, Y.; Buhler, E.; Candau, S.-J.; Kesselman, E.;
Talmon, Y.; Lehn, J.-M. J. Am. Chem. Soc. 2010, 132, 2573.
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(3) (a) Buchs (nee Levrand), B.; Fieber, W.; Vigouroux-Elie, F.;
Sreenivasachary, N.; Lehn, J.-M.; Herrmann, A. Org. Biomol. Chem.
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2011, 9, 2906.(b)Buchs(nee Levrand), B.; Godin, G.; Trachsel, A.; de Saint
Laumer, J.-Y.; Lehn, J.-M.; Herrmann, A. Eur. J. Org. Chem. 2011, 681. (c)
Herrmann, A. Org. Biomol. Chem. 2009, 7, 3195. (d) Herrmann, A.;
Giuseppone, N.; Lehn, J.-M. Chem.;Eur. J. 2009, 15, 117. (e) West, K.;
Otto, S. Curr. Drug Discovery Technol. 2005, 2, 123.
(7) Otto, S. Acc. Chem. Res. 2012, ASAP article DOI 10.1021/
ar200246j.
(8) Leclaire, J.; Vial, L.; Otto, S.; Sanders, J. K. M. Chem. Commun.
2005, 1959.
(9) Goral, V.; Nelen, M. I.; Eliseev, A. V.; Lehn, J.-M. Proc. Natl.
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(4) (a) Perez-Fernandez, R.; Pittelkow, M.; Belenger, A. M.; Lane,
L. A.; Robinson, C. V.; Sanders, J. K. M. Chem. Commun. 2009, 3708.
€
(b) Saggiomo, V.; Luning, U. Chem. Commun. 2009, 3711.
(5) (a) Otto, S.; Severin, K. Top. Curr. Chem. 2007, 277, 267. (b) Buryak,
A.; Severin, K. Angew. Chem., Int. Ed. 2005, 44, 7935. (c) Rochat, S.; Gao,
J.; Qian, X.; Zaubitzer, F.; Severin, K. Chem.;Eur. J. 2010, 16, 104. (d)
Zaubitzer, F.; Riis-Johannessen, T.; Severin, K. Org. Biomol. Chem. 2009,
Acad. Sci. U.S.A. 2001, 98, 1347.
(10) Rodriguez-Docampo, Z.; Otto, S. Chem. Commun. 2008, 5301.
(11) Gromova, A. V.; Ciszewski, J. M.; Miller, B. L. Chem. Commun.
2012, 48, 2131.
€
€
7, 4598. (e) Muller-Graff, P.-K.; Szelke, H.; Severin, K.; Kramer, R. Org.
Biomol. Chem. 2010, 8, 2327.
(6) (a) Hunt, R. A. R.; Otto, S. Chem. Commun. 2011, 847. (b) Ludlow,
R. F.; Otto, S. Chem. Soc. Rev. 2008, 37, 101.
(12) Orrillo, A. G.; Escalante, A. M.; Furlan, R. L. E. Chem.
Commun. 2008, 5298.
r
10.1021/ol3027335
Published on Web 11/15/2012
2012 American Chemical Society