Organica

ORGANIC
LETTERS

Freezing Imine Exchange in Dynamic
Combinatorial Libraries with Ugi
Reactions: Versatile Access to
Templated Macrocycles

2007
Vol. 9, No. 23
4733-4736

Ludger A. Wessjohann,* Daniel G. Rivera, and Fredy Leon
´
Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry,
Weinberg 3, D-06120 Halle/Saale, Germany
wessjohann@ipb-halle.de
ReceivedAugust 27, 2007

ABSTRACT

A novel approach to freeze the imine exchange process in dynamic combinatorial libraries by Ugi reactions was developed. Macrocyclic
oligoimine libraries previously formed and altered by addition of metal templates are efficiently quenched by multiple multicomponent reactions.
The approach may be considered as an alternative to the typical reduction with borohydridesand delivers polyazamacrocycles with variable
side arms. High dilution is not required to achieve high yields.

Dynamic combinatorial chemistry (DCC) has evolved as a
selection-based strategy to achieve novel supramolecular
receptors, guests, and ligands.1 Three different transimination
reactions have been employed in DCC: hydrazone, oxime,
and imine bond exchange.1
Despite the greaterstability of hydrazones and oximes,
the imine linkage still has preference for many authors due
to the better availability of amino and oxo functions in natural
and synthetic building blocks.2,3 However, because of the
(1) For reviews, see: (a) Corbett, P. T.; Leclaire, J.; Vial. L.; West, K.
R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem. ReV. 2006, 106, 3652.
(b) Cheeseman, J. D.;Corbett, A. D.; Gleason, G. L.; Kazlauskas, R. J.
Chem.sEur. J. 2005, 11, 1709. (c) Ramstrom, O.; Bunyapaiboonsri, T.;
¨
Lohmann, S.; Lehn, J.-M. Biochim. Biophys. Acta 2002, 1572, 178. (d)
Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2002, 41, 898. (e) Lehn, J.-M. Chem.sEur. J.
1999, 5, 2455.
10.1021/ol7021033 CCC: $37.00
Publishedon Web 10/09/2007

© 2007 American Chemical Society

instability of Schiff bases, the analysis of imine-based
dynamic combinatorial libraries (DCLs) always requires a
(2) For examples of acyclic imine-based DCLs, see: (a) Zameo, S.;
Vauzeilles, B.; Beau, J.-M. Angew. Chem., Int. Ed. 2005, 44, 965. (b)
Bugaut, A.; Toulmet, J.-J.; Bayner, B. Angew. Chem., Int. Ed. 2004, 43,
3144. (c)Albrecht, M.; Janser, I.; Runsink, J.; Raabe, G.; Weis, P.; Frohlich,
¨
R. Angew. Chem., Int. Ed. 2004, 43, 6662. (d) Hochgurtel, M.; Biesinger,
¨
R.; Kroth, H.; Piecha, D.; Hofmann, M. W.; Krause, S.; Shaaf, O.; Nicolau,
C.; Eliseev, A. V. J. Med. Chem. 2003, 46, 356. (e) Karan, C.; Miller, B.
L. J. Am. Chem. Soc. 2001, 123, 7455. (f) Huc, I.; Lehn, J.-M. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94,2106.
(3) For recent examples of macrocyclic imine-based DCLs, see: (a)
Gonzalez-Alvarez, A.; Alfonso, I.; Gotor, V. Chem. Commun. 2006, 2224.
´
Ä
(b) Gregolinki, J.; Lisowski, J.; Lis, T. Org. Biomol. Chem. 2005, 3, 3161.
´
(c) Katayev, E. A.; Pantos, G. D.; Reshetova, M. D.; Khrustalev, V. N.;
Lynch, V. M.; Ustynyuk, Y. A.; Sessler, J. L. Angew. Chem., Int. Ed., 2005,
44, 1. (d)Gonzalez-Alvarez, A.; Alfonso, I.; Lopez-Ortiz, F.; Aguirre, A.;
´
Ä
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Garcıa-Granda, S.; Gotor, V. Eur. J. Org. Chem. 2004, 1117. (e) Storm,
´
O.; Luning, U. Chem.sEur. J. 2002, 8, 793. (f) Star, A.; Goldberg, I.; Fuchs,
¨
B. Angew. Chem., Int. Ed. 2000, 39, 2685.

Scheme 1.

Ugi-4CR-Based Quenching Approach of Macrocyclic Oligoimine-Based DCLs Built from 1, 2, and 3

reduction step toallow the isolation of the library members.
To our knowledge, switching-off the imine exchange by
reduction is the only procedure performed to date to quench
the dynamic process of this type of DCLs.1-3
Herein we report the use of the Ugi four-component
reaction (Ugi-4CR) to freeze the exchange process of iminebased DCLs. The Ugi-4CR is the one-pot condensation of a
primary amine, an oxo...