Supramolecular compounds from multiple ugi multicomponent macrocyclizations: Peptoid-based cryptands, cages, and cryptophanes

Article abstract of DOI:10.1021/ja060720r

The first 3-fold multicomponent macrocyclizations of trifunctional building blocks were developed to produce, in one pot, cryptands, cages, and cryptophanes with peptoid tethers carrying additional recognition motifs. The straightforward, efficient, and d

Full text of DOI:10.1021/ja060720r

Published on Web 05/16/2006
Supramolecular Compounds from Multiple Ugi Multicomponent
Macrocyclizations: Peptoid-based Cryptands, Cages, and Cryptophanes
Daniel G. Rivera and Ludger A. Wessjohann*
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3,
D-06120 Halle/Saale, Germany
Received January 31, 2006; E-mail: wessjohann@ipb-halle.de
Scheme 1. Peptoid-Based Cryptands by 3-Fold Ugi-4CR-Based
Macrocyclizations
The design and synthesis of macrocycles capable of binding and
encapsulating a target species has been recognized as a milestone
in the development of supramolecular chemistry.1 Cryptands1 and
cryptophanes1,2 are among the most-studied types of macrocyclic
receptors due to their recognized capability to include either ions
or neutral molecules, depending on the size and nature of the cavity
as well as the binding properties of the tether chains.
Herein, we report a very efficient and straightforward methodol-
ogy for the synthesis of cryptands, cages, and cryptophanes
containing multidimensional arrays of peptoid cores suitable for
forming inclusion complexes. This approach features the one-pot
assembly of complex molecular architectures by Ugi-type multiple
multicomponent macrocyclizations3 of trifunctional building blocks.
The Ugi four-component reaction (Ugi-4CR) is a highly efficient
process in which a primary amine, an oxo compound, a carboxylic
acid, and an isocyanide react in one pot to form a peptoid.4 The
incorporation of Ugi-peptoid backbones into host-like macrocycles
represents a completely new and promising outlook for molecular-
recognition studies. The cyclic peptoid core may be seen as a
binding motif capable of complexing with ions in a manner similar
to cyclic peptides, where the amide bonds enable binding the guest
on the basis of the π- and σ-donor behavior or the hydrogen-bonding
pattern.
Scheme 1 summarizes the synthesis of cryptands by 3-fold Ugi-
4CR-based macrocyclizations unifying 12 reaction steps of 8
components in one pot. All macrocyclizations were accomplished
under pseudodilution conditions by slowly adding one of the
components to a stirred mixture of the others. The simplicity of
this procedure and the great complexity that can be achieved with
minimized synthetic cost make this methodology an interesting
candidate for the combinatorial generation of synthetic receptors.
The syntheses of cryptands 2, 8, and 9 show the prospect of
employing monoprotected amino acids and diamines to install
appended functionalities with additional binding capacity, e.g., NH2
and CO2H. Other Ugi-compatible amino acids presenting chemical
motifs of known catalytic or recognition relevance may also be
incorporated to produce desired properties.
Another key feature of this strategy is the rapid variation of
molecular topologies accessible by using constitutionally different
scaffolds. This is properly illustrated in Schemes 2 and 3, where
the synthetic planning is directed to demonstrate the possibility of
easily creating upper and lower receptor poles highly diverse in
shape and binding features. We focused also on the use of extended
structures to be incorporated into the host cores, thus creating highly
functionalized, cage-like structures with large interaction surfaces.
Aryl groups are the simplest and most readily available rigid
elements, albeit with two-dimensional functionalization. Addition-
ally, steroids represent an amenable preorganized scaffold for three-
dimensional functionalization with Ugi-reactive functional groups
and binding motifs tailored for complementarity of target guests.3a,5
Scheme 2 shows the rapid construction of macrobicycles featured
by a concave moiety on the northern pole of the cavity. For this,
the umbrella-shaped cholic acid and the bowl-shaped cyclotrivera-
trylene (CTV)6 were functionalized and submitted to 3-fold
multicomponent macrocyclizations to assemble the cages 11 and
13 and the hemicryptophanes 15 and 17. Compared to the, at this
stage, simpler cryptands, these cages and cryptophanes offer
enhanced possibilities to form inclusion complexes. For example,
by substituting one bridgehead with an extended, rigid skeleton it
is not only possible to enlarge and better define the interior of the
cavity but also to impose differentiation of the three peptoid tethers
and hence asymmetric interiors (e.g., cages 11 and 13). Indeed,
several trifunctionalized scaffolds with defined geometries can be
incorporated into the host cavity, especially to gain selectivity based
on differentiable recognition profiles and encapsulation properties.
Scheme 3 highlights the synthesis of nonrepetitive macromul-
ticyclic skeletons by sequential multicomponent macrocyclizations
of different multiplicity. Steroid-aryl hybrid macrocycles, produced
by an initial double Ugi-4CR-based macrocyclization, behave after
the corresponding deprotection as trifunctional building blocks for
a consecutive 3-fold Ugi-4CR-based macrocyclization. Macrotet-
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J. AM. CHEM. SOC. 2006, 128, 7122-7123
10.1021/ja060720r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Peptoid-Based Cages and Cryptophanes by 3-Fold
Multicomponent Macrocyclizations
Scheme 3. One-Pot Synthesis of Steroid-Aryl Hybrid Cages by
Sequential 2- and 3-Fold Ugi-4CR-Based Macrocyclizations
strategies toward supramolecular receptors due to its efficient and
diversity-oriented character.
Acknowledgment. We are grateful to the Deutsche Forschungs-
gemeinschaft (Grant: GRK-894) for financial support.
Supporting Information Available: Experimental and spectral data
for all compounds; selected NMR and HR-FT-ICR spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
racycles 22 and 23 were thus achieved by the incorporation of 13
building blocks, forming 20 new bonds in a very short, one-pot
reaction sequence that does not require isolation of the intermedi-
ates. This illustrates the formidable scope of the method to produce
highly functionalized receptors featuring unusual shapes, e.g. the
cross-linked igloo-shaped skeletons of cages 22 and 23, tetramac-
rocyclo[XYZR] systems, not counting the aromatic and steroidal
intrinsic rings. Indeed, the current procedure is suitable to produce
large cyclic skeletons that may combine a binding pocket tailored
for a target substrate with a catalytic site, just as in enzymes.
In conclusion, highly diverse, nonrepetitive macromulticycles can
be assembled in one pot by Ugi-type multiple multicomponent
macrocyclizations of polyfunctional building blocks. These host-
like compounds contain peptoids as tethers which carry structural
moieties of established recognition profiles, thus creating complex
three-dimensional arrays of binding functionalities suitable to form
inclusion complexes with various guests. We believe that this
macrocyclization approach may emerge as one of the most valuable
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