The Development of Novel Antibiotics Using ... - Jacobs University

FULL PAPER
Synthesis and ESI-MS Complexation Studies of Novel Chiral Tetra-(hydrazinecarboxamide)
cyclophane Macrocycles
Hany F. Nour, [a,b] Agnieszka Golon, [a] Tuhidul Islam, [a] Marcelo Fernández-Lahore, [a] and Nikolai
Kuhnert* [a]
Keywords: Macrocycles / Cyclophane / ESI-TOF MS / Dicarbohydrazides / Diisocyanates
We report the synthesis of novel C 2 -symmetric chiral polyamide
macrocycles, derived from chiral dioxolane dicarbohydrazides and
aromatic diisocyanates. The new macrocycles form in [2+2]-cyclocondensation
reactions in almost quantitative yields under conformational
bias of dicarbohydrazides. The reactions took place in
anhydrous THF at relatively high concentration of reactants without
addition of external templates or applying high dilution conditions.
The novel macrocycles showed potential recognition affinity in
the gas phase to a selection of chiral carboxylic acids and
oligopeptides. Structures of the novel macrocycles were fully
characterised by various spectroscopic techniques such as FT
IR, 1 H NMR, 13 C NMR, 2D ROESY NMR, 2D HMBC, 2D
HMQC, DEPT-135, CD spectroscopy and molecular recognition
was investigated by ESI-TOF/MS and tandem MS.
Introduction
The development of novel macrocyclic receptors with high
affinity to recognise wide variety of guests of different sizes is a
current challenge in supramolecular chemistry. Yet molecular
recognition demonstrated by any macrocyle towards a certain guest
is reckoned on its versatile design and its possession of interacting
functional groups. For an example, the urea functional group has
played for more than two decades a predominant role in supramolecular
chemistry, in particular in the field of anion recognition.
1,2 In 1992 Wilcox observed that urea derivatives were able
to interact strongly with phosphonates, sulfates and carboxylates in
non-polar solvents by forming a stable 1:1 complex held together
by two parallel N-H-O hydrogen bonds. 3 Further research showed
that the design of naturally occurring anion transporters is based on
the interaction of amide N-H bonds with anion oxygen functionalities,
stimulating further interest into the field of urea based anion
receptor chemistry, which has recently been reviewed by Amendola
et al. 4 In particular urea based structures have been elaborated
into powerful synthetic receptors in analytical chemistry based on
changes of their fluorescent properties, with compounds having
more than a single urea binding motif. The majority of receptors
developed are until now based on open chain structures with only
few macrocyclic compounds reported e.g. by Böhmer et al., despite
the fact that macrocyclic receptors offer clear advantages in
molecular recognition based on conformational restriction and
entropically favourable binding contributions. 5 Macrocycles
obtained in [n+n]-cyclocondensation reactions have attracted considerable
attention due to their ease of synthesis in large quantities
and their unique molecular architectures.
__
[a]
[b]
Centre of Nano and Functional Materials (NanoFun), Jacobs
University Bremen, Campus Ring 1, 28759 Bremen, Germany.
*Correspondence to: N. Kuhnert, email: n.kuhnert@jacobsuniversity.de
Fax: +49 421 200-3229, Tel: +49 421 200-3120.
Department of Photochemistry, National Research Centre, El-
Behoose street, P.O.Box 12622, Dokki, Egypt.
We reported in many occasions the synthesis of trianglimine
and trianglamine macrocycles under conformational bias of (1R,
2R)- and (1S,2S)-1,2-diaminocyclohexane in [3+3]-cyclocondensation
reactions. 6-14 Moreover, we have recently reported on a new
class of enantiomerically pure tetra-carbohydrazide cyclophane
macrocycles, which have at the same time been reported by
Gawroński and co-workers based on chiral tartaric acid dihydrazides,
obtained in a chemoselective [2+2]-cyclocondensation
reaction with aromatic dialdehydes. 15-17 An example for tetracarbohydrazide
cyclophane macrocycles is A.
The [2+2]-cyclocondensation reaction takes place at relatively
high concentration of the reactants under conformational bias of
dicarbohydrazides without addition of external templates or
applying high dilution conditions. We recently reported the first
application of tetra-carbohydrazide cyclophane macrocycles in
DCC (Dynamic combinatorial chemistry) as chiral hosts binding
efficiently in the gas phase to oligopeptides of biological interest. 18
In this contribution, we decided to investigate the reactivity of
chiral tartaric acid based dihydrazides with aromatic diisocyanates,
which would yield six novel macrocyclic compounds with a
hydrazido urea as a potential binding motif. The recognition
affinity of the novel macrocycles obtained by this approach to
chiral carboxylic acids and oligopeptides is demonstrated using
high resolution mass spectrometry (ESI-TOF) and tandem MS.
1