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

FULL PAPER
Novel synthesis of enantiomerically pure dioxaspiro[4.5]decane tetra-carbohydrazide
cyclophane macrocycles
Hany F. Nour, [a] Agnieszka Golon, [a] Adam Le-Gresley, [b] and Nikolai Kuhnert* [a]
Abstract: This paper describes a novel
highly efficient synthetic approach to
substituted enantiomerically pure tetracarbohydrazide
cyclophane macrocycles
in [2+2]-cyclocondensation reactions
of aromatic dialdehydes and substituted
chiral dihydrazides. The novel macrocycles
were obtained in quantitative
yields at relatively high concentration
of the reactants without using external
templates or dehydrating agents. Selfassembly
of the dihydrazide building
blocks in the gas phase to dimeric,
trimeric and tetrameric macrocycles
mediated by intramolecular hydrogen
bonding was recognised by ESI-TOF
MS. The compounds show a dynamic
behaviour in solution, which has been
rationalized in terms of an unprecedented
conformational interconversion between
two conformers one stabilised by
intramolecular hydrogen bonding and
π-π stacking interactions. Structures of
the novel macrocycles were fully assigned
and characterised by different spectroscopic
techniques, such as 1 H-NMR,
13 C-NMR, FT-IR, and ESI- or APCI-
TOF mass spectrometry.
Keywords: tetra-carbohydrazide
cyclophane • [2+2]-cyclocondensation
• macrocycle • self-assembly •
dicarbohydrazide
[a]
[b]
Introduction
Over the past few decades supramolecular chemistry has been
considered a stupendous field of endeavours. Macrocycles obtained
in [n+n]-cyclocondensation reactions have attracted considerable
and growing attention due to their relative ease of synthesis and
potential applications in molecular recognition. 1-8 Unlike calix[n]
arenes, 9,10 cyclodextrins, 11 cucurbiturils 12,13 and crown ethers, 14
macrocycles with reversible bond formation are of particular interest
for different supramolecular and dynamic combinatorial library
applications (DCL). 1 Inspired by the work initially done by Gawrónski
et al., 15 we reported on significant extensions for the synthesis of
chiral trianglimine macrocycles having different chemical functionalities
and variable cavity sizes. 16-23 We recently investigated the
mechanism and dynamic reversibility of trianglimine formation in
solution using real-time ESI-TOF mass spectrometry and proved
that trianglimine formation is indeed fully reversible. 24 Trianglimines
formed in [3+3]-cyclocondensation reactions showed their
promise in supramolecular chemistry as organo-catalysts and chiral
hosts for carboxylic and amino acid derivatives. 22,25
Prof. Dr. Nikolai Kuhnert, Hany F. Nour, Agnieszka Golon
Organic and Analytical Chemistry Department
School of Engineering and Science, Jacobs University Bremen
Campus ring 1, P. O. Box. 750 561, 28725 Bremen, Germany, Tel: +49
421 200 3120, Fax: (+) 49 421 200 3229.
E-mail: n.kuhnert@jacobs-university.de.
Dr. Adam Le Gresley
Pharmacy and Chemistry
Faculty of Science, Engineering and Computing, Kingston University, UK
Supporting information for this article (ESI- and APCI-MS, 1 H-NMR, 13 C-
NMR and proposed fragmentation mechanisms) is available on the WWW
under http://www.chemeurj.org/ or from the author.
However their low solubility in water or organic solvents is still a
current obstacle. In addition, their reported binding constants with
organic guests did not exceed the mM concentration range. To this
end, there is a growing demand for synthesizing new supramolecular
architectures, which combine structure diversity, ease of preparation,
recognition capability and most importantly sufficient solubility
in water and organic solvents. Improving the solubility can be
achieved by introducing polar functionalities into the macrocyclic
structure. In an attempt to synthesize novel macrocycles with
improved solubility, the reactivity of substituted dihydrazides,
obtained from tartaric acid, to [2+2]-cyclocondensation reactions
with aromatic bis-aldehydes was assessed. In this study the
efficiency of the [2+2]-cyclocondensation reaction to form spirotetracarbohydrazide
cyclophane macrocycles is demonstrated.
Results and Discussion
In continuation to our work with tetracarbohydrazide cyclophane
macrocycles, 24 we report in this paper a novel highly efficient synthetic
approach for preparing multigram quantities of substituted
enantiomerically pure tetracarbohydrazide macrocycles based on
[2+2]-cyclocondensation reactions of chiral dicarbohydrazides and
aromatic bis-aldehydes. Strategies for the synthesis of macrocycles
involve either applying high dilution conditions to prevent polymerization
or using a template, which acts by gathering the reactants
to a given predictable geometry. 26-30 Synthesis of macrocycles at
relatively high concentration of the reactants, is uncommon and
favour formation of polymeric or undesired by-products. The novel
macrocycles described here were quantitatively synthesized at 88-
99% yield in a one-pot [2+2]-cyclocondensation reaction in which
four new bonds form without using dehydrating agents or external
templates.
1