An 'impossible' macrocyclisation using conformation directing protecting groups

Article abstract of DOI:10.1016/j.tetlet.2009.02.186

A p-benzenetricarboxamide macrocycle linked through secondary cis amides is obtained via cyclisation and subsequent deprotection of a folded linear precursor. Secondary benzamides strongly prefer the trans conformation, therefore this synthesis can be con

Full text of DOI:10.1016/j.tetlet.2009.02.186

Tetrahedron Letters 50 (2009) 2236–2238
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Tetrahedron Letters
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An ‘impossible’ macrocyclisation using conformation directing
protecting groups
Fred Campbell a, Andrew J. Wilson a,b,
*
a School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom
b Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A p-benzenetricarboxamide macrocycle linked through secondary cis amides is obtained via cyclisation
and subsequent deprotection of a folded linear precursor. Secondary benzamides strongly prefer the trans
conformation, therefore this synthesis can be considered ‘impossible’ without recourse to protecting
groups.
Received 6 January 2009
Revised 12 February 2009
Accepted 24 February 2009
Available online 28 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Macrocycles
Foldamers
Supramolecular chemistry
Protecting groups
The efficient synthesis of macrocyclic scaffolds is the corner-
stone on which modern supramolecular chemistry is built. Macro-
cyclisation reactions are typically carried out under conditions of
high dilution and/or pre-organisation through non-covalent inter-
actions. These can be introduced via a template or are inherently
present in the linear precursor to macrocyclisation. Cyclisation of
aromatic oligoamide1–3 foldamers,4,5 represents an example of
the latter whereby cyclisation is commonly promoted through
intramolecular hydrogen bonding.6–9 In contrast, conformation-di-
rected macrocyclisation reactions are less well studied.10 In the
course of our studies on aromatic oligoamides,11,12 we exploited
the conformational bias of N-alkylated oligobenzamides13–16 to
synthesise N-alkylated benzene tricarboxamide macrocycles func-
tionalised regiospecifically at the periphery.12 N-Alkylated benzene
tricarboxamide macrocycles derived from ortho-, meta- and para-
aminobenzoic acids have been the target of numerous synthetic
efforts.17–21 However, the corresponding secondary benzamide
macrocycles are unknown. As illustrated in Scheme 1, a direct syn-
thesis of the para-derivative could be considered ‘impossible’ due
to the preferred trans-conformation of the secondary amide bonds
present in the linear precursor to macrocyclisation that would be
formed via iterative monomer additions or a one-pot approach.
In our prior work12 we obtained N-alkylated benzene tricarbox-
amide macrocycles by exploiting the folded conformation of linear
N-alkylated aromatic oligoamide precursors functionalised with
simple alkyl groups. Herein we demonstrate that the synthesis of
Scheme 1. Direct route to macrocycle 1.
para-derivative 1 can be achieved by applying this method to pre-
cursors possessing cleavable N-alkyl groups. Throughout the syn-
thesis, the cis-secondary benzamide of the product is protected
as a cis-tertiary benzamide. Whereas protecting group tuning is of-
ten necessary during synthesis to facilitate a cyclisation,22 the pri-
mary role of such groups is to prevent unwanted reactions. The
concept presented here differs in the fact that the protecting group
serves no other purpose than to act as a structure directing force.
Such an approach could be described as exploiting a ‘protected
conformation’ and is similar to protection by conformationally
restricted mobility where the steric congestion of a protecting
group prevents unwanted side reactions during cyclisation.23
The synthesis of the N-alkylated cyclic trimer 2 is shown in
Scheme 2. The elegance of our approach centres on an iterative
* Corresponding author. Tel.: +44 (0) 113 3436565; fax: +44 (0) 113 3431409.
E-mail address: A.J.Wilson@leeds.ac.uk (A.J. Wilson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.186

F. Campbell, A. J. Wilson / Tetrahedron Letters 50 (2009) 2236–2238
2237
Scheme 2. Synthetic route to macrocycle 1 employing protecting groups.
sequence of amide bond formation followed by unmasking and
subsequent alkylation of the latent N-terminal amine via reductive
amination. We retained the in situ imine formation and reduction
using boraneÁpicoline complex from our original work12 to intro-
duce the 2,4-dimethoxybenzyl (DMB) groups in unoptimised
yields ranging from 42% to 81%. Similarly, we retained the in situ
formation of the acid chloride using dichlorotriphenylphosphorane
from the prior work of ours12 and others18 for amide bond forma-
tion. However, in this work, we found that prolonged heating in the
presence of dichlorotriphenylphosphorane resulted in some cleav-
age of the DMB group during coupling and so we carried out all
amide bond-forming reactions in the presence of sodium hydrogen
carbonate. Again, unoptimised yields for this step ranged from 77%
to 93%. Hydrolysis of the C-terminal ester of 3 afforded acid 4,
which underwent ring closure using dichlorotriphenylphosphora-
ne to afford the macrocycle 2 in 60% yield. This is a lower yield than
that reported in our earlier work12 and presumably reflects the
greater steric bulk of the three DMB groups relative to simple alkyl
substituents. Similarly, in our hands, direct formation of macrocy-
cle 2 from N-(2,4-dimethoxybenzyl)-4-aminobenzoic acid using
dichlorotriphenylphosphorane19 or from methyl N-(2,4-dime-
thoxybenzyl)-4-aminobenzoate using lithium hexamethyldisilaz-
ide (LHMDS)24 was unsuccessful. In contrast to the facile removal
of the DMB groups during the synthesis of the linear precursor 4,
cleavage of the DMB groups on macrocycle 2 proved more chal-
lenging. A range of test reactions, including various acidic condi-
tions and scavengers or the use of ceric ammonium nitrate were
attempted, however, the isolation of macrocycle 1 proved elusive.
Nonetheless, we could achieve the transformation in quantitative
yield by refluxing the macrocycle in neat trifluoroacetic acid
(TFA) for 14 h with triisopropylsilane (TIPS) as a scavenger.
Figure 1 shows the 1H NMR spectra of macrocycles 1 and 2 illus-
trating the anticipated symmetrical spectra indicative of a single
defined conformation in solution. We also obtained IR spectra
(KBr disks) of the macrocycles 1 and 2, the linear precursor 3 and
benzanilide for comparison. Whereas the N-H stretch of benzani-
lide appears at 3343 cmÀ1 characteristic of a trans amide, the
N–H stretch of 1 appears at 3188 cmÀ1 more characteristic of a
cis amide. The amide I CO stretching frequency of macrocycle 1
at 1648 cmÀ1 is similar in wavelength to that observed for both 3
(1642 cmÀ1) and 2 (1643 cmÀ1), whereas for benzanilide this peak
appears at 1654 cmÀ1 suggesting that a similar conformation is
present for 1, 2 and 3. Molecular modelling also indicated that
Figure 1. 1H NMR spectra (500 MHz, DMSO-d6) of (a) macrocycle
macrocycle 1.
2
and (b)
Figure 2. (a) X-ray crystal structure of the tris-N-propyl-p-benzene tricarboxamide
macrocycle12 and (b) molecular model of macrocycle 1.

2238
F. Campbell, A. J. Wilson / Tetrahedron Letters 50 (2009) 2236–2238
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macrocycle 1 adopts a cis conformation at each of the amides. A
full Monte Carlo search and minimisation in MacroModel25 using
the MMFF force-field revealed the lowest energy conformer to be
the structure shown in Figure 2b. This structure is similar in nature
to the solid state structure of an N-alkylated trimer reported previ-
ously by us (Fig. 2a)12 and confirms that despite the preference for
a trans conformation at each of the amides, the less favourable cis
conformation is preserved in the macrocycle.
In conclusion, we have exploited the stereoelectronic effects16
of a protecting group to direct the synthesis of a p-benzenetricarb-
oxamide macrocycle. The synthesis of amides that adopt non-stan-
dard conformations, for example, quinuclidonium26 represents an
ongoing area of interest due to the conferred dramatic differences
in reactivity that plays a key role in biological processes, for exam-
ple, b-lactam antibiotics. We are therefore interested in the proper-
ties and reactivity that this new macrocycle exhibits given that it
possesses three amides that are constrained in a undesirable cis
geometry within a rigid but large ring. Our future efforts will focus
on studies to this effect.
Acknowledgements
This work was supported by the University of Leeds and the Engi-
neering and Physical Sciences Research Council [EP/D077842/1]. We
also wish to thank Dr. Stuart Warriner for useful discussions.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.186.
24. Yokoyama, A.; Maruyama, T.; Tagami, K.; Masu, H.; Katagiri, K.; Azumaya, I.;
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References and notes
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