Expedient synthesis of benzene tricarboxamide macrocycles derived from p-aminobenzoic acid

Article abstract of DOI:10.1016/j.tetlet.2009.12.137

The synthesis of macrocycles functionalized at the periphery in a regiospecific fashion is considered challenging. This Letter describes a six-step synthesis of N-alkylated benzene tricarboxamide macrocycles derived from p-aminobenzoic acid via the iterative coupling of Fmoc-protected monomers and cyclization of the resultant linear foldamers.

Full text of DOI:10.1016/j.tetlet.2009.12.137

Tetrahedron Letters 51 (2010) 1361–1363
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expedient synthesis of benzene tricarboxamide macrocycles derived
from p-aminobenzoic acid
Fred Campbell a, Colin A. Kilner a,b, Andrew J. Wilson a,b,
*
a School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
b Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of macrocycles functionalized at the periphery in a regiospecific fashion is considered chal-
lenging. This Letter describes a six-step synthesis of N-alkylated benzene tricarboxamide macrocycles
derived from p-aminobenzoic acid via the iterative coupling of Fmoc-protected monomers and cycliza-
tion of the resultant linear foldamers.
Received 6 November 2009
Revised 14 December 2009
Accepted 23 December 2009
Available online 7 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclizations
Host–guest systems
Macrocycles
Supramolecular chemistry
Amides
The efficient syntheses of highly functionalized macrocyclic
scaffolds are the basis of numerous studies in the area of molecular
recognition, including supramolecular self-assembly1 and bioac-
tive ligand discovery.2 However, whilst this ultimately requires
scaffolds possessing different functional groups in a defined se-
quence, rather than symmetrical presentation of functional
groups—with the exception of cyclic peptides3 and a few other
examples4–8—the construction of such scaffolds is synthetically
challenging. Statistical approaches9 have proven successful but
purification is challenging. Cyclization of foldamers10,11—of which
aromatic oligoamides12–14 are one class—represents an alternative
to this challenge. Hydrogen-bonding is commonly used as a direct-
ing force to promote cyclization of the constituent building blocks
of aromatic oligoamide foldamers15–21 and this approach has been
extended to the synthesis of macrocycles functionalized regiospe-
cifically at the periphery.4 We recently outlined a strategy for the
synthesis of regiospecifically functionalized benzentricarboxamide
macrocycles 1.5 In contrast to many aromatic oligoamide macrocy-
cles where hydrogen-bonding is used as a structure-directing
force, the approach exploits the conformational bias of N-alkylated
aromatic oligobenzamides22–25 to promote cyclization of itera-
tively assembled linear trimers with a pre-programmed sequence
of monomers. We subsequently extended the approach to the first
synthesis of the parent macrocycle 2 by employing a cleavable 2,4-
dimethoxybenzyl-protecting group as the macrocyclization-direct-
ing N-alkyl group.26
In our original syntheses, we employed a nitro-masked amine
as the building block and so both alkylation and acylation were
performed in a linear sequence that extended to nine steps. In this
Letter, we report a more convergent and shorter six-step approach
in which N-alkylated Fmoc-protected aminobenzoic acid mono-
mers are iteratively coupled and deprotected—an approach con-
ceptually similar to Kilbinger’s solid-phase synthesis of oligo(p-
benzamide foldamers).27
Our synthesis of the cyclic trimers 1a and 1b is shown in
Scheme 1. Following each amide bond formation, cleavage of the
Fmoc-protecting group using a secondary amine affords an aniline
ready for the next iterative step of the synthesis. Monomers were
prepared as shown in Scheme 2 via a simple reductive amination
using boraneÁpicoline with unoptimized yields ranging from 72–
80%. This was followed by reaction with Fmoc-chloride in the ab-
sence of base, again in good yield, to afford the protected building
blocks. With a suitable collection of monomers in hand, we applied
our synthetic approach to macrocycle 1a with three identical
dimethoxybenzyl (DMB) side chains and then to an example in
which three different substituents are incorporated—macrocycle
1b. As in our earlier work,5 we employed in situ formation of the
acid chloride using dichlorotriphenylphosphorane for amide bond
formation. However, in this work, we found that the prolonged
heating resulted in some cleavage of the DMB group during cou-
pling and so carried out all amide bond forming reactions in the
presence of sodium hydrogen carbonate. Unoptimized yields for
* Corresponding author. Tel.: +44 (0)113 3431409; fax: +44 (0)113 3436565.
E-mail address: A.J.Wilson@leeds.ac.uk (A.J. Wilson).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.137

1362
F. Campbell et al. / Tetrahedron Letters 51 (2010) 1361–1363
H
N
HN
R
a R1= R2 = R3 = 2,4-dimethoxybenzyl
O
b R1 = iPr, R2 = Et, R3 = Ph
O
HN
FmocN
R
20% piperidine
or NHEt2 in CH3CN
74%-quant.
NH
2
CO2H
O
NaOH, H2O, MeOH, 85-88%
Cl2PPh3, Δ
NaHCO3
CHCl3,
TFA, TIPSH
HN R3
HN R3
Δ, quant.
FmocN
O
R
1a
1b
50-95%
R3
N
3a,b
R2
4a,b
R2
O
O
N
O
N
N
R
O
N
NaOH, H2O
MeOH,
85-95%,
PPh3Cl2,
20% piperidine
or NHEt2 in
CH3CN, 83-95%
R1
N
R2
R1
CHCl3,
O
N
R1
Δ
,
O
N
44-93%
O
CO2H
Scheme 1. Synthesis of p-benzenetricarboxamide macrocycles.
CO2Me
Scheme 2. Synthesis of Fmoc-protected monomers used in the synthesis of
macrocycles 1a and 1b.
this step ranged from 50–95%. Hydrolysis of the C-terminal esters
3a and 3b afforded free acids 4a and 4b. Both underwent ring clo-
sure using dichlorotriphenylphosphorane to afford the macrocy-
cles 1a and 1b in yields of 44% and 93%, respectively. We were
also able to proceed directly to 4a,b by hydrolysis of the Fmoc-pro-
tected precursor (Fmoc-3a,b) and reduce the length of the synthe-
sis by a further step to give a linear sequence of only six steps.
Similarly to our previous report, cleavage of the 2,4-dimethoxy-
benzyl-protecting groups in 1a using refluxing trifluoroacetic acid
(TFA) in the presence of triisopropylsilane (TIPSH) as scavenger
afforded the parent p-benzene tricarboxamide macrocycle 2 in
good yield.
Single crystals of macrocycle 2 suitable for X-ray diffraction
studies were obtained from ethyl acetate in dimethylsulfoxide.
As anticipated, and consistent with earlier modelling studies, the
secondary amide bonds in macrocycle 2 adopt a cis geometry with
each of the three benzene rings twisted from a perpendicular
orientation relative to the amide bond (Fig. 1a). Individual macro-
cycles then self-assemble through intermacrocycle hydrogen-
Figure 1. X-ray crystal structure of macrocycles 1a and 2.
bonding interactions (Fig. 1b). In contrast to the R22 (8) hydrogen-
bonding motif that might be expected for self-assembly of cis-
amides, H-bonding occurs between amide bonds separated by
the aromatic ring with offset p–p stacking in between to generate
tapes. The remaining donor and acceptor sites are satisfied through
intertape H-bonding.
In conclusion, we have described the synthesis of N-alkylated
tricarboxamide macrocycles derived from para-aminobenzoic acid.
Tricarboxamide macrocycles derived from ortho-, meta- and para-
aminobenzoic acid have been the target of synthetic efforts for
nearly 30 years28–32 and this approach should be equally applica-
ble to these compounds. Importantly, this robust method should
allow rapid access to macrocycles possessing diverse functionality
in a regiospecific manner for use in areas such as protein surface
recognition33 and macrocycle self-assembly.34 Our ongoing studies
are focused towards this endeavour.

F. Campbell et al. / Tetrahedron Letters 51 (2010) 1361–1363
12. Gong, B. Chem. Eur. J. 2001, 7, 4336–4342.
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Supplementary data
Crystallographic data (excluding structure factors) for the struc-
ture in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication nos. CCDC
752786. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2009.12.137.
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