Macrocyclic scaffolds derived from p-aminobenzoic acid

Article abstract of DOI:10.1039/b704366j

The regiospecific synthesis of C₃ macrocyclic scaffolds possessing multiple different functional groups is described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b704366j

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Macrocyclic scaffolds derived from p-aminobenzoic acid{
Fred Campbell,a Jeffrey Plante,a Christopher Carruthers,a Michaele J. Hardie,a Timothy J. Priorb and
Andrew J. Wilson*a
Received (in Cambridge, UK) 22nd March 2007, Accepted 24th April 2007
First published as an Advance Article on the web 8th May 2007
DOI: 10.1039/b704366j
TFFH failed to give any reaction. Again unoptimised yields for
this step ranged from 73–83%. It is also noteworthy that direct
addition of 4-nitrobenzoyl chloride to a refluxing solution of the
secondary aniline and triethylamine also afforded decent yields of
product. Hydrolysis of the C-terminal esters 2a and 2b afforded
free acids 3a and 3b. These both underwent ring closure using
dichlorotriphenylphosphorane to afford the macrocycles 1a and 1b
in yields of 89 and 93% yield respectively. In our hands, direct
formation of macrocycle 1a from the N-propyl-4-aminobenzoic
acid using dichlorotriphenylphosphorane resulted in poor yields
and difficult purification.
The regiospecific synthesis of C3 macrocyclic scaffolds posses-
sing multiple different functional groups is described.
The efficient synthesis of macrocyclic scaffolds such as cyclo-
dextrins, calixarenes and porphyrins is the foundation on which
modern supramolecular receptors are built. However, with the
exception of cyclic peptides,1 their syntheses are not amenable to
construction of scaffolds possessing different peripheral functional
groups in a defined sequence. This is a requirement for modern
applications such as protein surface recognition.2 Although
statistical approaches3 often prove useful, there is a need for
synthetic methods that lead to scaffolds with these features.
Cyclisation of foldamers4,5—of which aromatic oligoamides6–8 are
one class—represents a means of achieving this goal. Indeed,
hydrogen-bonding has been used to promote cyclisation of the
constituent building blocks of aromatic oligoamide foldamers9–12
and more recently to synthesise tetramers with a defined sequence
of functional groups at the periphery.13 Herein we report a
different strategy that exploits the conformational bias of
N-alkylated aromatic oligobenzamides14–17 to achieve this goal
via an iterative synthesis of linear trimers and subsequent
cyclisation to yield macrocycles. Although cyclic trimers of this
nature18,19 can be made with identical substituents our approach
leads to regiospecific incorporation of functional groups.
Our synthesis of the cyclic trimers 1a and 1b is shown in
Scheme 1. The elegance of our approach derives from the fact that
after each amide bond formation is carried out, the latent amine
can be unmasked and then monoalkylated utilising reductive
amination conditions. We first applied this synthesis to macrocycle
1a with three identical propyl side chains and then to an example
in which three different substituents are incorporated— macro-
cycle 1b. Of a panel of different methods, we found in situ imine
formation and reduction using borane–pyridine or borane–picoline
complex to be ideal with unoptimised yields ranging from 79–95%.
Other reducing agents such as sodium cyanoborohydride gave
progressively poorer yields on chain elongation whilst isolation of
the imine and reduction using sodium borohydride gave poor
yields. As has previously been observed, we found that in situ
formation of the acid chloride using dichlorotriphenylphosphor-
ane20 was a convenient method of amide bond formation. Many
other peptide bond forming reagents including PyBOP, EDCI and
Scheme 1 Synthesis of cyclic trimers 1a and 1b.
aSchool of Chemistry, University of Leeds, Woodhouse Lane, Leeds, UK
LS2 9JT. E-mail: A.J.Wilson@leeds.ac.uk; Fax: +44(0)113-3436565;
Tel: +44(0)113-3431409
The cyclisation yields are remarkable, given that no special high
dilution conditions or templates are used. The reaction is so
efficient because the linear trimers adopt a folded conformation
enforced by the known preference of N-alkylphenylbenzamides for
the cis conformation.14–17 This is confirmed by single crystal
bCCLRC Daresbury Laboratory, Warrington, UK WA4 4AD
{ Electronic supplementary information (ESI) available: Synthetic proce-
dures, additional NMR data and X-ray diffraction studies. See DOI:
10.1039/b704366j
2240 | Chem. Commun., 2007, 2240–2242
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1
studies of compound 1a and 2a and H NMR and 2D NOESY
experiments for 1b and 2b.
Fig. 2 1H NMR spectra (500 MHz, CDCl3) of acyclic trimer 2b and
cyclic trimer 1b (arrows denote NOE cross peaks).
cross peaks are still present in the final macrocycle 1b (not shown).
In the 1H NMR spectrum of 1b, the amine resonance is lost whilst
the aromatic resonances move closer together, although interest-
ingly they remain well resolved despite only subtle differences in
alkyl substitution. This is not a conformational issue as little
change is observed upon heating a sample in C2D2Cl4 to 100 uC.
Fig. 1 X-Ray crystal structures of the acyclic protected trimer 2a and its
corresponding cyclic trimer 1a (above CPK representation, below stick
representation). Carbon is shown in grey, hydrogen in white, nitrogen in
blue and oxygen in red.{
1
Finally, the H NMR and NOESY spectrum of compound 2a is
Crystals suitable for X-ray diffraction were obtained by cooling
a wet solution of methanol and ether of the propyl-appended
linear trimer 2a.{ The structure (Fig. 1) clearly demonstrates the
mutual proximity of the amine and carboxylate groups with both
amides adopting a cis conformation. Crystals of macrocycle 1a
were obtained by slow evaporation of a toluene–dichloromethane
solution.{ The asymmetric unit contains 4 molecules of trimer and
4 molecules of toluene which pack into columns of alternate trimer
and toluene units held together by edge to face p–p interactions
(ESI Fig. S1{). Only one of the macrocycles 1a in the structure is
shown in Fig. 1. Although slight differences are observed for each
of the four trimers, the main structural features are the same. Thus,
the structure is similar in nature to the previously disclosed
N,N9,N0-trimethyl derivative18 and closely resembles the structure
of the linear ester 2a from which it derives. For 1a all three amide
groups necessarily adopt the cis conformation and the amides twist
out of conjugation with the aromatic ring—clearly indicating why
the structures can form so easily. From the crystal structure, the
similarly complicated to that for 2b but upon cyclisation simplifies
to just five resonances consistent with a C3 symmetric cyclic
compound (ESI Fig. S2 and S4).{ This again suggests only one
conformation is present in solution for these macrocycles.
In summary, we have described
a robust method for
regiospecific synthesis of differentially substituted C3 cyclic
supramolecular scaffolds. Future studies will focus on incorpora-
tion of protected aldehyde fragments that contain useful functional
groups for host–guest chemistry. We will report on these results in
due course.
We would like to thank EPSRC (EP/D077842/1) for a financial
support of this research and for an EPSRC DTA award (FC). We
would also like to thank CCLRC for access to Station 16.2SMX,
Daresbury Laboratory.
Notes and references
{ CCDC 641457 and 641458. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b704366j
3
˚
cavity volume is estimated to be y15 A . This is too small to be
useful for host–guest chemistry and indicates the macrocycles will
function exclusively as scaffolds onto which guest binding domains
can be added.
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The solid state conformational behaviour is maintained in
solution. Fig. 2 shows the 1H NMR spectra of compound 2b and
1b—NOE cross peaks (ESI Fig. S3) are highlighted for interacting
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