Solid-phase synthesis of oligo(p-benzamide) foldamers

Article abstract of DOI:10.1021/ol0603357

A coupling protocol has been developed which allows the synthesis of oligo(p-benzamide)s on solid support. Aromatic carboxylic acids are activated in situ with thionyl chloride and used to acylate secondary aromatic amines. N-p-Methoxy benzyl (PMB) as wel

Full text of DOI:10.1021/ol0603357

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1819-1822
Solid-Phase Synthesis of
Oligo(p-benzamide) Foldamers
Hannah M. Ko1nig, Robert Abbel, Dieter Schollmeyer, and
Andreas F. M. Kilbinger*
Johannes Gutenberg-UniVersita¨t Mainz, Institut fu¨r Organische Chemie,
Duesbergweg 10-14, 55099 Mainz, Germany
akilbing@uni-mainz.de
Received February 8, 2006
ABSTRACT
A coupling protocol has been developed which allows the synthesis of oligo(p-benzamide)s on solid support. Aromatic carboxylic acids are
activated in situ with thionyl chloride and used to acylate secondary aromatic amines. N-p-Methoxy benzyl (PMB) as well as N-hexyl protected
monomers were investigated. Heterosequences of both monomers were synthesized. Such nanoscale objects are important building blocks
for supramolecular chemistry.
Shape-persistent rigid rodlike molecules with dimensions on
the nanometer scale are important building blocks for
supramolecular architectures such as rod-coil block-
copolymers and have recently received increased attention.1
As most of these rodlike molecules are oligomers, solid-
supported synthesis is an ideal tool for their preparation via
repetitive coupling protocols. However, few examples de-
scribing the synthesis of rigid rodlike molecules on solid
support have been reported to date. Nelson2 as well as Huang3
et al. described a solid-supported synthesis of linear oligo-
(phenylene ethynylene)s, and Wang and co-workers synthe-
sized phenylacetylene dendrons on solid support.4 The
Fre´chet group successfully prepared oligothiophenes up to
the pentamer on the solid phase.5 Nanometer-sized molecular
rods of uniform length based on oligoamides were prepared
by Levins et al.6 Aromatic oligoamides have been synthesized
on soluble7,8 as well as solid support.9,10 Most recently, the
Whitesides group described the solid-supported synthesis of
rodlike oligopiperidines up to the decamer.11
Most rigid rods employed in supramolecular chemistry are
based on extended π-systems and aggregate via relatively
weak π-π interactions. Extended rigid rods that are capable
(4) Chi, C.; Wu, J.; Wang, X.; Zhao, X.; Li, J.; Wang, F. Macromolecules
2001, 34, 3812-3814.
(5) Malenfant, P. R. L.; Fre´chet, J. M. J. Chem. Commun. 1998, 2657-
2658.
(6) Levins, C. G.; Schafmeister, C. E. J. Am. Chem. Soc. 2003, 125,
4702-4703.
(7) Ko¨nig, B.; Papke, U.; Ro¨del, M. New J. Chem. 2000, 24, 39-45.
(8) Ko¨nig, B.; Ro¨del, M. Chem. Commun. 1998, 605-606.
(9) Baird, E. E.; Dervan, P. B. J. Am. Chemn. Soc. 1996, 118, 6141-
6146.
(10) Wurtz, N.; Turner, J. M.; Baird, E. E.; Dervan, P. B. Org. Lett.
2001, 3, 1201-1203.
(11) Semetey, V.; Moustakas, D.; Whitesides, G. M. Angew. Chem., Int.
Ed. 2006, 45, 588-591.
(1) Schwab, P. F. H.; Levin, M. D.; Michl, J. Chem. ReV. 1999, 99,
1863-1933. Schwab, P. F. H.; Smith, J. R.; Michl, J. Chem. ReV. 2005,
105, 1197-1279.
(2) Nelson, J. C.; Young, J. K.; Moore, J. S. J. Org. Chem. 1996, 61,
8160-8168. Young, J. K.; Nelson, J. C.; Moore, J. S. J. Am. Chem. Soc.
1994, 116, 10841-10842.
(3) Huang, S.; Tour, J. M. J. Org. Chem. 1999, 64, 8898-8906. Huang,
S.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 4908-4909. Jones, L.;
Schumm, J. S.; Tour, J. M. J. Org. Chem. 1997, 62, 1388-1410.
10.1021/ol0603357 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/30/2006

of strong directional intermolecular noncovalent interactions
such as hydrogen bonds are scarce.
Scheme 1. Synthesis of Monomers 5, 9, and 10 as Well as
Model Compounds 4 and 8
We have recently described the synthesis12 and solution
organization13 of block-copolymers in which hepta(p-ben-
zamide) rods are responsible for solution structure formation
via strong intermolecular hydrogen bonds between the rigid
rodlike molecules.
Herein, we describe the first solid-phase synthesis of oligo-
(p-benzamide)s (OPBA) up to the decamer via acylation of
secondary aromatic amines on a Wang resin support.
Our initial investigations explored the direct synthesis of
amide N-unprotected OPBA using a repetitive coupling cycle
in which we (1) acylated with p-nitrobenzoyl chloride
followed by (2) reduction of the nitro group with SnCl2, etc.
However, because of increasing intermolecular hydrogen
bond formation among the growing oligomers, the trimer
was the largest oligomer that could successfully be prepared
and isolated via this strategy.
To avoid hydrogen bonding among the immobilized oligo-
mers, the amide groups had to be protected. We chose the p-
methoxy benzyl (PMB) protective group, which is well estab-
lished for amide protection.14 We also prepared oligomers
with amide N-hexyl substitution for reasons discussed below.
As outlined in Scheme 1, p-amino benzoic acid was
reductively alkylated with hexanal or anisaldehyde to give
secondary aromatic amine 3 (87%) and 7 (69%), respectively.
These were either directly Fmoc protected using Fmoc-Cl
to give compounds 5 (94%) and 9 (85%) or reacted with
p-nitrobenzoyl chloride to give the amides 4 (90%) and 8
(98%).
For our initial attempts to build OPBAs on Wang resin
(1.2 mmol OH g-1), we chose Fmoc- and PMB-protected
p-amino benzoic acid 9. First residue attachment was easily
achieved using standard DCC coupling. Fmoc deprotection
with piperidine in DMF was also successful as determined
by UV spectroscopy and RP-HPLC analysis of an analytical
sample cleaved from the resin (TFA/DCM ) 1:1). The
attachment of the next residue, i.e., coupling of 9 with the
secondary aromatic amine immobilized on solid support, was,
however, unsuccessful with the standard coupling protocols
typically employed in R-peptide synthesis.15 Neither the
symmetrical anhydride method (with DIC) nor DIC/HOBt,
HBTU,10 or HATU activation of 9 gave the desired coupling
product. Coupling reagents typically used for the synthesis
of aromatic amides and polyamides such as DBOP16 and
TPP17 were also evaluated, but no product formation was
observed.
This was not unexpected, considering that even secondary
aliphatic amines pose considerable challenges in peptide
synthesis.18 Successful, however, was an activation method
described by Ueda et al. using 1 equiv of thionyl chloride in
NMP in which the carboxylic acid is turned into an acid
chloride under otherwise mild conditions.19 Activated 9 was
used to prepare a deca(p-benzamide) in 10 coupling steps
on solid support (Wang resin, 1.2 mmol OH g-1) as shown
in Scheme 2.
Encouraged by this success, we decided to prepare 10, an
Fmoc-protected dimer of 9, which would allow the synthesis
of larger oligomers in fewer coupling steps on the solid
phase. 9 was therefore activated using Ueda’s protocol and
reacted with 7 to give dimer 10 (36% after chromatographic
purification). The potential advantage of coupling a dimer
(12) Abbel, R.; Frey, H.; Schollmeyer, D.; Kilbinger, A. F. M. Chem.-
Eur. J. 2005, 11, 2170-2176.
(13) Abbel, R.; Schleuss, T. W.; Frey, H.; Kilbinger, A. F. M. Macromol.
Chem. Phys. 2005, 206, 2067-2074. Schleuss, T. W.; Abbel, R.; Gross,
M.; Schollmeyer, D.; Frey, H.; Maskos, M.; Berger, R.; Kilbinger, A. F.
M. Angew. Chem., Int. Ed. 2006 in press.
(14) Brooke, G. M.; Mohammes, S.; Whiting, M. C. Chem. Commun.
1997, 1511-1512. Yokozawa, T.; Ogawa, M.; Sekino, A.; Sugi, R.;
Yokoyama, A. J. Am. Chem. Soc. 2002, 124, 15158-15159.
(15) Chan, W. C.; White, P. D. In Fmoc Solid-Phase Peptide Synthesis,
A Practical Approach; Chan, W. C., White, P. D., Eds.; Oxford University
Press: Oxford, Great Britain, 2000.
(17) Yamazaki, N.; Matsumoto, M.; Higashi, F. J. Polym. Sci. Polym.
Chem. Ed. 1975, 13, 1373-1380.
(18) See, for example: Seewald, N. Angew. Chem., Int. Ed. 2002, 41,
4661-4663.
(16) Ueda, M.; Kameyama, A.; Hashimoto, K. Macromolecules 1988,
21, 19-24.
(19) Washio, I.; Shibasaki, Y.; Ueda, M. Org. Lett. 2003, 5, 4159-4161.
1820
Org. Lett., Vol. 8, No. 9, 2006

Scheme 2. Coupling Cycle for the Solid-Phase Synthesis of
Oligo(p-benzamide)s 11a-j
Figure 1. RP-HPLC elugrams of 11j after preparative HPLC
purification. The inset shows the ESI-MS spectrum of purified
11j.
On the other hand, the decamer 11j exhibits very good
solubility in solvents such as acetonitrile or chloroform, a
fact that cannot merely be due to the lack of hydrogen bonds
if the rigid rodlike shape persists. The improved solubility
is due to the preference of N-alkylated aromatic amides to
adopt a cis transformation and the preference of N-unsub-
stituted aromatic amides to adopt a trans conformation,21,22
allowing the oligomer 11j to explore more geometrically
diverse conformers which greatly reduce its tendency to
aggregate.
To test this hypothesis, dimeric model compounds 4 and
8 were prepared and revealed the expected cis conformation
in the solid state as well as in solution (see Supporting
Information).
The two monomers 5 and 9 can therefore be used to build
soluble OPBA precursors. Upon deprotection of the PMB
groups, linear trans-amide bonds (vide supra) are expected
to form whereas the hexyl-substituted amides should remain
in the cis conformation under these conditions. Designed
heterosequences of monomers 5 and 9 should therefore, after
deprotection of the PMB groups, allow the synthesis of
nanoscale shape-persistent objects with predefined geometry
composed of linear and “bent” segments.
instead of a monomer was lost, as the dimer 10 exhibited a
remarkably lower reactivity compared to the monomer 9.
RP-HPLC monitoring of the solid-supported oligomerization
of 9 and 10 (Scheme 2) revealed that a typical reaction cycle
using dimer 10 took at least 20 h, whereas activated monomer
9 could be coupled within 1 h. Such short coupling cycles
are on the same time scale as those for R-amino acid
couplings using standard Fmoc chemistry on a peptide
synthesizer.
As could be shown by RP-HPLC and 1H NMR spectros-
copy, the SOCl2 activation of 9 or 10 did not result in any
loss of the acid-labile PMB-protective groups.
Cleavage of the decamer 11j from the Wang resin was
achieved using TFA in DCM (1:1). 11j could be purified
by preparative RP-HPLC. The RP-HPLC elugram of purified
11j is shown in Figure 1. The ESI mass spectrum shows the
product peak as well as the product that has lost PMB
protective groups. The loss of PMB groups most likely occurs
in the mass spectrometer.
To the best of our knowledge, no unsubstituted OPBAs
larger than the tetramer have been reported.20 This is most
likely due to the very low solubility of these compounds as
a result of their rigid rodlike geometry combined with
perfectly aligned hydrogen-bond donors and acceptors.
To prove that heterosequences of 5 and 9 or 10 can be
prepared, the octamer 13 was synthesized on solid support
from two monomer units of 10 and four monomer units of
5 as shown in Scheme 3. To demonstrate that PMB-protected
(21) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui,
C.; Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N.; Yokozawa,
T. J. Am. Chem. Soc. 2005, 127, 8553-8561. Itai, A.; Toriumi, Y.; Saito,
S.; Kagechika, H.; Shudo, K. J. Am. Chem. Soc. 1992, 114, 10649-10650.
Masu, H.; Sakai, M.; Kishikawa, K.; Yamamoto, M.; Yamaguchi, K.;
Kohmoto, S. J. Org. Chem. 2005, 70, 1423-1431. Nishimura, T.; Maeda,
K.; Yashima, E. Chirality 2004, 16, S12-S22. Tanatani, A.; Kagechika,
H.; Azumaya, I.; Fukutomi, R.; Ito, Y.; Yamaguchi, K.; Shudo, K.
Tetrahedron Lett. 1997, 38, 4425-4428. Azumaya, I.; Kagechika, H.;
Yamaguchi, K.; Shudo, K. Tetrahedron 1995, 51, 5277-5290.
(22) Arylamides with a solvent-dependent cis-trans ratio have also been
observed: Forbes, C. C.; Beatty, A. M.; Smith, B. D. Org. Lett. 2001, 3,
3595-3598.
(20) For the synthesis of the tetramer, see: Bredereck, H.; von Schuh,
H. Chem. Ber. 1948, 81, 215-221.
Org. Lett., Vol. 8, No. 9, 2006
1821

Scheme 3. Coupling Cycle for the Solid-Phase Synthesis of
Octa(p-benzamide) 13
Figure 2. ESI mass spectrum of 13.
substituted p-amino benzoic acids. Such oligomers show a
dramatic increase in solubility in organic solvents compared
to the unsubstituted case. We explain this fact on the basis
of X-ray crystallographic and NOESY-NMR experiments
of model compounds: the N-unsubstituted oligomers exist
in a linear all-trans form, whereas the N-substituted oligomers
seem to adopt a more compact form due to the presence of
cis-amides thereby gaining solubility. Heterosequences of
differently N-substituted monomers can be synthesized as
was demonstrated by an octa(p-benzamide) carrying two
types of N-substituents. Designed heterosequences will allow
the synthesis of objects with different geometries consisting
of linear (trans) segments and bent (cis) segments. We are
currently investigating the synthesis of object-coil block-
copolymers with varying object geometries prepared by solid-
phase synthesis.
Acknowledgment. We thank the German Science Foun-
dation (DFG, SFB 625) and the Fonds der Chemischen
Industrie (FCI) for funding.
OPBA can be cleaved from Wang resin without loss of PMB
groups, nucleophilic cleavage with hexylamine in toluene
at 80 °C was carried out. Figure 2 shows the ESI mass
spectrum of 13.
In summary, a solid-phase coupling protocol has been
developed that allows the synthesis of oligomers of N-
Supporting Information Available: Crystallographic
data in CIF format, synthesis, and characterization of 2-13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0603357
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Org. Lett., Vol. 8, No. 9, 2006