Organic Letters
Letter
unanswered questions. For example, are the three-center
intramolecular H-bonds shown in A or B strong enough to
mediate the folding of a long oligoamide into an uninterrupted
multiturn helix? The X-ray structure of a type B symmetrical
nonamer, the only known crystal structure showing a helical
conformation for this series of oligoamides,3b revealed a short
(approximately one turn) helix having a pitch of ∼7.1 Å, which
indicates the absence of aromatic stacking within this helix. If a
multiturn helix does form, is the helix compact or extended?
How many residues constitute one turn in such a helix?
Herein, we report the synthesis of type A oligoamides by
coupling differently sized building blocks to a growing amine-
terminated oligoamide chain. Oligoamides with ≤24 residues
are obtained. The synthesized oligoamides were examined with
one-dimensional (1D) NMR spectroscopy, which revealed
upfield shifts of aromatic proton resonances that indicate the
involvement of intramolecular stacking in the folding of these
oligomers. The folded structures were computationally
optimized, which provided helices of different lengths. These
oligoamides were analyzed with two-dimensional (2D)
(ROESY or NOESY) NMR spectroscopy; the results are
consistent with the presence of helical conformations. In
addition, single crystals of a 16-residue oligomer were obtained
and led to the determination of the first crystal structure of a
multiturn helix for this series of aromatic oligoamides.
corresponding four-residue acid 2-COOH that was coupled
with dimer amine 1-NH2 to give hexamer 3. Chain extension
from the C- to N-temini proceeded smoothly by repeating the
steps of removing the tert-butyl group and coupling with 1-
NH2, which led to octamer 4, decamer 5, and 12mer 6 in
satisfactory yields after extensive purification.
Compared to coupling monomers or dimers, chain
elongation based on building blocks derived from longer
oligomers allows products of the same length to be obtained in
fewer steps. A potential disadvantage of using longer oligomers
as basic coupling units is the likely reduced reactivity and
decreased yields.
Scheme 1b shows chain extension using the four-residue 2-
NH2 derived from tetramer 2. Reacting the 12-residue acid 6-
COOH with 2-NH2 gave 16mer 7 in 51% yield. Coupling 16-
residue acid 7-COOH with four-residue amine 2-NH2 gave
20mer 8 in 48% yield. As shown in Scheme 1c, coupling
building blocks 4-COOH and 4-NH2, derived from octamer 4
by removing the Cbz and tert-butyl groups, respectively, led to
16mer 7 in 55% yield after extensive purification. Removing
the tert-butyl group of 16mer 7 gave the carboxyl-terminated 7-
COOH, which was then coupled with eight-residue amine 4-
NH2 to give 24mer 9 in 51% yield after extensive purification.
The yields of the isolated oligoamides from coupling four-
residue amine 2-NH2 and eight-residue amine 4-NH2 show no
noticeable difference. In fact, the yields of the coupling
reactions involving the two-, four-, and eight-residue amines 1-
NH2, 2-NH2, and 4-NH2, respectively, do not show a
correlation with the size of the basic coupling units. Under
the adopted conditions, the final products, i.e., oligoamides
with 4−24 residues, were prepared in satisfactory yields,
suggesting that our synthetic method is suitable for preparing
even longer oligoamides. In a recently published work on the
synthesis of a different series of aromatic oligoamides,9 Huc et
al. concluded that coupling of long sequences is slower but
does not stop the coupling. An increasing reaction times helps,
and an increasing concentration is critical.
Scheme 1 shows the synthetic routes for preparing tetramer
2 through 24mer 9. Coupling steps are based on building
Scheme 1. Synthetic Routes of Aromatic Oligoamides
Oligoamides 4−9 were fully optimized using a density
functional theory (DFT) method implemented in the CP2K
structures reveal structural parameters, including ∼6.3 residues
per helical turn,10 a diameter of ∼8.3 Å (O−O) for the inner
cavity, and a helical pitch of ∼3.5 Å indicating that the helical
structures are stabilized by effective aromatic stacking involving
the benzene residues and amide groups of adjacent turns
The 1H NMR spectra of oligoamides 4−9 (Figure S2) have
three distinct regions, i.e., from 9.62−10.30, 8.68−9.30, and
6.24−6.86 ppm, which show the signals of the backbone amide
protons, the “internal” aromatic protons, i.e., those placed
inside the cavities, and the “external” aromatic protons flanked
by the phenolic ether side chains. The overall sharpness and
wide resonance dispersion of the amide and aromatic signals
are consistent with the well-defined conformations adopted by
these oligomers.3c
The average chemical shift of the aromatic protons of
hexamer 3 through 24mer 9 was determined by dividing the
sum of the chemical shift values of these protons with the total
number of such hydrogens in each oligomer. The aromatic
proton signals exhibit an upfield shift with an increase in
oligomer length (Figure 2), indicating stacking of the aromatic
residues due to the adoption of helical conformations.11 From
hexamer 3 to decamer 5, which adopt conformations with
bears the orthogonal protecting carboxybenzyl (Cbz) and tert-
butyl groups at its N- and C-termini, respectively (Scheme 1a).
Reacting acid 1-COOH and amine 1-NH2, obtained by
removing the Cbz and tert-butyl groups of dimer 1,
respectively, in the presence of the coupling reagent HBTU
and N,N-diisopropylethylamine (DIEA) in CH2Cl2 for at least
12 h afforded tetramer 2 that bears an N-Cbz and a tert-butyl
ester group. Removing the tert-butyl group of 2 gives the
B
Org. Lett. XXXX, XXX, XXX−XXX