Intramolecular versus intermolecular induction of helical handedness in pyridinedicarboxamide oligomers

Article abstract of DOI:10.1002/ejoc.200400641

A new convergent synthetic scheme has been developed to prepare oligoamides of 2,6-diaminopyridine and 4-decyloxy-2,6-pyridinedicarboxylic acid. These compounds adopt stable single helical conformations in solution. NMR and circular dichroism studies show

Full text of DOI:10.1002/ejoc.200400641

FULL PAPER
Intramolecular Versus Intermolecular Induction of Helical Handedness in
Pyridinedicarboxamide Oligomers
Victor Maurizot,[a] Christel Dolain,[a] and Ivan Huc*[a]
Keywords: Chirality / Conformation analysis / Hydrogen bonds / Helical structures / Supramolecular chemistry
A new convergent synthetic scheme has been developed to
prepare oligoamides of 2,6-diaminopyridine and 4-decyloxy-
2,6-pyridinedicarboxylic acid. These compounds adopt
stable single helical conformations in solution. NMR and cir-
cular dichroism studies show that intramolecular and inter-
molecular chiral induction of handedness in these helices is
possible. Intramolecular induction is effected by attaching a
single chiral group to the end of an oligomer. Intermolecular
induction results from various noncovalent interactions be-
tween chiral carboxylic or sulfonic acids and the terminal res-
idues of the oligoamides. Intramolecular induction appears to
be more efficient than intermolecular induction. When both
effects compete, intramolecular induction prevails.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Numerous oligomers and polymers spontaneously adopt
right- or left-handed helical conformations.[1–4] When the
energy barrier between these two forms can be overcome
under experimental conditions, an equilibrium is formed.
In the absence of any chirality within the helices or in the
surrounding medium, the proportions of the two forms are
expected to be equal. However, when the helices interact
with chiral groups, the right- and left-handed conforma-
tions become diastereomeric. Thus, the equilibrium may be
shifted in one direction or the other and a particular hand-
edness may be induced (Scheme 1).[1,5]
A remarkable aspect of the chiral induction of helical
handedness is that it is often associated with chiral amplifi-
cation.[5,6] For an effective induction to take place, it need
not occur at each and every monomer of the helix. Instead,
it may simply occur at a small fraction of the monomers
and be propagated along the helical chain until any factor,
for example local uncoiling, interrupts the continuity of the
helix.[5,7] Recalling the analogy proposed by Green et al.,
the monomers that impose a helical bias may be likened to
sergeants, and the monomers that follow this bias to soldi-
ers.[8] Thus, the handedness of many monomers may be bi-
ased by just a small quantity of a chiral substance or by a
nearly − but not perfectly − racemic compound. The initial
weak chiral stimulus is amplified by the polymer and may
be easily detected by, for example, intense circular dichro-
ism bands that arise from chromophores in the helical
chain. Such phenomena have already been applied to the
detection, assignment, and quantification of chirality.[6,9]
Scheme 1. Schematic representation of the equilibria formed be-
tween enantiomeric left- and right-handed helices (top), and be-
tween diastereomeric left- and right-handed helices (bottom). The
chiral moiety in red may be covalently or noncovalently bound to
the helix. The bottom equilibrium has been arbitrarily shifted in
favor of the left-handed helix.
Other important aspects of the chiral induction of helical
handedness involve chirality switching and memorizing. For
instance, a right-handed bias induced in a helical polymer
by a group of given chirality may be converted to a left-
handed bias by changing the polarity of the solvent or the
temperature,[10–14] or even by more specific methods such
as the binding of nonchiral guest molecules[15] or by irradia-
tion with unpolarized[16–19] or circularly polarized
light.[20,21] Consequently, a small change in the environment
of the helical chain may give rise to a large chiroptical sig-
nal inversion, a feature that may be of use in some optical
devices. Chiral induction in helices has also been associated
with spectacular memory effects. Under particular condi-
tions, the handedness induced by a chiral stimulus may be
memorized even after the stimulus has been retrieved.[6,22]
Previously, we reported on the ability of oligoamides of
2,6-diaminopyridine and 2,6-pyridinedicarboxylic acid to
[a] Institut Européen de Chimie et Biologie,
2 rue Robert Escarpit, 33607 Pessac Cedex, France
Fax: +33-5-40003009
E-mail: i.huc@iecb.u-bordeaux.fr
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DOI: 10.1002/ejoc.200400641
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fold into helices that are stabilized by intramolecular aro- metrization of the diamine and diacid monomers. For clar-
matic–aromatic interactions and by both attractive and re- ity, the following synthetic intermediates are labeled accord-
pulsive electrostatic interactions involving either the amidic ing to the number of pyridine rings that they contain. As
hydrogen or oxygen atom on the one hand and the adjacent we recently reported,[28] monoester 1a can be obtained in
pyridineЈs nitrogen atoms and protons on the other.[23–26] 85% yield from the corresponding diester and one equiva-
Remarkably, these single helices can extend like springs and lent of KOH (Scheme 2). Similarly, the mono-amine mono-
wind around each other to form double helical molecular benzyl carbamate 1b can be prepared from commercially
duplexes.[23,27,28] The single helices have been characterized available 2,6-diaminopyridine and benzyl chloroformate in
in the solid state and even relatively short oligomers (15 84% yield. Activation of 1a to its acid chloride with SOCl2
pyridine units or less) have been shown to be remarkably and coupling with amine 1b yields dimer 2a. This com-
stable in a number of nonpolar and polar solvents, for ex- pound can be quantitatively deprotected at its C-terminus
ample, chloroform, toluene, DMSO, and water, over a wide by saponification and at its N-terminus by hydrogenolysis
temperature range. The stability of these structures and of the benzyl carbamate to yield dimers 2c and 2b, respec-
their ability to remain folded in helices allows us to specu- tively. After activation of acid 2c with SOCl2, these two di-
late that polymers in this series should have a consistent mers can be coupled to yield tetramer 4a (Scheme 2). Start-
handedness over many helical turns. Given the interest in ing from 4a, another cycle of deprotection, activation with
chiral induction mentioned above, we have investigated SOCl2, and coupling gives octamer 8a, which can in turn
whether it is possible to bias helical handedness in these be saponified, activated using HBTU and coupled to (R)-
compounds through intramolecular and intermolecular in- or (S)-phenethylamine following standard procedures[29] to
teractions. We briefly mentioned this possibility in a pre- yield (R)-1 and (S)-1.
vious communication[26] and here we give the first full re-
port of our results. For the intramolecular induction of heli-
cal handedness, we prepared octamer 1, which has a chiral
(R)- or (S)-phenethylamino group (Figure 1). For the inter-
molecular induction of helical handedness, we used nonchi-
ral heptamer 2 and studied its behavior in the presence of
various chiral acids 3–6.
Figure 1. Structures of compounds 1–6.
Scheme 2.
The structure of dimer 2a was characterized in the solid
Results and Discussion
state by single-crystal X-ray diffraction analysis. Figure 2
shows that 2a has a planar crescent-like shape and illus-
Synthesis
trates the conformational preferences of these compounds
The synthesis of the symmetrical heptamer 2 has been at each pyridine–amide linkage. The amidic carbonyl moi-
described previously.[24] It follows a highly convergent strat- ety diverges away from the neighboring endocyclic nitrogen
egy, but involves a low-yielding late desymmetrization step. atoms of the pyridine moiety, whereas the amidic proton
On the other hand, octamer 1 was prepared according to a converges towards them. Upon increasing the length of this
new scheme[28] based on an early and high-yielding desym- molecular strand, the crescent shape will extend until a ste-
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Helical Handedness in Pyridinedicarboxamide Oligomers
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ric clash forces the two ends of the strand to deviate from
planarity and adopt a helical conformation. The helices are
characterized by a pitch equal to the thickness of one aro-
matic ring (3.45 Å) and by a curvature of 4.5 units per
turn.[23–25] Heptamer 2 thus consists of one-and-a-half heli-
cal turns and octamer 1 of almost two turns.
Figure 3. (a) Electronic absorption and CD spectra of 1 m solutions
of (S)- and (R)-1 in CHCl3 at various temperatures. Spectra could
not be measured below 210 nm because the oligomers are not solu-
ble in solvents that do not absorb at these wavelengths. Part of the
1H NMR (400 MHz) spectra of (R)-1 showing the amide reso-
nances in (b) CDCl3 and (c) [D8]toluene. The circles indicate signals
from the minor helical diastereomer.
–20 °C [see (a) in Figure 3]. This may be a result of more
efficient chiral induction at low temperatures which causes
the difference in the population of the P-1 and M-1 dia-
stereoisomers to increase. It may also arise without a
change in the diastereoisomer populations, for example,
when the helices adopt a more consistently folded helical
Figure 2. Crystal structure and molecular packing of 2a.
Intramolecular Chiral Induction
The chiral induction in octamer 1, which has one coval- conformation at low temperatures.
ently linked chiral group, was demonstrated by circular di- The NMR spectra have allowed us to evaluate the extent
1
chroism spectroscopy (CD). In contrast to the silent CD of chiral induction. At 25 °C, the H NMR spectrum of a
spectra of helical oligomers that have no chiral groups, the 1 mm solution of (R)-1 shows one set of slightly broadened
spectrum of (R)-1 features two intense negative bands at signals. Upon cooling to 10 °C, the equilibrium between the
270 (Δε
=
12 Lmol–1 cm–1) and 322 nm (Δε
=
right- and left-handed helices slows on the NMR time scale,
21 Lmol–1 cm–1) allied to the electronic transitions of the and the signals split into two sets of different intensities
pyridine chromophores [see (a) in Figure 3]. For compari- which can be assigned to helices with favored and unfavored
son, when the phenethylamine moiety is appended to a very handedness [see (b) in Figure 3]. The two sets of signals
short oligomer such as dimer acid 2c, which is too short to partly overlap and integration is not very accurate. Never-
be helical, no CD is observed above 250 nm. Thus, in octa- theless, the ratio of the two diastereoisomers can be esti-
mer 1, intramolecular interactions between the single chiral mated to be 70:30 which corresponds to a diastereomeric
phenethylamino group and the helix differ in the right-han- excess of 40%. Upon cooling further to –20 °C (not shown),
ded (R-P) and in the left-handed (R-M) helical dia- the diastereomeric excess does not change significantly. This
stereomers leading to different stabilities of the P and M shows that the variation in the intensity of the CD bands
helices in solution. Conversely, the CD spectrum of (S)-1 with temperature in this solvent is not due to a variation in
features two positive bands at the same wavelengths show- the efficiency of chiral induction, but presumably arises
ing that, as expected, the sign of chiral induction is reversed from slight changes in the helical conformation of the oligo-
upon inverting the chirality at the asymmetric carbon.
mers, for example, better folding at a lower temperature. In
The sign of the CD bands alone does not allow us to [D8]toluene, the same two sets of signals are observed even
assign the favored and unfavored handedness to the P or M at 25 °C and coalesce upon heating. This shows that the
helix, as was already the case for related oligomers derived rate of helix inversion is lower in this solvent than in
from quinoline.[29] We looked at molecular models of the CDCl3. On the other hand, the diastereomeric excess in tol-
two diastereoisomers of (R)-1 but there is no obvious differ- uene is identical to that observed in CDCl3.
ence between them to indicate which should be the most
These NMR spectra also show that a 1 mm solution of
stable in solution.
octamer 1 in CDCl3 or [D8]toluene shows no sign of double
The intensities of the induced CD bands increase by helix formation between –20 and 60 °C.[23,27,28] The induced
around 30% upon decreasing the temperature from 50 to handedness observed in 1 in the CD and NMR spectra con-
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cerns only its single helical form. Duplex formation does tored by 1H NMR spectroscopy (Figure 4). The amidic pro-
occur at higher concentrations and/or lower temperatures. tons of 2 give rise to four distinct signals. Six of these pro-
However, the dimerization constant could not be measured tons are strongly deshielded as a result of intramolecular
accurately because the signals of the monomers P-1 and M- hydrogen bonding and give three signals between 10 and
1 overlap with the numerous signals that arise from the 11 ppm. The two peripheral amides are not involved in hy-
head-to-head and head-to-tail forms of dimers P-12 and M- drogen bonding and give one signal at 7.5 ppm. Upon ad-
12. For comparison, the dimerization constant of octamer dition of the acid, only two of these four signals shift down-
ester 8a is estimated to be less than 5 Lmol–1 in CHCl3 at field. The largest shift is recorded for the signal of the ter-
25 °C.
minal amidic proton (Δδ = 0.4 ppm as opposed to Δδ =
0.15 ppm for the other proton). This is consistent with the
formation of hydrogen bonds between the carboxylic acid
and the peripheral acylaminopyridine units of 2, as shown
in Scheme 3. The chemical shift of one of the amide signals
is unchanged during the titration and the fourth signal even
undergoes an upfield shift which we have assigned to shield-
ing effects of the phenyl group of the (S)-phenylpropionic
acid bound to the terminal amide groups.
Intermolecular Chiral Induction
The equilibrium between a right- and left-handed helix
may be shifted when chiral molecules interact noncovalently
with the helices. For example, strong handedness induction
has been observed when multiple chiral molecules interact
with helical polymers such as polyacetylene,[6] polyani-
line,[30] polyguanidine,[31] or polyisocyanate.[32] The in-
clusion of a chiral molecule in the helix hollow of oligo-
phenylenes-acetylenes also results in such a chiral bias.[33,34]
A combination of chiral induction and amplification has
been demonstrated in nonchiral α-helical peptides in which
the interaction of a single chiral carboxylic acid with the
N-terminal ammonium leads to an induction of helical han-
dedness.[35]
In the case of the pyridinedicarboxamide oligomers, we
suggested that chiral induction may occur by well-charac-
terized hydrogen bonding between carboxylic acids and
acylaminopyridines.[36] Binding to diacylaminopyridine
units residing at the center of helical pyridinedicarboxamide
oligomers should be disfavored because the amidic protons
of these units are already hydrogen bonded to the pyridine’s
nitrogen atoms of the adjacent pyridinecarboxamide units.
Moreover, these units are buried in the hollow of the helix
and so should not be available in any great number for hy-
drogen bonding unless partial unfolding occurs. However,
the amide groups of the diacylaminopyridine units residing
at the terminal positions of the oligomers are not buried in
the helix hollow, and the most peripheral amidic protons
are not involved in intramolecular hydrogen bonding. The
terminal units should thus be available for hydrogen bond-
ing with chiral carboxylic acids, possibly giving rise to chiral
induction of helical handedness (Scheme 3).
1
Figure 4. Part of the H NMR (400 MHz) spectra of a 1 mm solu-
tion of 2 in CDCl3 showing amide (10–11 ppm) and aromatic reso-
nances (7–8.5 ppm) in the presence of increasing amounts of (S)-
phenylpropionic acid. The arrows indicate the signal arising from
the terminal amidic protons. The asterisks indicate the signals of
trace amounts of the double helix of 2 that disappear upon ad-
dition of the acid (eq. = equivalents).
Note that a variation of 0.4 ppm in the chemical shift is
smaller than expected for the formation of an acid–acylami-
nopyridine complex. Variations in chemical shifts as high as
2 ppm have been recorded in similar systems.[36] The small
variation in the chemical shift observed for 2 is due to the
fact that saturation is not reached at the low concentration
of heptamer 2 used despite the excess of carboxylic acid
added. The association constants between carboxylic acids
and acylaminopyridines are low (typically less than
50 Lmol–1) and for oligomer 2, this value is probably re-
duced by the presence of the neighboring pyridinedicarbox-
amide units. Thus only partial binding occurs under the
conditions employed in the titration. Upon increasing the
oligomer concentration, the titration is perturbed by the
Scheme 3. Expected hydrogen-bonding modes between carboxylic
acids and the terminal acylaminopyridine units of 2.
To test whether carboxylic acids bind to the terminal formation of double helices of 2. Even in a 1 mm solution
diacylaminopyridine units, heptamer 2 was titrated against of 2, a small amount of the double helical dimer can be
(S)-phenylpropionic acid 3 and the experiment was moni- detected in the NMR spectra (for this compound Kdim
=
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Helical Handedness in Pyridinedicarboxamide Oligomers
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30 Lmol–1 at 25 °C), which disappears upon addition of
(S)-phenylpropionic acid (Figure 4). Addition of larger
quantities of the acid seems to lead to partial unfolding of
the strand (see below) possibly due to the bonding of acids
to the central diacylaminopyridines or to a partial proton-
ation of the pyridine rings.[26] Given the many equilibria
involved, quantitative analysis of the titration data was not
attempted.
That binding of chiral carboxylic acids to oligomer 2 re-
sults in the chiral induction of helical handedness was dem-
onstrated by monitoring the titration experiments by CD
spectroscopy. The titration of 2 against (S)-phenylpropionic
acid (3) resulted in the appearance of two positive CD
bands at 270 and 322 nm allied to the electronic transitions
of the pyridine chromophores of heptamer 2 [see (a) in Fig-
ure 5]. These bands appear to be allied to the same chromo-
phores as the bands observed in the spectra of chiral octa-
mer 1 [see (a) in Figure 3]. The intensities of these bands
reach a maximum when 10 equiv. of 3 are added. Upon
addition of more acid, these intensities slowly decrease (not
shown), which suggests that partial unfolding of the helices
occurs. The maximum CD intensity reached with (S)-phen-
ylpropionic acid (3) is about half that observed with chiral
octamer 1 at the same temperature. This may result from a
less efficient intermolecular chiral induction of handedness
despite the fact that there are two sites of induction in the
adduct 2·3, whereas 1 has only one site of induction. The
reduced intensity of the CD bands may also partly arise
from the fact that hetpamer 2 is a little shorter than octa-
mer 1, which should result in a lower value of Δε, and also
from the fact that, under the conditions used, binding of
phenylpropionic acid (3) to heptamer 2 does not reach satu-
ration.
Figure 5. CD spectra of 1 mm solutions of heptamer 2 in CHCl3
upon addition of increasing amounts of (a) (S)-phenylpropionic
acid (3), (b) (R)-mandelic acid (4), (c) l-N-acetylphenylalanine (5),
and (d) (R)-camphorsulfonic acid (6). The arrows indicate bands
assigned to the four acids, the intensities of which increase as the
concentration of added acid increases (eq. = equivalents).
Interestingly, the bands induced by (S)-phenylpropionic
acid (3) bound to heptamer 2 and the bands induced by the
(S)-phenethylamino group of 1 all have the same sign. This
indicates that the handedness induced intramolecularly in
one case and intermolecularly in the other are identical. As
shown in Figure 6, noncovalent binding of the (R)-phenyl-
propionic acid and covalent binding to the (S)-phen-
ethylamino group may lead to comparable positioning of
the proton, methyl and phenyl moieties at the asymmetric
carbon atom. In the energy-minimized right-handed helices,
the phenyl rings of the phenethylamino group and of phen-
ylpropionic acid are both involved in the face-to-face aro-
matic stacking of the helix, whilst the methyl groups point
away from the helix (Figure 6). These energy-minimized
conformations compare well with the conformations ob-
Figure 6. Comparison of the energy-minimized models of the right-
handed helical diastereoisomers of octameric strand (R)-1, which
comprise a covalent bond to a (R)-phenethylamino group (left),
and of a hydrogen-bonded complex between heptameric strand 2
and (R)-phenylpropionic acid (right). Alkoxy chains and benzyl
carbamates were removed before energy minimization.
served in crystal structures of related quinoline-derived chi- ilar manner in both compounds, and that the hydroxy
ral oligomers.[29] These simple calculations thus suggest that group of 4 plays the same role as the methyl group of 3. On
the intra- and intermolecular inductions might occur by the the other hand, l-N-acetylphenylalanine (5) fails to induce
same mechanism. However, further investigations will be re- any handedness [see (c) in Figure 5]. The titration with (R)-
quired to demonstrate this point.
camphorsulfonic acid (6) results in chiral induction, how-
Chiral induction of helical handedness is also observed ever it is evident from the CD spectra that 2 behaves dif-
when 2 is titrated against (R)-mandelic acid (4) [see (b) in ferently with 6 than it does with acids 3 and 4 on addition
Figure 5]. The signs of the resulting CD bands are negative of increasing amounts of the acid [see (d) in Figure 5]. A
instead of positive as obtained with (S)-phenylpropionic more intense induced CD is observed after adding a single
acid (3). This suggests that chiral induction occurs in a sim- equivalent of 6, and it reaches a maximum after the ad-
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dition of 2 equivs. of 6. The addition of further acid causes stronger intramolecular induction that occurs when the ter-
a rapid decrease and ultimately the disappearance of the minal diacylaminopyridine unit of 1 is protonated and
induced band at 322 nm. This behavior results from the fact adopts the conformation shown in Figure 7. The enhance-
that the sulfonic acid 6 is considerably more acidic than ment is slightly stronger with (S)-6 than with (R)-6. This
carboxylic acids 3 and 4 and that it binds to heptamer 2 by different behavior is consistent with cooperation between
a different mode. As we have shown previously,[26] sulfonic intra- and intermolecular chiral induction in one case and
acids such as 6 in fact quantitatively protonate diacyl- competition in the other. However, the effect is small, and
aminopyridines in chloroform and lead to a conformational the changes may as well be assigned to small differences in
rearrangement of these units (Figure 7). The sulfonate the relative orientation of the chromophores in the various
anion interacts with the oligomeric strand through strong diastereomeric complexes involved. Upon addition of fur-
electrostatic interactions and hydrogen bonding to the am- ther camphorsulfonic acid, the induced CD intensity de-
idic protons.[37–39] Heptamer 2 is expected to remain helical creases because of the unfolding of the helix that results
even after the protonation of both its terminal units, and from its progressive protonation (Figure 8). However, the
chiral induction of helical handedness thus occurs in the decrease in the CD intensity occurs much faster with (R)-6
presence of 2 equivs. or less of added (R)-camphorsulfonic than with (S)-6. Again, this is consistent with a positive
acid (6). However, further protonation of the diaminopyri- cooperativity of intra- and intermolecular chiral induction
dine units leads to the unfolding of the strand to an ex- in the case of (S)-6 and a negative cooperativity in the case
tended linear structure in which chiral induction is no of (R)-6.
longer possible.[26]
Figure 7. Rearrangement of the conformation of hetamer 2 upon
protonation by acid 6.
Figure 8. CD spectra of 1 mm solutions of octamer (S)-1 in CHCl3
upon addition of increasing amounts of (a) (R)-camphorsulfonic
Intramolecular versus Intermolecular Chiral Induction
acid and (b) (S)-camphorsulfonic acid. The arrows indicate the
bands assigned to the two acids (eq. = equivalents).
The results presented in the two previous sections suggest
that intramolecular induction of helical handedness in 1 is
more efficient than intermolecular induction in 2 even
though two sites in heptamer 2 are likely to be involved in
the intermolecular induction. We evaluated directly which
of the two induction modes is the most efficient by titrating
octamer (S)-1 against chiral acids 3–6. Octamer (S)-1 pos-
Conclusions
In summary, we have shown that both intramolecular
sesses a chiral phenylethylamino group at one end which and intermolecular chiral induction of handedness in heli-
results in a bias of helical handedness leading to two posi- cal oligoamides of 2,6-diaminopyridine and 2,6-pyridined-
tive CD bands. Octamer (S)-1 also possesses a “free” icarboxylic acid is possible. Intramolecular induction is ef-
diacylaminopyridine unit at the other end which should be fected by attaching a single chiral group to the end of an
available for binding to chiral acids. Titration of (S)-1 oligomer. Intermolecular induction results from various
against carboxylic acids 3–5 has no significant effect on its noncovalent interactions between chiral carboxylic or sul-
CD spectrum regardless of the configuration of the acid. fonic acids and the terminal residues of the oligoamides.
This means that intramolecular induction of handedness Intramolecular induction appears to be more efficient than
prevails when intermolecular induction should act against intermolecular induction and prevails when both effects
it, and that no cooperativity occurs when both effects compete.
should operate simultaneously. Different behavior was ob-
Several important aspects of these phenomena are still
served upon titrating (S)-1 against chiral sulfonic acids (S)- to be explored. First, the handedness of the induced confor-
and (R)-6 (Figure 8). Unexpectedly, after the addition of mation has not been assigned to a right- or left-handed he-
one equivalent of acid, the CD absorption of (S)-1 at lix, and this remains a particularly challenging task. Sec-
322 nm was enhanced in both cases. This may simply be a ondly, it might be possible to achieve intense chiral amplifi-
result of a change in the chromophore from the pyridine to cation and chiral memory effects by using longer oligomers
the pyridinium moiety. It may also be the result of a or polymers for which inversion of helical handedness is
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Helical Handedness in Pyridinedicarboxamide Oligomers
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OCH2CH2), 5.22 (s, 2 H, OCH2Ph), 7.33–7.42 (m, 5 H, Caryl-H),
expected to be very slow. Finally, this paper has dealt only
with the single helical conformations of the oligopyridined-
icarboxamides. It will be interesting to see whether similar
intra- and intermolecular induction of chiral handedness
also occurs in their double helical conformations.
4
7.46 (s, 1 H, NH), 7.72–7.80 (m, 3 H, Caryl-H), 7.91 (d, JH,H
=
4
3
2.5 Hz, 1 H, Caryl-H), 8.04 (dd, J1
= 2.5, J2
= 6 Hz, 1 H,
H,H
H,H
Caryl-H), 10.27 ppm (s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ
= 14.5 (CH3), 23.0 (CH2), 26.2 (CH2), 29.1 (CH2), 29.6 (CH2), 29.9
(CH2), 32.2 (CH2), 53.6 (OCH3), 67.5 (OCH2), 69.6 (OCH2), 108.9
(CHaryl), 109.8 (CHaryl), 112.4 (CHaryl), 114.9 (CHaryl), 128.4
(CHaryl), 128.6 (CHaryl), 128.8 (CHaryl), 135.9 (Cquat.), 141.0
(Cquat.), 149.4 (Cquat.), 150.6 (Cquat.), 150.8 (Cquat.), 153.5 (Cquat.),
Experimental Section
162.0 (Cquat.), 168.3 ppm (Cquat.). IR (ATR): ν = 3358, 2923, 2852,
˜
General Remarks: Solvents (THF, toluene, and CH2Cl2) were dried
by filtration through activated alumina on a commercially available
setup. 1H (400 MHz) and 13C (100 MHz) NMR spectra were re-
corded with a Bruker 400 Ultrashield spectrometer. Residual sol-
vent peaks were used as internal standards. The following notation
was used for the 1H NMR splitting patterns: singlet (s), doublet
(d), triplet (t), quintuplet (q), multiplet (m), and double doublet
(dd). FTIR spectra were recorded with a Bruker FS 55 FT-IR spec-
trometer when using KBr pellets and with a Digilab TFS 2000
Scimitar instrument when using ATR. Melting points are uncor-
rected.
2360, 2341, 1739, 1712, 1698, 1586, 1533, 1508, 1452, 1344, 1293,
1253, 1156, 1109, 1088, 1031, 902, 875, 846, 806, 788, 762, 733,
694 cm–1. MALDI-TOF MS: m/z = 563.20 [M + H]+ (calcd. for
C31H39N4O6: 563.29).
Tetramer Carbamate Ester 4a: As described in the general coupling
procedure, dimer acid 2c (1.95 g, 3.55 mmol) and dimer amine 2b
(1.5 g, 3.55 mmol) were coupled to give tetramer 4a as a white pow-
1
˚
der (3 g, yield 89%). M.p. 134–136C. H NMR (400 MHz, CDCl3):
3
δ = 0.88 (t, JH,H = 7 Hz, 6 H, CH2CH3), 1.2–1.4 (m, 28 H), 1.48
(q, JH,H = 7 Hz, 4 H), 1.85 (m, 4 H, OCH2CH2), 3.79 (s, 3 H,
OCH3), 4.06 (t, JH,H = 7 Hz, 2 H, OCH2CH2), 4.19 (t, JH,H
3
3
3
=
Benzyl (6-Aminopyridin-2-yl)carbamate (1b): At –78 °C, a 2.5 m
solution of BuLi in hexane (132 mL, 330 mmol) was added to a
solution of 2,6-diaminopyridine (10.9 g, 100 mmol) in anhydrous
THF. After 1 h at this temperature the mixture was allowed to
warm to room temp. for 1 h. The reaction mixture was then cooled
to –78 °C and benzyl chloroformate (19 mL, 110 mmol) was added
dropwise. The reaction mixture was then stirred at room temp. for
2 h before being cautiously quenched with water. The solvent was
evaporated and the residue was dissolved in dichloromethane and
washed with water. The organic layer was dried over MgSO4, fil-
tered, and the solvents evaporated. The residue was purified by
flash chromatography on silica gel (eluent: CH2Cl2/EtOAc 95:5
v/v) to give the monoprotected amine 1b as a white solid (20.3 g,
7 Hz, 2 H, OCH2CH2), 5.01 (s, 2 H, OCH2Ph), 7.03–7.17 (m, 5 H,
4
CarylH), 7.47 (d, JH,H = 2 Hz, 1 H, CarylH), 7.70 (dd, 3J1
=
H,H
3J2
= 8 Hz, 1 H, CarylH), 7.74 (dd, 3J1
=
3J2
= 8 Hz, 1
H,H
H,H
H,H
3
4
H, CarylH), 7.81 (d, JH,H = 8 Hz, 1 H, CarylH), 7.84 (d, JH,H
=
2.5 Hz, 1 H, CarylH), 7.91 (d, 4JH,H = 2.5 Hz, 1 H, CarylH), 7.93 (d,
4JH,H = 2.5 Hz, 1 H, CarylH), 8.01 (d, JH,H = 8 Hz, 1 H, CarylH),
3
3
8.10 (d, JH,H = 8 Hz, 1 H, CarylH), 8.14 (s, 1 H, NH), 8.15 (d,
3JH,H = 8 Hz, 1 H, CarylH), 10.55 (s, 1 H, NH), 10.62 (s, 1 H, NH),
10.69 ppm (s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 14.60,
23.19, 26.37, 26.41, 29.34, 29.36, 29.42, 29.84, 29.85, 29.88, 29.90,
30.08, 30.10, 30.15, 53.24, 67.03, 69.58, 69.66, 69.77, 108.16,
108.73, 110.18, 110.54, 110.94, 111.78, 112.05, 127.69, 128.21,
128.65, 148.85, 149.45, 149.82, 150.35, 150.58, 152.74, 161.68,
1
yield 84%). M.p.: 60–65 °C. H NMR (400 MHz, CDCl3): δ = 4.2
3
164.66, 167.53, 168.21, 115.28, 161.29, 151.72 ppm. IR (ATR): ν =
(s, 2 H, NH2), 5.10 (s, 2 H, OCH2), 6.07 (d, J(H,H) = 8.5 Hz, 1
˜
3
3284, 2924, 2854, 1733, 1692, 1585, 1504, 1450, 1394, 1343, 1292,
1243, 1212, 1157, 1111, 1087, 1037, 1003, 880, 840, 798, 767, 733,
695 cm–1. MALDI-TOF MS: m/z = 959.50 [M + H]+ (calcd. for
C53H67N8O9: 959.50).
H, C(3)-H), 7.17 (d, JH,H = 8.5 Hz, 1 H, C(5)-H), 7.23–7.3 (m, 5
H, Aryl-H), 7.33 (dd, t, 3J1
=
3J2
= 8.5 Hz, 1 H, C(4)-H),
H,H
H,H
7.54 ppm (s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 66.9,
101.7, 103.3, 128.1, 128.2, 128.4, 135.9, 139.9, 150.1, 152.9,
157.3 ppm. IR (KBr): ν = 3438, 3374, 3323, 3196, 1740, 1706, 1630,
˜
Octamer Carbamate Ester 8a: According to the general coupling
procedure, tetramer acid 4c (700 mg, 0.753 mmol) and tetramer
amine 4b (610 mg, 0.753 mmol) were coupled to give octamer 8a
(720 mg, yield 55%). M.p.: 205–207 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.90 (m, 12 H, CH2CH3), 1.23–1.50 (m, 56 H), 1.56
(q, 3JH,H = 7.3 Hz, 8 H), 1.92 (q, 3JH,H = 7.4 Hz, 8 H, OCH2CH2),
3.58 (s, 3 H, OCH3), 3.97–4.31 (m, 8 H, OCH2CH2), 4.84 (m, 1 H,
OCH2Ph), 5.23 (m, 1 H, OCH2Ph), 6.99–7.12 (m, 5 H), 7.27–7.37
(m, 4 H), 7.53–7.76 (m, 4 H), 7.79 (s, 1 H, NH), 7.80–7.91 (m, 4
H), 7.89 (d, JH,H = 8.1 Hz, 1 H, CarylH), 8.17 (d, JH,H = 8.1 Hz,
1 H, CarylH), 10.32 (s, 1 H, NH), 10.41 (s, 1 H, NH), 10.43 (s, 1
H, NH), 10.45 (s, 1 H, NH), 10.52 (s, 1 H, NH), 10.54 (s, 1 H,
NH), 10.81 ppm (s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ =
14.2, 22.8, 26.0, 26.1, 29.0, 29.5, 29.7, 32.0, 52.8, 66.9, 69.2, 69.4,
107.8, 108.4, 109.7, 109.9, 110.1, 110.9, 111.2, 111.3, 111.4, 111.5,
112.1, 115.2, 127.1, 127.6, 128.2, 135.8, 140.8, 141.0, 141.4, 146.1,
148.5, 148.6, 148.7, 148.9, 149.1, 149.2, 149.3, 149.9, 150.1, 151.6,
152.1, 160.3, 160.4, 161.1, 161.2, 161.6, 164.0, 167.2, 167.6, 167.9,
1609, 1577, 1528, 1457, 1419, 1294, 1195, 1167, 1085, 1043, 905,
870, 846 cm–1. EIMS: m/z = 243.30 [M]+ (calcd. for C13H13N3O2:
243.10).
General Procedure for the Coupling Reaction (compounds 2a, 4a,
and 8a): The starting acid (1a, 2c, or 4c) was converted to its corre-
sponding acid chloride in refluxing SOCl2 (50 equiv.). The reaction
was stopped when no more gas formation was observed. The re-
maining SOCl2 was distilled off and the resulting solid was dried
in vacuo and then dissolved in anhydrous toluene or CH2Cl2 before
2 equiv. of diisopropylethylamine were added. Amine 1b, 2b, or 4b
(1 equiv.) was added to this solution. The reaction mixture was
stirred at room temp. for 12 h and then quenched with water. The
solution was extracted with CH2Cl2. The organic phase was dried
over MgSO4, filtered, and the solvents evaporated. The resulting
solid was purified by flash chromatography on silica gel.
3
3
Dimer Carbamate Ester 2a: As described in the general coupling
procedure, monoacid-monoester 1a (3.85 g, 11.42 mmol) and
monoamine 1b (2.78 g, 11.42 mmol) were coupled to give dimer 2a
as a white powder (6.54 g, yield 98%). M.p.: 138–140 °C. 1H NMR
168.0 ppm. IR (KBr): ν = 2925, 2854, 1736, 1699, 1587, 1522, 1458,
˜
1392, 1376, 1345, 1299, 1246, 1213, 1158, 1115, 1086, 1038, 998,
879, 800, 730, 693 cm–1. ESMS: m/z = 1752.20 [M + H]+ (calcd.
for C97H124N16O15: 1752.94), 876.60 [M + 2H]2+ (calcd. for
C97H125N16O15: 876.97).
3
(400 MHz, CDCl3): δ = 0.88 (t, JH,H = 7 Hz, 3 H, C-CH3), 1.2–
3
3
1.4 (m, 14 H), 1.47 (q, JH,H = 7 Hz, 2 H), 1.84 (q, JH,H = 7 Hz,
3
2 H, OCH2CH2), 4.02 (s, 3 H, O-CH3), 4.15 (t, JH,H = 7 Hz, 2 H,
Eur. J. Org. Chem. 2005, 1293–1301
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1299

V. Maurizot, C. Dolain, I. Huc
FULL PAPER
General Procedure for the Saponification of the Methyl Esters (Prep-
aration of 2c, 4c, and 8c): Ester 2a, 4a, or 8a was dissolved in a
mixture of dioxane/H2O (8:2 v/v) in the presence of KOH (4 equiv.).
The reaction was monitored by TLC and stirred at room temp.
until no starting material could be detected. The reaction mixture
was then neutralized with acetic acid and the dioxane was evapo-
rated. The resulting white solid was filtered, washed with water, and
dried under vacuum. It was used in the next step without further
purification. Its purity was checked only by 1H NMR and mass
spectrometry.
3JH,H = 7.8 Hz, 1 H, CarylH), 7.74 (d, 4JH,H = 2.5 Hz, 1 H, CarylH),
4
7.93 (d, JH,H = 2.5 Hz, 1 H, CarylH), 10.20 ppm (s, 1 H, NH).
MALDI-TOF MS: m/z = 429.20 [M + H]+ (calcd. for C23H33N4O4:
429.25).
Tetramer Ester Amine 4b: Tetramer amine 4b was obtained as a
white powder from tetramer 4a (720 mg, 0.76 mmol) according to
the general hydrogenation procedure (610 mg, yield 99%). 1H
3
NMR (400 MHz, CDCl3): δ = 0.88 (t, JH,H = 6.4 Hz, 6 H,
3
CH2CH3), 1.2–1.4 (m, 28 H), 1.48 (q, JH,H = 6.4 Hz, 4 H), 1.85
3
(m, 4 H, OCH2CH2), 3.96 (s, 3 H, OCH3), 4.16 (t, JH,H = 6.7 Hz,
3
Dimer Carbamate Acid 2c: Saponification of dimer 2a (2 g,
3.56 mmol) as described in the general procedure, gave acid 2c as a
white solid (1.95 g, yield 98%). 1H NMR (400 MHz, [D6]DMSO): δ
2 H, OCH2CH2), 4.19 (t, JH,H = 6.7 Hz, 2 H, OCH2CH2), 4.68 (s,
3
3
2 H, NH2), 6.31 (d, JH,H = 7.9 Hz, 1 H, CarylH), 7.56 (t, JH,H
=
7.9 Hz, 1 H, CarylH), 7.75 (d, 4JH,H = 2.6 Hz, 1 H, CarylH), 7.78 (d,
3
3JH,H = 8.2 Hz, 1 H, CarylH), 7.87 (dd, J1
= J2
= 8.2 Hz,
3
3
= 0.85 (t, JH,H = 7 Hz, 3 H, CH2CH3), 1.16–1.37 (m, 14 H), 1.42
H,H
H,H
3
3
4
4
(q, JH,H = 7 Hz, 2 H), 1.78 (q, JH,H = 7 Hz, 2 H, OCH2CH2),
1 H, CarylH), 7.94 (d, JH,H = 2.6 Hz, 1 H, CarylH), 7.98 (d, JH,H
= 2.6 Hz, 1 H, CarylH), 7.99 (d, JH,H = 2.6 Hz, 1 H, CarylH), 8.14
(dd, JH,H = 8.2, JH,H = 0.6 Hz, 1 H, CarylH), 8.26 (dd, JH,H
8.2, JH,H = 0.6 Hz, 1 H, CarylH), 10.26 (s, 1 H, NH), 10.44 ppm
(s, 2 H, NH). MALDI-TOF MS: m/z = 825.50 [M + H]+ (calcd.
for C45H61N8O7: 825.47).
3
4
4.26 (t, JH,H = 7 Hz, 2 H, OCH2CH2), 5.19 (s, 2 H, OCH2Ph),
7.30–7.46 (m, 5 H, CarylH), 7.65 (dd, JH,H = 7.8, JH,H = 1.0 Hz,
1 H, CarylH), 7.75 (d, JH,H = 2.5 Hz, 1 H, CarylH), 7.84 (d, JH,H
= 2.5 Hz, 1 H, CarylH), 7.85–7.95 (m, 2 H, CarylH), 10.36 (s, 1 H,
NH), 10.53 ppm (s, 1 H, NH). MALDI-TOF MS: m/z = 549.20
[M + H]+ (calcd. for C30H37N4O6: 549.27).
3
4
3
4
3
=
4
4
4
Chiral Octamer Carbamate Amides (S)-1 and (R)-1: Octamer acid
8c (8 mg, 4,6 μmol) was dissolved in anhydrous DMF (2 mL) be-
fore diisopropylethylamine (50 μL) was added followed by HBTU
(2 mg, 5.2 μmol). The mixture was stirred at ambient temperature
for 10 min. (R)- or (S)-α-methylbenzylamine (0.6 μL, 5 μmol) was
added and the mixture was stirred for 2 h. The solvent was evapo-
rated in vacuo and the residue was purified by silica gel chromatog-
raphy to give chiral octamer (R)-1 or (S)-1 as a white solid. M.p.:
180–183 °C. 1H NMR (400 MHz, CDCl3): δ = 0.78–0.96 (m), 1.05–
1.63 (m), 1.80–2.03 (m), 4.0–4.33 (m, 8 H, OCH2CH2), 4.78–4.87
(m, 2 H, OCH2Ph and NHCHPh), 5.13 (m, 1 H, OCH2Ph), 6.94–
Tetramer Carbamate Acid 4c: Tetramer 4a (720 mg, 3.56 mmol) was
saponified, as described in the general saponification procedure,
1
to give acid 4c as a white powder (700 mg, yield 98%). H NMR
3
(400 MHz, [D6]DMSO): δ = 0.04 (t, JH,H = 6.5 Hz, 6 H,
CH2CH3), 0.38–0.58 (m, 28 H), 0.65 (m, 4 H), 1.01 (m, 4 H,
OCH2CH2), 3.31 (t, 3JH,H = 6.2 Hz, 2 H, OCH2CH2), 3.40 (t, 3JH,H
= 6.1 Hz, 2 H, OCH2CH2), 4.26 (s, 2 H, OCH2Ph), 6.37 (m, 5 H),
4
3
6.85 (d, JH,H = 2.2 Hz, 1 H, CarylH), 6.87 (d, JH,H = 8 Hz, 1 H,
3
3
C
arylH), 6.96 (dd, J1
= J2
= 8 Hz, 1 H, CarylH), 6.95 (dd,
= 8 Hz, 1 H, CarylH), 7.00–7.12 (m, 5 H, CarylH),
H,H
H,H
H,H
3J1
= J2
3
H,H
3
3
3
7.16 (d, JH,H = 7.8 Hz, 1 H, CarylH), 7.33 (dd, J1
= J2
=
4
7.16 (m), 7.20 (d, JH,H = 1.9 Hz, 1 H, CarylH), 7.33 (s), 7.40 (d,
H,H
H,H
4JH,H = 1.9 Hz, 1 H, CarylH), 7.58–7.74 (m), 7.75–7.81 (m), 7.88 (d,
4JH,H = 2.4 Hz, 1 H, CarylH), 7.88–7.98 (m), 8.07–8.15 (m), 8.26
7.8 Hz, 1 H, CarylH), 8.56 (s, 1 H, NH), 10.27 (s, 1 H, NH), 10.28
(s, 1 H, NH), 10.43 ppm (s, 1 H, NH). MALDI-TOF MS: m/z =
945.50 [M + H]+ (calcd. for C52H65N8O9: 945.49).
Octamer Carbamate Acid 8c: Acid 8c was obtained as a white pow-
der by saponification of the octamer 8a (200 mg, 0.114 mmol) fol-
lowing the general procedure (190 mg, yield 98%). NMR spectra
showed broad signals in all the solvents tested. MALDI-TOF MS:
m/z = 1737.69 [M + H]+ (calcd. for C96H121N16O15: 1737.92),
1759.66 [M + Na]+ (calcd. for C97H120N16NaO15: 1759.90).
Table 1. Crystallographic data for compound 2a.
Compound
2a
Formula
C31H38N4O6
562.66
Mol. mass [gmol–1]
Crystal system
Space group
a [Å]
monoclinic
¯
P1
General Procedure for the Hydrogenolysis of Benzyl Carbamate Pro-
tecting Groups (Synthesis of 2b and 4b): The protected amine 2a or
4a and 10% palladium on activated carbon (10%, wt/wt) were
mixed in a mixture of DMF/methanol (8:2, v/v). The mixture was
placed under hydrogen and stirred until no starting compound
could be observed by TLC. The suspension was then diluted with
CH2Cl2 and filtered through a Celite pad to remove the catalyst.
The filtrate was evaporated to give the free amine. The amine was
used without further purification, but was rigorously dried by using
a Dean–Stark apparatus and by running a continuous distillation
in toluene at atmospheric pressure before performing subsequent
coupling reactions. The purity of the amine was simply checked by
NMR and mass spectrometry.
8.131(1)
10.991(2)
18.612(2)
74.70(1)
81.13(1)
68.55(1)
1490.2(4)
1.254
b [Å]
c [Å]
α [°]
β [°]
γ [°]
V [Å3]
Dcalcd. [gcm–3]
Z
2
F[000]
600
0.715
Colorless
0.5×0.25×0.15
μ (Cu-Kα) [mm–1]
Crystal color
Crystal size [mm]
Data collection
θmin, θmax [°]
Temperature [K]
Reflections collected
Reflections unique
Refinement
No. of parameters
R1 [I Ͼ 2σ(I)]
wR2 (all data)
GOF
4.44, 65.12
296(2)
5080
Dimer Ester Amine 2b: Hydrogenation, following the general pro-
cedure described above, of dimer 2a (2 g, 3.56 mmol) for 2 h leads
to the formation of amine 2b as a white powder (1.5 g, yield 100%).
5080
3
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, JH,H = 7 Hz, 3 H,
3
377
CH2CH3), 1.2–1.4 (m, 14 H), 1.47 (q, JH,H = 7 Hz, 2 H), 1.84 (q,
3JH,H = 7 Hz, 2 H, OCH2CH2), 4.03 (s, 3 H, OCH3), 4.15 (t, 3JH,H
0.0462
0.1354
1.041
3
= 7 Hz, 2 H, OCH2CH2), 4.41 (s, 2 H, NH2), 6.31 (d, JH,H
=
7.8 Hz, 1 H, CarylH), 7,52 (t, 3JH,H = 7.8 Hz, 1 H, CarylH), 7.72 (d,
1300
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1293–1301

Helical Handedness in Pyridinedicarboxamide Oligomers
FULL PAPER
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NH), 10.47 (br. s, 2 H, NH), 10.66 ppm (s, 2 H, NH). The 13C
NMR spectrum is broad and very complex. At the high concentra-
tion used for acquisition, it contains signals belonging to multiple
species such as the right- and left-handed single helices, and various
right- and left-handed double helices with parallel or antiparallel
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˜
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1691, 1686, 1665, 1655, 1648, 1637, 1587, 1571, 1560, 1523, 1459,
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on a CAD4 Enraf–Nonius diffractometer with graphite-monochro-
matized Cu-Kα radiation. The cell parameters were determined by
least-squares from the setting angles of 25 reflections. An empirical
absorption correction was applied. The data were also corrected for
Lorentzian and polarization effects. The crystals are mechanically
fragile as well as unstable in air. During exposure to X-rays, the
crystals and some of the mother liquor were sealed in a Lindemann
glass capillary. The positions of non-hydrogen atoms were deter-
mined by the SHELXS-97 program[40] and the position of the hy-
drogen atoms were deduced from coordinates of the non-hydrogen
atoms and confirmed by Fourier synthesis. Hydrogen atoms were
included for structure factor calculations but were not refined.
CCDC-249796 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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This work was supported by the CNRS (predoctoral fellowship to
C. D.), the University of Bordeaux I, and by the Conseil Régional
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