Controlling helix handedness in water-soluble quinoline oligoamide foldamers

Article abstract of DOI:10.1002/ejoc.201402247

For biological applications, the control of the helix handedness of water-soluble quinoline-based oligoamide foldamers has been investigated by the installation of chiral end groups at either the C or N terminus. This has resulted in the development of monomer units capable of unequivocally inducing helical sense without impacting the aqueous solubility. Furthermore, we showed that very slow helix handedness inversion in water can be exploited. The incorporation of a chiral moiety with no handedness-induction properties allows the chromatographic separation of P and M helices as diastereoisomers with kinetically locked handedness. Copyright

Full text of DOI:10.1002/ejoc.201402247

FULL PAPER
DOI: 10.1002/ejoc.201402247
Controlling Helix Handedness in Water-Soluble Quinoline Oligoamide
Foldamers
Simon J. Dawson,[a,b] Ádám Mészáros,[c] Lilla Petho˝,[c] Cinzia Colombo,[a,b]
Márton Csékei,[c] András Kotschy,*[c] and Ivan Huc*[a,b]
Keywords: Chirality / Helical structures / Conformation analysis / Foldamers / Oligoamides
For biological applications, the control of the helix hand-
edness of water-soluble quinoline-based oligoamide folda-
mers has been investigated by the installation of chiral end
groups at either the C or N terminus. This has resulted in
the development of monomer units capable of unequivocally
inducing helical sense without impacting the aqueous solu-
bility. Furthermore, we showed that very slow helix hand-
edness inversion in water can be exploited. The incorpora-
tion of a chiral moiety with no handedness-induction proper-
ties allows the chromatographic separation of P and M heli-
ces as diastereoisomers with kinetically locked handedness.
ure 1), feature properties that make them promising candi-
dates for the recognition of protein and nucleic acid sur-
faces: they adopt well-defined, predictable conformations,
they are medium sized (0.5–5.0 kDa), they are resistant to
proteolytic degradation and have been shown to possess
cell-penetrating properties.[4] However, as they do not
closely resemble the biological structures they mimic, the
challenge to design ligands for proteins and nucleic acids
becomes all the more difficult. One rapid method for
screening quinoline oligoamides for activity against a given
biological surface relies on the fact that short sequences (Ͻ5
units) without any stereogenic centre exist as a mixture of
interconverting P and M helical conformations. If binding
to a target surface is helix sense dependent, then the equilib-
rium will be shifted towards the preferred conformer, and
this process can be monitored by induced circular dichroism
(ICD). Indeed, the P and M helices possess opposite sign
CD bands that cancel each other. When equilibrium devi-
ates from a 50:50 mixture, CD bands emerge. This tech-
nique has recently been used to screen short quinoline oli-
goamide sequences tethered to human carbonic anhydrase
II (HCA) through a ligand (Figure 2), and a sequence was
Introduction
The chirality of secondary structures such as helices is a
property fundamental to the complex molecular interac-
tions involved in cellular processes, for example, at protein–
protein interfaces. The importance of diastereomeric selec-
tivity in biological target recognition highlights the need to
investigate right-handed (P) or left-handed (M) conformers
of helical foldamers as distinct entities, as such compounds
are considered to be useful ligands for biopolymer recogni-
tion.[1] By extension, the ability to reliably induce helix han-
dedness under biocompatible conditions is a must.
The induction of handedness in helical foldamers is an
attractive concept, as it allows the display of functionality
in a specific one-handed array along the face of a scaffold
and, thus, the potential ability to recognize a particular bio-
logical surface with high selectivity. The induction of hand-
edness is inherent in peptidic foldamers as chirality is im-
parted by the amino acid building blocks.[2] Aromatic amide
backbones do not possess stereogenic centres and form ra-
cemic mixtures of P and M helices in solution.[3] Therefore,
in this case, it is necessary to consider other methods for
the control of handedness.
Helical aromatic oligoamide foldamers, such as those
consisting of 8-amino-2-quinolinecarboxylic acid (Fig-
[a] Université de Bordeaux, CBMN (UMR 5248), Institut
Européen de Chimie et Biologie,
2 rue Robert Escarpit, 33607 Pessac, France
E-mail: i.huc@iecb.u-bordeaux.fr
www.iecb.u-bordeaux.fr
[b] CNRS, CBMN (UMR5248), Institut Européen de Chimie et
Biologie
2 Rue Robert Escarpit, 33607 Pessac
[c] Servier Research Institute of Medicinal Chemistry,
Záhony utca 7, 1031 Budapest, Hungary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402247.
Figure 1. Cationic octamer and camphanyl inducing groups.
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A. Kotschy, I. Huc et al.
FULL PAPER
identified that not only possessed affinity for the protein candidates were then reassessed for binding, and one exam-
surface but also induced the formation of a new HCA di- ple indicated a preference for the M helix.[14]
mer.[5] The induction of helix handedness has also been ob-
However, the quantitative induction of helix handedness
served between a fully cationic side-chain-functionalized (deϾ 99%) is a challenging objective, and success has been
tetramer and G-quadruplex DNA[6] and between helical limited to a few cases.[6,10i,15] Although the camphanyl
capsules and their chiral guests.[7] In the former two cases, group can successfully induce handedness in aromatic oli-
handedness induction is not required, because the bio- goamide foldamers, its bulky and hydrophobic nature may
logical target itself exerts control over helix sense.
be problematic with respect to the water solubility of the
final compound and also to the function of the foldamer as
an efficient ligand.[14] Therefore, it was clear to us that there
was a need to further develop methods to control the helix
handedness of quinoline oligoamide foldamers for applica-
tions in water.
Presented here are two methods that allow the prepara-
tion of isolated P and M helices of water-soluble quinoline
oligoamides. Firstly, we investigated the concept that the
incorporation of a chiral moiety with no handedness-induc-
tion properties could potentially allow chromatographic
separation of P and M helices as diastereoisomers, as longer
sequences (Ͼ6 units) are essentially kinetically “locked”
into position under aqueous conditions. Secondly, we
studied the effect of appending a chiral moiety onto the 8-
position of a quinoline monomer unit (QY, Figure 2), which
could potentially allow it to act as an N-terminal hand-
edness inducer.
These units were deliberately designed to permit solubil-
ity under both organic and aqueous conditions. This al-
lowed us to incubate the foldamer in organic solvents and
take advantage of the fast handedness-inversion kinetics to
quickly reach equilibrium and then subsequently “lock” the
handedness conformation in water.
Results and Discussion
Separation of Diastereoisomers Arising from Helix
Handedness
Figure 2. (a) QXxx monomers, (b) HCA inhibitor structure, (c) QY
chiral monomers and (d) summary of foldamer sequences.
Previously, the installation of a C-terminal phenylalanine
group was found to be a poor method for controlling helix
However, the kinetics of helix handedness inversion of 8- handedness in organic solvents.[10b] However, it was noted
amino-2-quinolinecarboxylic acid oligoamides slow down that the resulting P and M diastereoisomers possessed strik-
as strand length increases.[8] This effect is so pronounced in ingly different retardation factors on silica gel chromatog-
protic solvents that handedness becomes kinetically stable raphy, which allowed their separation at low temperatures.
for octameric sequences,[9] and a biological target is not re- Reequilibration of each isolated diastereoisomer to the ra-
quired as a handedness inducer. An alternative is to induce cemic mixture then rapidly occurred at room temperature.
helix handedness in the oligomer through the incorporation We reasoned that if the same principle could be applied
of a chiral unit either at an end[10] or middle[11] of the se- to reversed-phase (RP) chromatography with water-soluble
quence or by the presence of a chiral side chain.[12] Both oligomers, we could take advantage of the kinetic inertness
enantiomers can then be assessed independently for binding under aqueous conditions to isolate diastereoisomers that
affinity to the target. This approach has been used in the would not racemize, provided they were exposed only to
assessment of G-quadruplex DNA binding of quinoline oli- aqueous solvent mixtures.
goamide foldamers. The systematic evolution of ligands by
Initial work focussed on the preparation of the all-cat-
exponential enrichment (SELEX)[13] was used to identify ionic side-chain-functionalized octamer (4, Figure 2). Low-
G-rich aptamers with affinity for a fully cationic side-chain- loading Wang resin was functionalized with Fmoc-Phe-OH
functionalized octamer (1, Figure 1). The separate P and M (Fmoc = fluorenylmethyloxycarbonyl) by using the well-
helices of the octamer were then produced by installation documented anhydride method.[16] Fmoc deprotection was
of the (1S)-(–)-camphanyl (2) or (1R)-(+)-camphanyl (3) then performed with piperidine in N,N-dimethylformamide
group, respectively, at the N terminus,[10i] and the aptamer (DMF; 20% v/v), and the first Fmoc-QOrn unit was in-
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Controlling Helix Handedness in Oligoamide Foldamers
stalled through its acid chloride, which was formed by using
1-chloro-N,N,2-trimethyl-1-propenylamine (Scheme 1).[17]
The oligoamide was then prepared by the microwave-as-
sisted Fmoc solid-phase synthesis (SPS) strategy previously
reported by our group (see Exp. Sect.).[18] Removal from
the resin with concomitant side-chain tert-butyloxycarbonyl
(Boc) deprotection was subsequently performed by treat-
ment of the resin with 95:2.5:2.5 TFA/H2O/iPr3SiH v/v/v
(TFA = trifluoroacetic acid). The crude material was ana-
lyzed by RP-HPLC and indeed was found to consist of two
well-separated main products (Figure 3) of approximately
equal peak area; this was in concordance with the 1H NMR
analysis, which demonstrated the presence of 14 amide sig-
nals that correspond to two discrete octameric products
(Figure 4, a).
1
Figure 4. Carboxamide region of the H NMR spectra of 4 and 5
in [D6]DMSO at 298 K: (a) crude mixture of diastereoisomers of 4
after SPS (reflects the ratio of diastereoisomers in the TFA cleavage
mixture), (b) (P)-4, (c) (M)-4, (d) crude mixture of diastereoisomers
of 5 after SPS, (e) (P)-5 and (f) (M)-5.
the expected octameric diastereoisomers. Analysis of the
CD spectrum of each product was also important to con-
firm the separation of the P and M helices. Although the
P-4 and M-4 helices are diastereomers and not enantio-
mers, the helical aromatic foldamer parts of their structures
are mirror images and give rise to virtual “mirror image”
spectra of opposing sign. Indeed, CD experiments (Fig-
Scheme 1. SPS of fully cationic-side-chain octamer 4. Reagents and ure 5) showed the expected deflections at 390–410 nm, the
conditions: (i) 20% v/v piperidine in DMF, room temp., 10 min,
absorption region of the quinoline chromophores. By anal-
repeat once; (ii) (a) Fmoc-QOrn(Boc)-OH, 1-chloro-N,N,2-trimethyl-
ogy to previous work,[10b] the first eluted diastereoisomer
1-propenylamine, CH2Cl2, r.t., 1 h; (b) product from (a), iPr2EtN,
was determined to be the P helix (positive band near
400 nm), and the second was determined to be the M helix
(negative band).
THF, microwave 50 W, ramp to 50 °C, hold 50 °C for 15 min, re-
peat once; (iii) 20% v/v piperidine in DMF, r.t., 10 min, repeat
twice; (iv) repeat steps (ii)–(iii); (v) acetyl chloride, iPr2EtN, THF,
microwave 50 W, ramp to 60 °C, hold 60 °C for 15 min, repeat once;
(vi) TFA/iPr3SiH/H2O (95:2.5:2.5), r.t., 2 h.
Figure 5. CD spectra of separated P and M diastereoisomers of
50–60 µm solutions of 4 and 5 in H2O and H2O/DMSO (99:1),
respectively, at 293 K.
Figure 3. HPLC profile showing separation of the diastereoisomers
of 4. First eluting peak identified by CD (see Figure 5) as P-4,
second eluting peak identified as M-4.
The stability of the separate diastereoisomers of 4 in
water was assessed by HPLC, which revealed no detectable
interconversion between handedness forms over a period of
The crude mixture was purified by preparative RP- five days at room temperature. Unlike peptidic α helices,
HPLC, and analysis of each product by 1H NMR spec- which tend to be destabilized when they consist exclusively
troscopy and mass spectrometry confirmed their identity as of positively charged residues,[19] cationic aromatic oli-
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goamide helices remain stable even when they possess mul- Induction of Helix Handedness through an N-Terminal
tiple positive charges. This was in contrast to their behav- Quinoline-Based Chiral Building Block
iour in dimethyl sulfoxide (DMSO), in which a degree of
We sought to further enhance our toolkit for the isola-
racemization was observed after only two hours and com-
tion of discrete helix handedness forms and to develop a
plete equilibration after 2–3 d (see Supporting Infor-
method that could be applied regardless of the sequence, in
mation). Interestingly, in DMSO, it appears that the phenyl-
particular, for longer oligomers that are not amenable to
alanine unit possesses a moderate ability to induce helix
diastereomer separation. This led us to reconsider the pos-
sense, and there is ca. 40% diastereomeric excess in favour
sibility of using a terminal functional group with the ability
of the P helix.
to induce handedness. Our experiments with inducing
The ability to separate P and M helices by using a C-
groups at the N and C termini demonstrated incomplete
terminal group allows the N terminus to be left free for
handedness induction, except in the case of the large and
other purposes, that is, the incorporation of functionalities.
hydrophobic camphanyl group.[10a–10c,10i] We speculated
This was of interest to us with respect to recent results con-
that bringing stereogenic centres as close as possible to the
cerning the attachment of foldamers to HCA through an
quinoline backbone might offer strong inducing properties
N-terminal inhibitor moiety.[5] Therefore, we tested the sep-
and decided to introduce a chiral centre directly connected
aration of helix sense diastereoisomers in the context of
to the 8-position of an N-terminal quinoline unit. Further-
HCA ligands and used SPS to prepare octamer 5, which
more, we chose groups that would potentially allow solubil-
includes an N-terminal HCA inhibitor moiety and a C-ter-
ity in a range of solvents. This way, long foldamers could
minal Phe unit (Figure 2). Once again, the crude HPLC
be designed to allow incubation in an organic solvent, in
demonstrated the presence of two major products assigned
which inversion kinetics are relatively fast; after completion
1
to the P and M helices. This was also reflected in the H
of the induction, transfer to water would then lock the con-
NMR spectrum (Figure 4, d). The separation of the two
formation.
diastereoisomers by preparative HPLC was also straightfor-
Three designs were proposed, all of which are accessible
ward, and both could be obtained in reasonable purity and
from a common ketone precursor 12 (Scheme 2), the syn-
afforded analogous CD profiles to those of 4 (Figure 5).
thesis of which has been described previously.[20] One face
Interestingly, the order of diastereoisomer elution was the
same as previously, that is, the P helix eluted first.
The aqueous stability of the separate diastereoisomers of
5 was also assessed, although for solubility reasons this re-
quired the addition of a small proportion (0.5–1%) of
DMSO. Once again, no interconversion between hand-
edness forms could be detected over a period of five days
at room temperature (see Supporting Information).
Considering the diverse nature of the side chains in com-
parison to those of the octamer 4, this data suggested to us
that this method could potentially be applied to a greater
range of sequences. To determine whether this method
could be used to access pure diastereoisomers of longer fol-
damers, we prepared the 12-mer 6 (Figure 2). HPLC analy-
sis again revealed the presence of two distinct diastereoiso-
1
mers, as confirmed by MS and H NMR spectroscopy, but
baseline separation could not be afforded with a number of
different gradients and, thus, preparative HPLC was not
attempted in this case.
In summary, the incorporation of a chiral centre at the
C terminus afforded separable helix sense diastereoisomers
of two octameric sequences with diverse side-chain func-
tionality. This way, both P and M helices could be afforded
by a single synthesis. The separated diastereoisomers were
kinetically inert in water over long periods (days). This is
important with respect to their use for targeting protein sur-
faces, as each diastereoisomer could be assessed separately
Scheme 2. Synthesis of chiral quinoline monomers. Reagents and
for binding by techniques such as surface plasmon reso-
nance (SPR) without the risk of racemization. Shorter se-
quences (Յ5 units) can simply be presented to the target as
a racemic mixture, and the interactions can be assessed by
ICD, as this is permitted by their faster handedness-inver-
sion kinetics.
conditions: (i) Me2SO4, K2CO3, acetone, reflux, 1 h; (ii) NaBH4,
C2H4Cl2, 55 °C, 8 h; (iii) phenol, di-tert-butyl azodicarboxylate
(DBAD), PPh3, toluene, 80 °C, 3 h; (iv) morpholine, Na(OAc)3BH,
C2H4Cl2, 55 °C, 24 h; (v) 2-(1-piperazinyl)ethanol, Na(CN)BH3,
AcOH, C2H4Cl2, 55 °C, 3 h; (vi) LiOH·H2O, dioxane/H2O, 1 h;
(vii) Ac2O, diisopropylethylamine (DIEA), CHCl3, 4 h [performed
on (R)-20].
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Controlling Helix Handedness in Oligoamide Foldamers
of the QPhen monomer (Figure 2) is hindered by the steric acid functions into acid chlorides. No such problems were
bulk of a pendant phenoxy group. This was also hoped to associated with the QPhen building block.
stabilize the preferred helix formation through stacking in-
teractions.
The remaining two designs incorporated either morph-
oline or piperazine through the amine functionality. Al-
though these would not be capable of stacking interactions
with the aromatic foldamer backbone, they would be useful
as solubilising groups. In addition, the installation of a
piperazine moiety might also allow further functionaliza-
tion of the foldamer through the terminal amine group.
The starting quinolinone 12 was functionalized with a
simple methoxy group at the 4-position to yield the com-
mon ketone precursor. This was then either reduced and
subsequently treated with phenol under Mitsunobu condi-
tions to yield the racemic QPhen monomer or the morph-
oline or piperazinylethanol moiety was incorporated by di-
Scheme 3. Synthesis of pentamers bearing N-terminal handedness
rect reductive amination. The subsequent separation of
inducing groups from the tetramer amine precursor 13. Reagents
each enantiomer from the racemic mixture by preparative
and conditions: (i) (a) chiral monomer unit, 1-chloro-N,N,2-tri-
chiral HPLC was followed by saponification to yield the
methyl-1-propenylamine, CH2Cl2, room temp., 1 h; (b) product
free acids of the monomers. The terminal alcohol function-
ality of the QPip monomer was then acetylated before acti-
vation as the acid chloride to avoid the possibility of side-
reactions at this position. The configurations of both
enantiomers of the QMorph monomer were confirmed by
their crystal structures. The remaining monomers proved
difficult to crystallize. Therefore, their configurations were
inferred from their CD signs at 300 nm by comparison with
those of the QMorph enantiomers (see Supporting Infor-
mation).
from (a), iPr2EtN, CHCl3, r.t., 20 h. [the configuration of 10 was
inferred from its CD spectrum (i.e., the resulting induction of M
helix) and comparison between the CD spectra of QPip and QMorph
See Supporting Information].
.
1H NMR analysis of pentamer 7 indicated the presence
of both P and M diastereoisomers in an almost 1:1 ratio,
as demonstrated by the eight carboxamide resonances be-
tween δ = 11 and 12 ppm (Figure 6). This was confirmed
by CD experiments (Figure 7), which showed negligible de-
To assess handedness induction by QPip, QMorph and
Q
Phen, we initially designed a pentameric sequence with
side-chain functionality compatible with a range of organic
solvents. We have previously demonstrated that adjusting
the length of an oligomer and the solvents in which it is
dissolved gave us the ability to “tune” the rate of helix hand-
edness inversion.[8,9] In this case, a pentameric sequence in
a nonpolar solvent such as chloroform would possess slow
enough handedness-inversion kinetics on an NMR times-
cale that the separate diastereoisomers could be visualized
as a distinct set of resonances. However, this behaviour
would still be sufficiently fast that equilibration between
handedness forms would be complete after minutes; thus,
the degree of handedness induction could be accurately as-
sessed. Therefore, quantitative induction could be initially
Figure 6. Carboxamide region of the 1H NMR spectra of (a) 7, (b)
the unprotonated form of 8 (* shows a minor set of peaks) and (c)
the hydrochloride salt of 8 in CDCl3 at 298 K.
1
determined by analysis of the H NMR spectrum, which
should show a single set of resonances. Analysis by CD
would then confirm the induction of a single helix hand-
edness form, as indicated by a deflection at the quinoline
chromophore absorption region; the possibility that the
separate diastereoisomers possess exactly overlapping
NMR resonances is discounted.
The tetramer amine 13 (Scheme 3) was synthesized by
the procedures previously reported by our group[21] and
functionalized with a terminal chiral building block as the
acid chloride. The tertiary amine groups of the QMorph and
Q
Pip units could interfere with the activation. The prior pro-
Figure 7. CD spectra of 50–60 µm solutions of 7–l0 in CHCl3 and
tonation of these amines allowed the clean activation of 11 in H2O at 293 K.
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flection at 390–410 nm. In contrast, pentamers 8 and 9 with those of QMorph. As with the morpholine-functionalized
the R and S enantiomers of the QMorph monomer, respec- monomer, the protonation state appeared to slightly affect
tively, were each found to afford an identical single set of induction efficiency (see Supporting Information).
1H NMR signals, which indicates quantitative handedness
To assess handedness-induction efficiency in water, we
induction. This was also observed in CD3CN/CDCl3 (3:1), returned to the solid-phase synthesis methodology for the
[D3]MeOH and [D6]DMSO. Compound 8 was found to re- production of a simple pentameric sequence consisting of
tain one set of NMR signals in [D6]DMSO for more than an N-terminal (R)-QMorph monomer plus four QOrn resi-
four weeks at room temperature and even after 24 h at dues. Including the morpholine functionality, this sequence
50 °C.
would be a pentacationic species after deprotection and,
Analysis by CD confirmed single helix handedness, and thus, was anticipated to be highly water-soluble at neutral
intense bands were observed at 390–410 nm. Again, by pH or below. In addition, this pentameric sequence would
analogy to previous work, the negative sign of these bands also possess handedness-inversion kinetics fast enough in
indicate a preferred M handedness for 8, which possesses water to permit racemization and, thus, the assessment of
the (R)-QMorph monomer, and the inverse was observed for handedness induction in this medium.
9 [with the (S)-QMorph monomer], which indicates that P
Low-loading Wang bromide resin was prepared by using
handedness is preferred. Interestingly, the protonation state the procedure of Morales and co-workers[22] and function-
of the morpholine unit appeared to slightly enhance hand- alized with the first quinoline monomer in the presence of
1
edness-induction efficiency; the H NMR spectrum of the Cs2CO3.
unprotonated form of 8 showed the presence of minor
The Fmoc group was deprotected, and SPS was contin-
amide resonances (Figure 6), thought to be those of the un- ued by using the methodology previously detailed in the
favoured P diastereoisomer, which were eliminated on con- literature (Scheme 4). The activation of the (R)-QMorph unit
version to the hydrochloride salt. CD experiments (see Sup- was preceded by protonation of its tertiary amine group to
porting Information) supported this, and the small re- enable efficient coupling. The crude foldamer was removed
duction in intensity observed for the unprotonated form from the resin with 50:48:2 TFA/CH2Cl2/iPr3SiH v/v/v and
perhaps indicates a slight decrease in induction efficiency.
purified by RP-HPLC. 1H NMR analysis of the product in
The QPip monomer also demonstrated an ability to quan- both D2O and [D6]DMSO revealed the presence of a single
titatively induce helix handedness; compound 10 showed a set of signals, indicative of quantitative handedness induc-
negative CD deflection of approximately the same magni- tion, and this was confirmed by CD experiments, which
tude as that of 8 at 390–410 nm. This indicates that the showed the expected negative deflection (Figure 7). Com-
monomer is of the R configuration and supports our earlier pound 11 was found to remain as one set of NMR signals
inference from comparison of the QPip CD spectra with in D2O even after 48 h at 40 °C.
Scheme 4. SPS of water-soluble pentamer with N-terminal helix sense inducing group. Reagents and conditions: (i) Fmoc-QOrn(Boc)-OH,
Cs2CO3, iPr2EtN, DMF, microwave 50 W, ramp to 50 °C, hold 50 °C for 5 min, repeat once; (ii) 20% v/v piperidine in DMF, room temp.,
10 min, repeat twice; (iii) (a) Fmoc-QOrn(Boc)-OH, 1-chloro-N,N,2-trimethyl-1-propenylamine, CH2Cl2, r.t., 1 h; (b) product from (a),
iPr2EtN, THF, microwave 50 W, ramp to 50 °C, hold 50 °C for 15 min, repeat once; (iv) repeat steps (ii)–(iii); (v) (a) (R)-QMorph, 1-chloro-
N,N,2-trimethyl-1-propenylamine, CH2Cl2, r.t., 1 h; (b) product from (a), iPr2EtN, CHCl3, microwave 50 W, ramp to 50 °C, hold 50 °C
for 30 min, then repeat at r.t., 20 h.
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Controlling Helix Handedness in Oligoamide Foldamers
(QMorph and QPip syntheses). RP-HPLC analyses were performed
at 1.5 mLmin–1 by using a Macherey–Nagel Nucleodur C18 or C8
gravity column (4.6ϫ100 mm, 3 μm). The mobile phase was com-
posed of 0.1% (v/v) TFA/H2O (solvent A) and 0.1% TFA/CH3CN
(solvent B) with the following gradients: 5–30% B over 13 min,
then 30–100% B over 5 min (system A), 5–100% B over 13 min
then 100% B for 5 min (system B) or 20–60% B over 25 min then
60–100% B for 5 min (system C). Monitoring was performed by
UV detection at 214, 254 and 300 nm with a diode array detector.
Semipreparative purifications of oligomers were performed at
4 mLmin–1 by semipreparative HPLC by using a Macherey-Nagel
Nucleodur C18 HTEC column (21 mmϫ125 mm, 5 μm). The mo-
bile phase was the same as for the analytic system with the follow-
ing gradients: 5–26% B over 40 min (system D), 5–40% B over
20 min (system E) or 20–55% B over 35 min (system F). Monitor-
ing was performed by UV detection at 254 and 300 nm with a diode
array detector. High-resolution electrospray ionization time of
flight (ESI-TOF) mass spectra were recorded in the positive ion
mode with a Waters/Micromass Q-Tof Ultima spectrometer. X-ray
diffraction experiments were performed with a high-flux RIGAKU
FRX rotating anode at the Cu-Kα wavelength.
Conclusions
Two methods for the isolation of separate P and M heli-
ces of quinoline oligoamides have been assessed. The incor-
poration of a phenylalanine residue at the C terminus of
two diversely functionalized water-soluble octamers in both
cases afforded a mixture of the P and M diastereoisomers
with strikingly different retention times. RP-HPLC separa-
tion of the diastereoisomers was straightforward, and each
demonstrated a marked stability in water, which indicates
the extremely slow kinetics of handedness inversion under
these conditions, regardless of side-chain composition and
even in the case of multicationic species. The facility of this
method and the availability of the N terminus for further
functionalization make it attractive when foldamer length
(and therefore the resulting slow kinetics of handedness in-
version) preclude the use of ICD to determine chirality-
dependent interactions with biological targets such as pro-
tein surfaces.
Two chiral quinoline monomers offered quantitative in-
duction of helix handedness in both organic and aqueous
conditions when installed at the N termini of pentameric
sequences. These units should provide solubility in a greater
range of solvents than the camphanyl group and, owing to
their smaller steric bulk, may be less likely to disrupt poten-
tial foldamer–biomolecule interactions. In addition, the
piperazine moiety provides the opportunity for further
functionalization of the foldamer after the chiral unit, for
example, the tethering of fluorescent probes or small-
molecule enzyme inhibitors.
CCDC-990870 [for (1R)-16] and -990871 [for (1S)-16] contain 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.
Monomer Synthesis: Fmoc-QHyd, Fmoc-QAla, Fmoc-QLeu, Fmoc-
QAsp and Fmoc-QOrn were synthesized by using the methods pre-
viously reported.[4,17] Fmoc-QTEG was provided by the Servier Re-
search Institute of Medicinal Chemistry, Hungary.
Methyl 8-Acetyl-4-methoxyquinoline-2-carboxylate (13): Methyl 8-
acetyl-4-hydroxyquinoline-2-carboxylate[20] (491 mg, 2.00 mmol)
was dissolved in acetone (10 mL), and potassium carbonate
(553 mg, 4.00 mmol) and dimethyl sulfate (182 μL, 2.00 mmol)
were added. The mixture was stirred at reflux for 1 h and then
cooled to room temp. Water was added, and the resulting precipi-
tate was collected by filtration and washed with water to afford the
title compound as a white solid (424 mg, 82%). 1H NMR
(400 MHz, [D6]DMSO): δ = 8.30 (dd, J = 8.3, 1.5 Hz, 1 H), 7.93
(dd, J = 7.1, 1.5 Hz, 1 H), 7.73 (dd, J = 8.3, 7.1 Hz, 1 H), 7.57 (s,
1 H), 4.13 (s, 3 H), 3.96 (s, 3 H), 2.88 (s, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 202.9, 165.6, 163.5, 149.3, 145.2,
139.9, 130.6, 127.9, 125.2, 121.8, 101.1, 57.1, 53.4, 33.2 ppm.
HRMS: calcd. for C14H13NO4 [M + H]+ 259.0845; found 260.0916.
These methods for handedness control will serve not only
to aid investigation into the chirality dependence of fold-
amer–target interactions but also to facilitate the isolation
of discrete, stable handedness forms of a foldamer sequence
for use in biological and biophysical assays.
Experimental Section
General Methods: Low-loading Wang resin was purchased from
Novabiochem. Ghosez reagent (1-chloro-N,N,2-trimethyl-1-prop-
enylamine) was purchased from Sigma–Aldrich. N,N-Diisopropyl-
ethylamine was distilled from calcium hydride. Analytical grade or-
ganic solvents were used for solid-phase synthesis. Anhydrous tetra-
hydrofuran (THF) and CHCl2 for solution and solid-phase synthe-
sis were dispensed from an MBRAUN SPS-800 solvent purification
system. HPLC-quality acetonitrile and MilliQ water were used for
RP-HPLC analyses and purification. Reactions requiring anhy-
drous conditions were performed under nitrogen. 1H NMR spectra
were recorded at 300, 400 or 500 MHz, and 13C NMR spectra were
recorded at 75, 100 or 125 MHz. Chemical shifts are reported in
ppm and are calibrated against the residual solvent signals of
CDCl3 (δ = 7.26, 77.2), [D6]DMSO (δ = 2.50, 39.4) or D2O (δ =
4.79 ppm). All coupling constants are reported in Hz. Signal multi-
plicities are abbreviated as s, singlet; br s, broad singlet; d, doublet;
t, triplet; q, quartet; m, multiplet, dd, doublet of doublets. Silica
gel chromatography was performed with Merck Kieselgel Si 60.
Thin layer chromatography was performed with Merck Kieselgel Si
60 F254 plates. Chiral preparative HPLC was performed by using a
Daicel Chiralpak AD column with isocratic ethanol/heptane mix-
tures as the eluent at either 100 (QPhen synthesis) or 50 mLmin–1
Methyl 8-(1-Hydroxyethyl)-4-methoxyquinoline-2-carboxylate (14):
Methyl
8-acetyl-4-methoxyquinoline-2-carboxylate
(7.519 g,
29.00 mmol) was dissolved in dry 1,2-dichloroethane (200 mL), and
sodium borohydride (3.292 g, 87.00 mmol) was added. The mixture
was stirred at 55 °C for 8 h and then cooled to room temp. The
mixture was diluted with dichloromethane (100 mL), and acetic
acid was added to quench the reaction. The mixture was then
washed with water and brine and extracted with CH2Cl2. The com-
bined organic layers were dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
silica gel chromatography (heptane/EtOAc) to afford the title com-
1
pound as a white solid (5.096 g, 67%). H NMR (500 MHz, [D6]-
DMSO): δ = 8.07 (dd, J = 8.3, 1.4 Hz, 1 H), 7.94 (d, J = 7.0 Hz,
1 H), 7.68 (dd, J = 8.1, 7.3 Hz, 1 H), 7.55 (s, 1 H), 5.84 (m, 1 H),
5.36 (d, J = 4.7 Hz, 1 H), 4.12 (s, 3 H), 3.96 (s, 3 H), 1.45 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 166.0,
163.4, 148.4, 146.5, 145.1, 128.2, 126.9, 121.6, 120.2, 100.5, 64.5,
56.9, 53.3, 26.2 ppm. HRMS: calcd. for C14H15NO4 [M + H]+
261.1001; found 262.1072.
Eur. J. Org. Chem. 2014, 4265–4275
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4271

A. Kotschy, I. Huc et al.
FULL PAPER
Methyl (1R)- and (1S)-4-Methoxy-8-[1-phenoxyethyl]quinoline-2- CH2Cl2. The combined organic layers were dried with Na2SO4, fil-
carboxylate (15): Methyl 8-(1-hydroxyethyl)-4-methoxyquinoline-2- tered and concentrated under reduced pressure. The crude product
carboxylate (4.734 g, 18.12 mmol), phenol (2.555 g, 27.15 mmol) was purified by silica gel chromatography (CH2Cl2/MeOH) to af-
and di-tert-butylazodicarboxylate (8.335 g, 36.20 mmol) were dis-
solved in dry toluene (400 mL), and polymer-bound triphenylphos-
phine (12.067 g, 36.20 mmol, 3 mmol/g) was added. The mixture
was stirred at 80 °C under a nitrogen atmosphere for 3 h, filtered,
and washed with ethyl acetate, and the filtrate was concentrated
under reduced pressure. The crude product was purified by silica
gel chromatography (heptane/EtOAc) to afford racemic methyl 4-
ford racemic methyl 8-{1-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl}-
4-methoxyquinoline-2-carboxylate (2.631 g, 54%). The enantio-
mers were separated by chiral chromatography (ethanol/heptane,
15:85 with 0.05% v/v diethylamine) to obtain the first eluted
enantiomer in 99.8%ee and the second eluted enantiomer in
94.4%ee. The absolute configuration of the enantiomers was not
determined; however, comparison of the CD spectrum of the QPip
monomer precursors with those of the QMorph monomers (see Sup-
porting Information) indicated that the first eluted enantiomer was
methyl 8-{(1R)-1-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl}-4-meth-
oxyquinoline-2-carboxylate and the second eluted enantiomer was
methyl 8-{(1S)-1-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl}-4-meth-
oxyquinoline-2-carboxylate. 1H NMR (400 MHz, [D6]DMSO): δ =
8.08 (dd, J = 8.3, 1.4 Hz, 1 H), 7.91 (dd, J = 7.2, 1.4 Hz, 1 H), 7.69
(dd, J = 8.2, 7.4 Hz, 1 H), 7.55 (s, 1 H), 4.95 (q, J = 6.7 Hz, 1 H),
4.31 (t, J = 5.4 Hz, 1 H), 4.12 (s, 3 H), 3.96 (s, 3 H), 3.42 (m, 2 H),
2.38 (br. s, 4 H), 2.32 (m, 2 H), 2.30 (br. s, 4 H), 1.33 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.1, 163.4,
148.3, 146.3, 143.4, 128.5, 128.1, 121.8, 120.2, 100.4, 60.8, 58.9,
methoxy-8-[1-phenoxyethyl]quinoline-2-carboxylate
(3.388 g,
55%). The enantiomers were then separated by chiral chromatog-
raphy (ethanol/heptane, 15:85) to obtain each enantiomer in eeՆ
99.8%. The absolute configuration of the enantiomers was not de-
termined; however, comparison of the CD spectra of the QPhen
monomer precursors with those of the QMorph monomers (see Sup-
porting Information) indicated that the first eluted enantiomer was
4-methoxy-8-[(1S)-1-phenoxyethyl]quinoline-2-carboxylate and the
second eluted enantiomer was 4-methoxy-8-[(1R)-1-phenoxyethyl]-
quinoline-2-carboxylate. 1H NMR (400 MHz, [D6]DMSO): δ =
8.11 (dd, J = 8.3, 1.4 Hz, 1 H), 7.83 (dd, J = 7.2, 1.2 Hz, 1 H), 7.65
(dd, J = 8.3, 7.3 Hz, 1 H), 7.62 (s, 1 H), 7.14 (m, 2 H), 6.84–6.78
(m, 3 H), 6.61 (q, J = 6.3 Hz, 1 H), 4.14 (s, 3 H), 3.99 (s, 3 H), 56.9, 56.4, 55.4, 54.1, 53.3, 50.6, 20.8 ppm. HRMS: calcd. for
1.68 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 165.5, 163.1, 157.4, 148.5, 144.6, 141.4, 129.5, 127.9, 126.7,
121.3, 120.8, 120.5, 115.3, 100.6, 70.0, 56.5, 52.9, 23.6 ppm.
HRMS: calcd. for C20H19NO4 [M + H]+ 337.1314; found 338.1389
for first eluted enantiomer and 338.1396 for second eluted enantio-
mer.
C20H27N3O4 [M + H]+ 373.2002; found 374.2064 for first eluted
enantiomer and 374.2053 for second eluted enantiomer.
General Method for QY Monomer Precursor Saponification: The
corresponding ester was dissolved in dioxane/water 5:1 (10 mL/
mmol) and lithium hydroxide monohydrate (3 equiv.) was added.
The mixture was stirred at room temp. until no further conversion
was observed by TLC. The mixture was then neutralized with
1.25 m HCl in ethanol (3 equiv.) and concentrated under reduced
pressure. The crude product was purified by preparative reversed-
phase chromatography by using an Armen Spot liquid chromatog-
raphy system with a Gemini-NX® 10 μm C18, 250 mmϫ50 mm i.d.
column from Phenomenex at a flow rate of 118 mLmin–1 with UV
diode array detection (210–400 nm); 5 mm aqueous ammonium for-
mate solution and acetonitrile or water and acetonitrile were used
as eluents.
Methyl (1R)- and (1S)-4-Methoxy-8-(1-morpholinoethyl)quinoline-2-
carboxylate (16): Methyl 8-acetyl-4-methoxyquinoline-2-carboxyl-
ate (1.919 g, 7.40 mmol) was dissolved in dry 1,2-dichloroethane
(110 mL), and morpholine (3.87 mL, 44.40 mmol) and sodium tri-
acetoxyborohydride (4.705 g, 22.20 mmol) were added. The mix-
ture was stirred at 55 °C for 24 h, then diluted with water (150 mL)
and extracted with CH2Cl2. The combined organic layers were
dried with Na2SO4, filtered and concentrated under reduced pres-
sure. The crude product was purified by silica gel chromatography
(heptane/EtOAc) to afford racemic methyl 4-methoxy-8-(1-morph-
olinoethyl)quinoline-2-carboxylate (1.847 g, 76%). The enantio-
mers were then separated by chiral chromatography (ethanol/hept-
ane, 15:85 with 0.05% v/v diethylamine). The first eluted enantio-
mer was determined to be methyl 4-methoxy-8-[(1S)-1-morpholino-
ethyl]quinoline-2-carboxylate by X-ray diffraction (See Supporting
Information), and the second eluted enantiomer was determined to
be methyl 4-methoxy-8-[(1R)-1-morpholinoethyl]quinoline-2-carb-
oxylate, also by X-ray diffraction (see Supporting Information). 1H
NMR (500 MHz, [D6]DMSO): δ = 8.10 (dd, J = 8.3, 1.4 Hz, 1 H),
7.93 (dd, J = 7.2, 1.3 Hz, 1 H), 7.70 (dd, J = 8.1, 7.5 Hz, 1 H), 7.55
(s, 1 H), 4.95 (q, J = 6.8 Hz, 1 H), 4.12 (s, 3 H), 3.96 (s, 3 H), 3.56
(m, 4 H), 2.48 (m, 2 H), 2.29 (m, 2 H), 1.33 (d, J = 6.8 Hz, 3 H)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 166.1, 163.4, 148.4,
146.3, 143.0, 128.6, 128.1, 121.8, 120.3, 100.5, 67.0, 56.9, 56.8, 53.3,
51.4, 20.5 ppm. HRMS (racemate): calcd. for C18H22N2O4 [M +
H]+ 330.1580; found 331.1639.
1
(R/S)-QPhen (18): H NMR (500 MHz, [D6]DMSO): δ = 13.33 (br
s, 1 H), 8.10 (dd, J = 8.3, 1.5 Hz, 1 H), 7.73 (dd, J = 7.2, 1.2 Hz,
1 H), 7.63 (dd, J = 8.3, 7.2 Hz, 1 H), 7.63 (s, 1 H), 7.14 (m, 2 H),
6.86 (m, 2 H), 6.80 (m, 1 H), 6.77 (q, J = 6.3 Hz, 1 H), 4.13 (s, 3
H), 1.65 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (125 MHz, [D6]-
DMSO): δ = 166.3, 163.2, 157.4, 149.1, 144.4, 141.6, 129.4, 127.8,
126.6, 121.3, 120.7, 120.4, 115.3, 100.2, 70.0, 56.5, 23.7 ppm.
HRMS: calcd. for C19H17NO4 [M + H]+ 323.1158; found 324.1229
and 324.1228.
(R/S)-QMorph (19): 1H NMR (500 MHz, [D6]DMSO): δ = 8.11 (dd,
J = 8.4, 1.4 Hz, 1 H), 7.92 (dd, J = 7.2, 1.3 Hz, 1 H), 7.70 (dd, J
= 8.3, 7.3 Hz, 1 H), 7.59 (s, 1 H), 4.91 (q, J = 6.7 Hz, 1 H), 4.15
(s, 3 H), 3.61 (m, 4 H), 2.55 (m, 2 H), 2.35 (m, 2 H), 1.36 (d, J =
6.7 Hz, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 165.4,
163.9, 149.9, 144.2, 140.7, 128.9, 127.5, 121.2, 120.2, 100.0, 66.2,
57.5, 56.7, 50.7, 19.5 ppm. HRMS: calcd. for C17H20N2O4 [M +
H]+ 316.1423; found 317.1502 [(S)-QMorph) and 317.1506 [(R)-
QMorph].
Methyl (1R)- and (1S)-8-{1-[4-(2-Hydroxyethyl)piperazin-1-yl]-
ethyl}-4-methoxyquinoline-2-carboxylate (17): Methyl 8-acetyl-4-
methoxyquinoline-2-carboxylate (3.370 g, 13.00 mmol) was dis-
solved in anhydrous 1,2-dichloroethane (200 mL), and then 2-(1-
piperazinyl)ethanol (14.36 mL, 117.00 mmol), glacial acetic acid
(2 mL, 35 mmol) and sodium cyanoborohydride (2.042 g,
32.50 mmol) were added. The mixture was stirred at 55 °C for 3 h
and then diluted with saturated NaCl (200 mL) and extracted with
(1R)- and (1S)-8-{1-[4-(2-Hydroxyethyl)piperazin-1-yl]ethyl}-4-
methoxyquinoline-2-carboxylic Acid (20): 1H NMR (500 MHz,
[D6]DMSO): δ = 8.09 (dd, J = 8.3, 1.4 Hz, 1 H), 7.88 (dd, J = 7.3,
1.3 Hz, 1 H), 7.66 (dd, J = 8.2, 7.3 Hz, 1 H), 7.56 (s, 1 H), 4.94 (q,
J = 6.7 Hz, 1 H), 4.12 (s, 3 H), 3.48 (t, J = 6.2 Hz, 2 H), 2.58 (br
s, 4 H), 2.49–2.23 (m, 6 H), 1.38 (d, J = 6.7 Hz, 3 H) ppm. 13C
4272
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4265–4275

Controlling Helix Handedness in Oligoamide Foldamers
NMR (125 MHz, [D6]DMSO): δ = 166.2, 163.5, 151.9, 144.4,
140.3, 128.5, 127.0, 121.0, 120.2, 100.0, 59.8, 58.0, 57.5, 56.5, 52.8,
49.4, 19.6 ppm. HRMS: calcd. for C19H25N3O4 [M + H]+ 359.1845;
found 360.1931 and 360.1937.
NMR (300 MHz, [D6]DMSO): δ = 11.58 (s, 1 H), 11.45 (s, 1 H),
11.16 (s, 1 H), 11.03 (s, 1 H), 10.99 (s, 1 H), 10.88 (s, 1 H), 10.80
(s, 1 H), 10.72 (s, 1 H), 9.13 (t, J = 5.9 Hz, 1 H), 8.05–7.31 (m, 27
H), 7.20–7.05 (m, 5 H), 6.91 (s, 1 H), 6.84–6.62 (m, 6 H), 6.58 (s,
1 H), 6.55 (s, 1 H), 6.36 (m, 3 H), 6.14 (s, 1 H), 6.12 (s, 1 H), 5.99
(s, 1 H), 5.92 (br s, 1 H), 4.98–4.69 (m, 7 H), 4.39 (m, 2 H), 4.23–
4.11 (m, 5 H), 3.93 (m, 3 H), 3.65 (m, 3 H), 1.35–1.26 (m, 8 H),
1.20–1.16 (m, 6 H), 1.05 (m, 4 H) ppm. HRMS: calcd. for
C126H114N22O27S [M]+ 2398.7945; found 2398.7971.
(R)-QPip (21): 8-{(1R)-1-[4-(2-Hydroxyethyl)piperazin-1-yl]ethyl}-
4-methoxyquinoline-2-carboxylic acid (300 mg) was dissolved in
CHCl3, and the solution was stirred at room temp. under N2.
iPr2EtN (0.872 mL, 5.00 mmol, 6 equiv.) was then added, followed
by Ac2O (0.237 mL, 2.50 mmol, 3 equiv.), and the mixture was
stirred at room temp. for 4 h under N2. The solvents were evapo-
rated under reduced pressure, and the crude residue was dissolved
in THF/H2O (1:1, 6.0 mL) and stirred for 3 h at room temp. 1 m
HCl was then added dropwise to bring the mixture to pH 2, and
the solvents were evaporated under reduced pressure. The crude
residue was purified by silica gel chromatography (100% CH2Cl2
Compound 6: Synthesized on a 0.022 mmol scale (50 mg of Wang
resin, loading 0.44 mmolg–1) by using the general methods pre-
viously reported[18] to yield 55 mg of crude material (67% crude
yield) as a yellow solid. RP-HPLC (C8, system B): major peaks at
1
Rt = 6.82 and 6.91 min. H NMR (300 MHz, [D6]DMSO): ca.1:1
ratio of diastereoisomers: δ = 11.11 (s, 1 H), 10.93 (s, 2 H), 10.83
to CH2Cl2/MeOH, 85:5) to yield the title compound as a white
foam (225 mg, 67%). H NMR (300 MHz, CDCl3): δ = 8.30 (dd, (m, 10 H), 9.93 (m, 4 H), 8.30 (s, 2 H), 7.67–6.60 (m, 72 H), 6.52
(s, 1 H), 10.77 (s, 2 H), 10.73 (s, 1 H), 10.69 (s, 1 H), 10.25–10.41
1
J = 8.4, 1.3 Hz, 1 H), 7.99 (s, 1 H), 7.80 (m, 1 H), 7.70 (dd, J =
8.3, 7.4 Hz, 1 H), 4.32 (s, 3 H), 4.29 (m, 1 H), 4.21 (t, J = 5.8 Hz,
2 H), 2.94–2.84 (m, 6 H), 2.76 (m, 2 H), 2.70 (m, 2 H), 2.07 (s, 3 H),
1.61 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 171.0, 168.4, 153.0, 138.1, 134.1, 132.2, 128.0, 122.5, 101.2, 64.0,
61.7, 57.8, 56.2, 52.2, 21.0, 18.2 ppm. HRMS: calcd. for
C21H27N3O5 [M + H]+ 401.1951; found 402.2041.
(s, 1 H), 6.35 (m, 13 H), 4.82 (m, 9 H), 4.63 (m, 6 H), 4.38 (m, 5
H), 3.97–3.49 (m, 122 H), 3.39–3.09 (m, 50 H), 2.34–2.09 (m, 17
H), 1.27 (m, 24 H) ppm. ESI-MS: m/z = 1862.67 [M + 2H]2+
,
1242.27 [M + 3H]3+
.
Compound 7: QPhen (11.6 mg, 0.036 mmol) was dissolved in anhy-
drous CH2Cl2 (550 μL), and the solution was stirred at room temp.
under N2. 1-Chloro-N,N,2-trimethyl-1-propenylamine (9.5 μL) was
added, and the mixture was stirred for 1 h at room temp. and then
evaporated to dryness with a vacuum manifold. Compound 13[21]
(30 mg, 0.030 mmol) was dissolved in anhydrous CHCl3 (230 μL),
to which was added iPr2EtN (12.6 μL, 0.072 mmol), and the mix-
ture was stirred at 0 °C under N2. The acid chloride was then added
Compound 4: Synthesized on a 0.022 mmol scale (50 mg of Wang
resin, loading 0.44 mmolg–1) by using the general methods pre-
viously reported.[18] The crude mixture of diastereoisomers was
purified by RP-HPLC (system D) to yield each pure diastereoiso-
mer as a yellow solid. (P)-4: (corresponding to the first analytical
1
peak, 5.0 mg, 21%). RP-HPLC (C18, system A) Rt = 9.83 min. H dropwise in anhydrous CHCl3 (230 μL) over ca. 5 min, and the
NMR (300 MHz, [D6]DMSO): δ = 11.51 (s, 1 H), 11.30 (s, 1 H), mixture was stirred at room temp. for 15 h. It was then diluted with
11.08 (s, 1 H), 10.99 (s, 1 H), 10.94 (s, 1 H), 10.87 (s, 1 H), 8.49 (s,
1 H), 7.95–8.29 (m, CHAr), 7.34–7.89 (m, 13 H), 7.08–7.23 (m, 3
H), 6.99 (s, 1 H), 6.87 (s, 1 H), 6.78 (m, 1 H), 6.46–6.65 (m, 9 H),
CHCl3 and washed with a saturated solution of NaHCO3, 0.1 m
HCl, H2O and brine, and the organic phase was dried with MgSO4.
The crude residue was then purified by silica gel chromatography
6.34 (s, 1 H), 6.25 (m, 2 H), 5.97 (s, 1 H), 3.78–4.49 (m, 16 H), (100% cyclohexane to cyclohexane/EtOAc, 7:3) to yield the title
3.03–3.17 (m, 16 H) ppm. HRMS: calcd. for C115H117N25O19 [M compound as a pale yellow solid (28 mg, 72%). 1H NMR
+ H]+ 2151.8958; found 2152.9098. (M)-4: (corresponding to the
(300 MHz, CDCl3): ca. 55:45 ratio of diastereoisomers: δ = 11.97
(s, 1 H), 11.94 (s, 1 H), 11.93 (s, 1 H), 11.87 (s, 1 H), 11.79 (s, 1
H), 11.77 (s, 1 H), 11.61 (s, 1 H), 11.16 (s, 1 H), 8.72 (m, 2 H), 8.55
(m, 2 H), 8.27 (m, 2 H), 8.16 (m, 1 H), 8.08 (m, 7 H), 7.92 (m, 1
second analytical peak, 4.5 mg, 19%). RP-HPLC (C18, system A):
1
Rt = 10.11 min. H NMR (300 MHz, [D6]DMSO): δ = 11.27 (s, 1
H), 11.14 (s, 1 H), 11.06 (s, 1 H), 11.00 (s, 1 H), 10.90 (s, 1 H),
10.84 (s, 1 H), 8.47 (s, 1 H), 7.96–8.22 (m, CHAr), 7.34–7.82 (m, H), 7.81 (m, 1 H), 7.75–7.57 (m, 5 H), 7.53 (s, 1 H), 7.48 (s, 1 H),
13 H), 7.06–7.23 (m, 3 H), 6.97 (s, 1 H), 6.86 (s, 1 H), 6.76 (m, 3 7.43–7.28 (m, 5 H), 7.03 (m, 4 H), 6.82 (m, 4 H), 6.70 (m, 2 H),
H), 6.51 (s, 1 H), 6.39 (m, 3 H), 6.31 (s, 1 H), 6.20 (s, 1 H), 5.96
(s, 1 H), 4.07–4.46 (m, 16 H), 3.11 (m, 16 H), 2.22 (m, 16 H) ppm.
HRMS: calcd. for C115H117N25O19 [M + H]+ 2151.8958; found
2152.9098.
6.57 (s, 1 H), 6.45–6.26 (m, 7 H), 6.14 (t, J = 7.2 Hz, 1 H), 5.75
(m, 1 H), 5.65 (m, 1 H), 4.49–3.38 (m, 8 H), 4.27 (m, 2 H), 3.95–
3.79 (m, 10 H), 3.70 (m, 2 H), 3.20 (s, 3 H), 3.15 (s, 1 H), 2.53 (m,
2 H), 2.40–2.17 (m, 6 H), 1.43–1.11 (m, 48 H), 0.91 (d, J = 5.9 Hz,
3 H), 0.34 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.9, 163.8, 163.7, 163.1, 163.0, 162.3, 162.2, 161.9, 161.7,
161.6, 161.3, 161.0, 160.6, 157.9, 151.0, 150.1, 149.6, 148.9, 141.1,
139.1, 138.6, 138.4, 134.1, 134.0, 133.8, 133.7, 132.5, 129.1, 128.4,
127.8, 127.6, 127.1, 127.0, 126.9, 125.6, 122.7, 122.5, 122.2, 122.0,
121.9, 120.0, 119.6, 117.1, 117.0, 116.9, 116.5, 116.2, 115.8, 115.6,
114.8, 100.3, 99.6, 99.4, 98.7, 98.3, 97.8, 97.6, 97.2, 75.6, 75.4, 75.2,
75.0, 74.9, 70.0, 68.7, 56.2, 52.1, 28.4, 28.3, 28.2, 28.1, 26.9, 21.4,
19.5, 19.4, 19.3, 16.8 ppm. HRMS: calcd. for C76H75N9O12 [M +
H]+ 1305.5535; found 1306.5644.
Compound 5: Synthesized on a 0.019 mmol scale (50 mg of Wang
resin, loading 0.38 mmolg–1) by using the general methods pre-
viously reported.[5,18] The crude mixture of diastereoisomers was
purified by RP-HPLC (system F) to yield each pure diastereoiso-
mer as a pale yellow solid. (P)-5: (corresponding to the first analyti-
cal peak) 2.2 mg (9%). RP-HPLC (C18, system C) Rt = 14.37 min.
1H NMR (300 MHz, [D6]DMSO): δ = 11.61 (s, 1 H), 11.54 (s, 1
H), 11.44 (s, 1 H), 11.20 (s, 1 H), 11.02 (s, 1 H), 10.98 (s, 1 H),
10.87 (s, 1 H), 10.77 (s, 1 H), 9.14 (t, J = 6.1 Hz, 1 H), 8.13–7.33
(m, 25 H), 7.22–7.06 (m, 4 H), 6.93 (m, 2 H), 6.85–6.63 (m, 6 H),
6.46 (m, 3 H), 6.17 (m, 3 H), 5.99 (s, 1 H), 5.95 (br. s, 1 H), 5.05– General Method to Couple Tertiary Amine-Based Chiral Monomer
4.61 (m, 7 H), 4.40 (m, 2 H), 4.32–4.15 (m, 5 H), 3.94 (m, 3 H), Units, Exemplified by Compound 8: (R)-QMorph (17.5 mg,
3.68 (m, 3 H), 1.37–1.27 (m, 8 H), 1.21–1.16 (m, 6 H), 1.06 (m, 4 H) 0.055 mmol) was suspended in THF (1 mL), and conc. HCl
ppm. HRMS: calcd. for C126H114N22O27S [M]+ 2398.7945; found (5.4 μL, 0.055 mmol) was added. The mixture was stirred at room
2398.7935. (M)-5: (corresponding to the second analytical peak)
temp. for 20 min, and then the solvents were evaporated under re-
duced pressure (coevaporated twice with toluene). The resulting hy-
2.8 mg (11%). RP-HPLC (C18, system C) Rt = 14.53 min. 1H
Eur. J. Org. Chem. 2014, 4265–4275
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4273

A. Kotschy, I. Huc et al.
FULL PAPER
drochloride salt was dissolved in anhydrous CH2Cl2 (850 μL), and
the solution was stirred at room temp. under N2. Chloro-N,N,2-
trimethyl-1-propenylamine (15.0 μL) was then added, and the mix-
ture stirred for 1 h at room temp. and then evaporated to dryness
with a vacuum manifold. Compound 13[21] (46 mg, 0.046 mmol)
was dissolved in anhydrous CHCl3 (350 μL), to which was added
iPr2EtN (19.2 μL, 0.110 mmol), and the mixture was stirred at 0 °C
under N2. The acid chloride was then added dropwise in anhydrous
CHCl3 (350 μL) over ca. 5 min, and the mixture was stirred at room
temp. for 15 h. It was then diluted with CHCl3 and washed with a
saturated solution of NaHCO3, 0.1 m HCl, H2O and brine, and the
organic phase was dried with MgSO4. The crude residue was then
purified by silica gel chromatography (100% cyclohexane to cyclo-
hexane/EtOAc, 7:3) to yield the title compound as a pale yellow
125.5, 125.3, 124.8, 122.7, 122.6, 122.1, 121.7, 121.5, 117.5, 117.1,
116.7, 116.6, 116.4, 116.0, 115.7, 100.3, 99.9, 99.7, 98.1, 97.6, 75.6,
75.3, 75.0, 58.7, 57.6, 56.6, 55.2, 52.1, 30.3, 28.3, 28.2, 28.1, 21.5,
20.7, 19.5, 19.4, 19.3, 19.2, 14.3 ppm. HRMS: calcd. for
C78H85N11O13 [M + H]+ 1383.6328; found 1384.6437.
Compound 11: Synthesized on a 0.019 mmol scale (50 mg of Wang
resin, loading 0.38 mmolg–1) by using the general method pre-
viously reported.[18] The crude material was purified by RP-HPLC
(C18, system E) to afford the title compound as a pale yellow solid
(6 mg, 17%). RP-HPLC (system A): Rt = 7.58 min. 1H NMR
(D2O/H2O): δ = 11.17 (s, 1 H), 11.12 (s, 1 H), 11.03 (s, 1 H), 10.80
(s, 1 H), 8.24 (m, 1 H), 7.93 (m, 3 H), 7.81–7.71 (m, 6 H), 7.52 (m,
4 H), 7.43–7.20 (m, 5 H), 7.13 (s, 1 H), 7.05 (s, 1 H), 6.95 (m, 1
H), 6.46 (s, 1 H), 5.85 (m, 1 H), 3.39 (m, 6 H), 2.92 (m, 2 H), 2.74–
2.16 (m, 14 H), 0.01 (d, J = 6.7 Hz, 3 H) ppm. HRMS: calcd. for
C69H72N14O12 [M + H]+ 1288.5454; found 1289.5561.
1
solid (43 mg, 72%). H NMR (300 MHz, CDCl3): δ = 12.10 (m, 1
H), 11.98 (s, 1 H), 11.79 (s, 1 H), 11.74 (s, 1 H), 11.32 (s, 1 H), 8.72
(dd, J = 7.6, 1.0 Hz, 1 H), 8.47 (dd, J = 7.6, 1.2 Hz, 1 H), 8.34 (dd,
J = 8.1, 0.9 Hz, 1 H), 8.18–7.91 (m, 6 H), 7.80–7.63 (m, 3 H), 7.52–
7.35 (m, 4 H), 7.16 (m, 3 H), 6.94 (s, 1 H), 6.88 (s, 1 H), 6.59 (s, 1
H), 4.93 (m, 1 H), 4.44 (m, 4 H), 4.22 (m, 1 H), 4.06–3.92 (m, 4
H), 3.82 (m, 3 H), 3.70 (m, 1 H), 3.49 (m, 1 H), 3.19 (m, 5 H), 2.53
(m, 1 H), 2.36 (m, 7 H), 1.92 (m, 1 H), 1.24 (m, 24 H), 0.35 (d, J
= 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.3, 164.0,
163.7, 163.3, 163.2, 162.4, 161.9, 161.7, 161.4, 161.0, 151.8, 150.6,
150.2, 149.1, 145.4, 145.0, 139.0, 138.4, 137.9, 137.7, 135.8, 134.0,
133.6, 133.4, 131.3, 131.3, 129.1, 128.2, 127.7, 127.4, 127.0, 126.9,
125.5, 124.1, 122.7, 122.3, 122.2, 121.8, 121.7, 117.4, 117.2, 117.0,
116.9, 116.5, 116.1, 100.4, 99.8, 99.3, 98.2, 97.9, 75.7, 75.6, 75.4,
75.1, 63.2, 58.8, 56.6, 52.1, 51.3, 50.1, 34.3, 30.3, 28.4, 28.3, 28.2,
28.1, 19.5, 19.4, 19.3, 19.2, 14.8 ppm. HRMS: calcd. for
C74H78N10O12 [M + H]+ 1298.5801; found 1299.5896.
Supporting Information (see footnote on the first page of this arti-
cle): CD data, NMR and HPLC-based studies of helix stability, 1H
and 13C NMR spectra and details of X-ray diffraction experiments.
Acknowledgments
The authors would like to thank Dr. B. Kauffmann for diffraction
measurements of the QMorph monomer and Dr. Y. Ferrand for as-
sistance in preparing the figures for this manuscript. This work was
supported by the European Union’s Seventh Framework Pro-
gramme through Marie Curie actions (FP7-IAPP-2008-230662-
Foldappi, postdoctoral fellowships to S. D. and C. C.) and through
the European Research Council (Grant Agreement Number ERC-
2012-AdG-320892, postdoctoral fellowship to S. D.).
Compound 9: Synthesized on a 0.042 mmol scale by using the gene-
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ral method described above to yield the title compound as a pale
1
yellow solid (32 mg, 59%). H NMR (CDCl3): δ = 12.10 (m, 1 H),
11.97 (s, 1 H), 11.79 (s, 1 H), 11.74 (s, 1 H), 11.32 (s, 1 H), 8.72
(m, 1 H), 8.47 (m, 1 H), 8.35 (m, 1 H), 8.18–7.91 (m, 6 H), 7.80–
7.63 (m, 3 H), 7.49–7.35 (m, 4 H), 7.17 (m, 1 H), 6.98 (s, 1 H), 6.94
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4.23 (m, 1 H), 4.03–3.92 (m, 4 H), 3.83 (m, 3 H), 3.70 (m, 1 H),
3.49 (m, 1 H), 3.20 (m, 5 H), 2.55 (m, 1 H), 2.35 (m, 7 H), 1.92
(m, 1 H), 1.26 (m, 24 H), 0.35 (d, J = 6.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 164.3, 164.0, 163.7, 163.3, 163.2, 162.4,
161.9, 161.7, 161.4, 161.0, 151.8, 150.6, 150.2, 149.2, 145.4, 145.0,
139.0, 138.4, 137.9, 137.7, 134.0, 133.6, 133.4, 131.3, 131.3, 129.1,
128.2, 127.7, 127.4, 127.0, 125.5, 125.3, 124.1, 122.7, 122.3, 122.2,
121.8, 121.7, 117.4, 117.2, 117.0, 116.9, 116.5, 116.1, 100.4, 99.8,
99.3, 99.2, 98.2, 97.9, 75.7, 75.6, 75.4, 75.1, 63.2, 58.8, 56.6, 52.1,
51.4, 50.1, 30.3, 29.7, 28.4, 28.3, 28.2, 28.1, 19.5, 19.4, 19.3, 19.2,
14.9 ppm. HRMS: calcd. for C74H78N10O12 [M + H]+ 1298.5801;
found 1299.5878.
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Compound 10: Synthesized on a 0.043 mmol scale by using the ge-
neral method described above to yield the title compound as a pale
yellow solid (34 mg, 57%). 1H NMR (CDCl3): δ = 12.37 (br s, 1
H), 11.95 (s, 1 H), 11.79 (s, 1 H), 11.73 (s, 1 H), 11.25 (br s, 1 H),
8.73 (m, 1 H), 8.49 (m, 1 H), 8.40 (m, 1 H), 8.16–7.96 (m, 5 H),
7.76–7.60 (m, 4 H), 7.52 (m, 1 H), 7.42 (m, 2 H), 7.34 (m, 1 H),
7.15 (m, 1 H), 6.87 (s, 1 H), 6.86 (s, 1 H), 6.56 (s, 1 H), 5.15 (br s,
1 H), 4.42 (m, 4 H), 4.22 (m, 1 H), 3.98–3.78 (m, 7 H), 3.56 (m, 1
H), 3.20 (m, 7 H), 2.98 (m, 2 H), 2.54 (m, 1 H), 2.32 (m, 5 H), 1.86
(m, 3 H), 1.24 (m, 24 H), 0.39 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.7, 164.3, 163.9, 163.8, 163.2, 163.1, 162.3, 162.0,
161.5, 160.9, 152.7, 150.0, 149.1, 145.3, 144.7, 139.0, 138.3, 137.5,
134.0, 133.7, 133.5, 129.8, 129.1, 128.2, 127.8, 127.3, 126.9, 126.1,
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Received: March 12, 2014
Published Online: May 7, 2014
Eur. J. Org. Chem. 2014, 4265–4275
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4275