Synthesis of complementary double-stranded helical oligomers through chiral and achiral amidinium-carboxylate salt bridges and chiral amplification in their double-helix formation

Article abstract of DOI:10.1021/ja108514t

A series of complementary molecular strands from 2-mer to 5-mer that are composed of m-terphenyl units bearing chiral/achiral amidine or achiral carboxyl groups linked via Pt(II) acetylide complexes were synthesized by sequential stepwise reactions, and their chiroptical properties on the double-helix formation were investigated by circular dichroism (CD) and ¹H NMR spectroscopies. In CHCl₃, the "all-chiral" amidine strands consisting of (R)- or (S)-amidine units formed preferred-handed double helices with the complementary achiral carboxylic acid strands through the amidinium-carboxylate salt bridges, resulting in characteristic induced CDs in the Pt(II) acetylide complex regions, indicating that the chiral substituents on the amidine units biased a helical sense preference. The Cotton effect patterns and intensities were highly dependent on the molecular lengths. The complementary double-helix formation was also explored using the chiral/achiral amidine strands with different sequences in which a chiral amidine unit was introduced at the center (center-chiral) or a terminus (edge-chiral) of the amidine strands. The effect of the sequences of the chiral and achiral amidine units on the amplification of chirality (the "sergeants and soldiers" effect) in the double-helix formation was investigated by comparing the CD intensities with those of the corresponding all-chiral amidine double helices with the same molecular lengths. Variable-temperature CD experiments of the all-chiral and chiral/achiral amidine duplexes demonstrated that the Pt(II)-linked complementary duplexes are dynamic and their chiroptical properties including the chirality transfer from the chiral amidine unit to the achiral amidine ones are significantly affected by the molecular lengths, sequences, and temperatures. On the basis of the above results together with molecular dynamics simulation results, key structural features of the Pt(II)-linked oligomer duplexes and the effect of the chiral/achiral amidine sequences on the amplification of chirality are discussed.

Full text of DOI:10.1021/ja108514t

ARTICLE
pubs.acs.org/JACS
Synthesis of Complementary Double-Stranded Helical Oligomers
through Chiral and Achiral Amidinium-Carboxylate Salt Bridges and
Chiral Amplification in Their Double-Helix Formation
||
Hiroshi Ito,†,§ Masato Ikeda,†, Takashi Hasegawa,†,‡ Yoshio Furusho,†,‡ and Eiji Yashima*,†,‡
†Yashima Super-structured Helix Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology
Agency (JST), Japan
‡Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603,
Japan
S Supporting Information
b
ABSTRACT: A series of complementary molecular strands from
2-mer to 5-mer that are composed of m-terphenyl units bearing
chiral/achiral amidine or achiral carboxyl groups linked via Pt(II)
acetylide complexes were synthesized by sequential stepwise reac-
tions, and their chiroptical properties on the double-helix forma-
1
tion were investigated by circular dichroism (CD) and H NMR
spectroscopies. In CHCl3, the “all-chiral” amidine strands consist-
ing of (R)- or (S)-amidine units formed preferred-handed double
helices with the complementary achiral carboxylic acid strands
through the amidinium-carboxylate salt bridges, resulting in characteristic induced CDs in the Pt(II) acetylide complex regions,
indicating that the chiral substituents on the amidine units biased a helical sense preference. The Cotton effect patterns and
intensities were highly dependent on the molecular lengths. The complementary double-helix formation was also explored using the
chiral/achiral amidine strands with different sequences in which a chiral amidine unit was introduced at the center (center-chiral) or
a terminus (edge-chiral) of the amidine strands. The effect of the sequences of the chiral and achiral amidine units on the
amplification of chirality (the “sergeants and soldiers” effect) in the double-helix formation was investigated by comparing the CD
intensities with those of the corresponding all-chiral amidine double helices with the same molecular lengths. Variable-temperature
CD experiments of the all-chiral and chiral/achiral amidine duplexes demonstrated that the Pt(II)-linked complementary duplexes
are dynamic and their chiroptical properties including the chirality transfer from the chiral amidine unit to the achiral amidine ones
are significantly affected by the molecular lengths, sequences, and temperatures. On the basis of the above results together with
molecular dynamics simulation results, key structural features of the Pt(II)-linked oligomer duplexes and the effect of the chiral/
achiral amidine sequences on the amplification of chirality are discussed.
’ INTRODUCTION
helical conformations have been reported to date,2,3 only a limited
number of structural motifs and strategies are available for con-
structing multiple-stranded helical structures,6g,h in particular,
double-stranded helices.2v,4 Metal coordination is the most fre-
quently used driving force to construct double, triple, and quad-
ruple helices consisting of metal cations and ligand-containing
strands, that is, helicates.5 Interstrand hydrogen-bonding and
aromatic-aromatic interactions have also proved effective for
constructing double helices in a few oligoamides6 and peptide
analogues of nucleic acids (peptide nucleic acids (PNAs)).7
With the aim of accessing the one handedness in the biological
helices, the control of helicity in helicates and PNAs has also
been achieved by introducing a chiral substituent into the back-
bone of the ligand strands or attachment of a chiral residue at
The multiple helix is one of the most fundamental structures in
biological macromolecules as observed in nucleic acids, collagen,
and polysaccharides, which are spontaneously formed from each
component resulting from self-assembly and are closely linked to
their exquisite biological functions.1 For example, R-helices in DNA
binding proteins are of vital significance,1a and the double-helical
DNA efficiently preserves, replicates, and translates the genetic
information due to its complementarity in each strand.1b Moreover,
the collagen’s triple helix is critical and of key importance to the
fibril formation through a self-assembly process.1c Inspired by such
sophisticated biological helices, chemists have been challenged to
construct artificial multiple-stranded helical structures through self-
assembly assisted by noncovalent bonding interactions not only to
mimic the structures of biological helices but also to develop chiral
materials with a functionality.2-11 Although a number of synthetic
polymers and oligomers (foldamers) which fold into single-handed
Received: September 21, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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Figure 1. Double-helix formation of complementary chiral amidine 2-mer and achiral carboxylic acid 2-mer.
the terminus or middle of the ligand strands, leading to a
helix-sense bias in supramolecular double- or triple-stranded
helices.5b,c,7b-7f In contrast, enantiomeric multistranded helices
showing optical activity due to helicity itself remain quite rare.
Spontaneous resolution infrequently yields nonracemic
helicates.5d The method using chiral auxiliary scaffolds developed
by Siegel et al. is a versatile approach to generate enantiomeric
double-stranded helicates with an optical activity,5e-g involving
the transfer of chiral information from the terminal scaffolds to
the subsequent achiral ligand strands followed by removal of the
scaffold.12 A similar chirality transfer and succeeding amplifica-
tion of the helical chirality during double-helix formation have
also been observed by Nielsen and co-workers in PNA-PNA
duplexes assisted by a chiral residue inserted either at a terminus
and/or in the center of an achiral PNA strand.7
Recently, we developed a modular strategy to construct com-
plementary artificial double-stranded helices with a controlled
helicity stabilized by salt bridges.11 The helical structure is char-
acterized by crescent-shaped m-terphenyl groups with diacetylene
linkages and amidinium-carboxylate salt bridges,11a and the helix
sense of the intertwined two strands is directed by the chirality
introduced at the amidine units; duplex A (Figure 1) composed of
the achiral carboxylic acid strand and chiral amidine strand derived
from (R)-1-phenylethylamine was revealed to adopt a right-handed
double-helical structure as determined by an X-ray crystallographic
analysis. By taking advantageof this modular strategy, welinked the
m-terphenyl units through the trans-Pt(II) acetylide moieties, and
the Pt(II) complex-containing strands were also proved to produce
analogous complementary double helices with an optical activity
(R = Ph, B in Figure 1) whose helical senses can be biased either by
the chiral amidines11b,c or by the chiral phosphine ligands attached
on the Pt atom connecting the achiral amidine units.11e
Metal acetylides complexes, in particular, the Pt(II)-acetylide
ones with triethylphosphine ligands, have often been used as
effective and variable components for the metal-directed self-
assembly to construct supramolecular architectures with well-
defined two- andthree-dimensionalshapes includingmetallocycles,
metallopolyynes, and metallodendrimers because of their synthetic
accessibility by the stepwise formation of Pt(II)-acetylides and the
kinetic inertness of the robust Pt(II)-alkynyl linkage.13,14
In this study, we synthesized a series of chiral amidine strands,
from 2-mer to 5-mer, that are composed of (R)- or (S)-1-
phenylethyl and/or achiral isopropyl amidine units with different
sequences ((R)-2a-5a, (R)-2b-5b, (R)-3c, and (R)-5c), using
the Pt(II)-acetylide linkage as a versatile linker via the sequen-
tial stepwise reactions, and investigated their double-helix
formation with the complementary achiral carboxylic acid
strands (2d-4d and 5e) and the chain length dependence on
the helix-sense bias induction along with the effect of the
sequences of the chiral/achiral amidine units on the amplification
of the helical chirality in the double-helix formation (the “ser-
geants and soldiers” effect)2a,d,15,16 by absorption, circular di-
chroism (CD), and 1H NMR spectroscopies together with
molecular dynamics (MD) simulations (Figure 2).
’ RESULTS AND DISCUSSION
Synthesis of Oligomers. The chiral and achiral amidine
2-mers ((R)- and (S)-2a and 2f, respectively) were synthesized
by the Cu(I)-catalyzed reaction of PtCl2(PEt3)2 and the mono-
ethynyl amidines ((R)- and (S)-1a-H and 1f-H) with m-terphe-
nyl groups, which had been obtained by the monodesilylation of
the corresponding amidines ((R)- and (S)-1a and 1f)
(Scheme 1) according to a previously reported method.11a,c
Treatment of the monoethynyl amidines with an excess of
PtCl2(PEt3)2 in the presence of CuI and piperidine afforded
the monochloroplatinum-acetylide complexes ((R)-1a-PtCl
and 1f-PtCl) in moderate yields, which were employed as
building blocks for the synthesis of the longer oligomers.
The all-chiral amidine strands from 3- to 5-mers ((R)-3a-5a)
were prepared in a stepwise manner as shown in Scheme 2. The
diethynyl amidine monomer ((R)-1a-2H) was allowed to react
with (R)-1a-PtCl in the presence of CuI to give the all-chiral
3-mer ((R)-3a). (R)-2a and (R)-3a were treated with tetra-n-
butylammonium fluoride (TBAF) in THF to afford the diethynyl
2-mer and 3-mer ((R)-2a-2H and (R)-3a-2H, respectively),
which were further converted to the 4-mer and the 5-mer
((R)-4a and (R)-5a, respectively), by the Cu(I)-catalyzed reac-
tion with (R)-1a-PtCl in the presence of diethylamine.
The edge-chiral amidine strands bearing a chiral amidine unit
at the one terminus ((R)-2b-(R)-5b) were prepared in a
stepwise fashion as shown in Scheme 3. The edge-chiral 2-mer,
(R)-2b, was obtained by the Cu(I)-catalyzed reaction of 1f-H
with (R)-1a-PtCl. The all-achiral amidine strands with a mono-
ethynyl group (2f-H-4f-H) were synthesized by the combina-
tion of desilylation with TBAF and the Cu(I)-catalyzed coupling
reaction with 1f-PtCl. 2f-H, 3f-H, and 4f-H were then converted
to (R)-3b, (R)-4b, and (R)-5b, respectively, by the Cu(I)-
catalyzed reaction with (R)-1a-PtCl.
The center-chiral amidine strands bearing a chiral amidine unit
at the center ((R)-3c and (R)-5c) were synthesized according to
Scheme 4. The chiral amidine with two ethynyl groups at both
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Figure 2. (A) Chiral/achiral amidine strands and achiral carboxylic acid strands synthesized in this study: (a) All-chiral amidine strands; (b) edge-chiral
amidine strands; (c) center-chiral amidine strands; (d) achiral carboxylic acid strands. (B) Schematic illustration of chiral amplification in
complementary double-stranded helical oligomers (5-mers) composed of chiral/achiral amidine strands and achiral carboxylic acid strands through
chirality transfer from the chiral amidine unit at one terminus or at the center.
ends ((R)-1a-2H) was allowed to react with 1f-PtCl in the
presence of a catalytic amount of CuI to yield (R)-3c, which
was further converted to (R)-5c by treatment with TBAF
followed by reaction with 1f-PtCl.
All the oligomers were purified by column chromatography
and characterized and identified using 1H and 13C or 31P NMR
spectroscopies, elemental analyses, and mass measurements (see
the Supporting Information).
Complementary Double-Helix Formation of All-Chiral
Amidine Strands with Achiral Carboxylic Acid Strands. First,
the double-helix formation of the all-chiral amidine 2-mer ((R)-
2a) and its complementary achiral carboxylic acid 2-mer (2d)
The achiral carboxylic acid strands bearing Pt(II)-acetylide
linkers (2d-5d and 5e) were similarly synthesized to the
all-chiral amidine strands (Scheme 5). The monoethynyl carboxylic
acid monomer (1d-H) was treated with an excess of PtCl2(PEt3)2 in
the presence of CuI and diethylamine to afford the monochloropla-
tinum-acetylide complex (1d-PtCl). 2d-5d were obtained from
1d-H by the repetitive procedures of the Cu(I)-catalyzed coupling
reaction and desilylation with TBAF. However, an increase in the
chain lengths of the oligomers resulted in a drastic solubility decrease,
especially for the 5-mer. This problem was overcome by appending a
1-octynyl chain at the “tail” as a solubility enhancer to the carboxylic
acid unit. The 5-mer with 1-octynyl chains (5e) was prepared from
the corresponding 1-mer bearing a 1-octynyl chain at the 50-position
of the m-terphenyl group (1e-2H) in a manner similar to that for 5d.
1
1
was investigated by H NMR (Figure 3A). Although the H
NMR spectrum of (R)-2a in CDCl3 was complicated at 25 °C,
because of the presence of several conformers originating from
the E-Z isomerism of the CdN double bonds and the restricted
rotation about the C-C bond between the amidine and the m-
terphenyl groups, the complex (R)-2a 2d showed clear signals,
3
indicating that the geometry around the amidine residues is fixed
in the E-configuration.11a The resonances of the N-H protons
(c0) were observed as two broadened doublets at low magnetic
fields (13.62 and 13.00 ppm), indicating the salt bridge formation
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Scheme 1. Synthesis of Chiral and Achiral Amidine 2-mers
Scheme 2. Synthesis of All-Chiral Amidine Strandsa
a Reagents and conditions: (a) TBAF/THF; (b) (R)-1a-PtCl, CuI (cat.), Et2NH/CHCl3.
as well as the molecular motion of the duplex that is slightly
restricted probably due to the steric repulsion of the triethylpho-
sphine ligands. Similar but much broadened N-H proton
resonances were observed for an analogous duplex bearing
triphenylphosphine ligands instead of the triethylphosphine ones
as previously reported (B in Figure 1; R = Ph).11b The methine
(a0 and b0) and methyl protons (d0 and f0) of the amidine groups
gave two doublets for each. The nonequivalency of these signals
A series of all-chiral amidine-bound duplexes from 3-mer to
5-mer, (R)-3a 3d, (R)-4a 4d, and (R)-5a 5e, were also prepared
3
3
3
by mixing the corresponding all-chiral amidine strands, (R)-3a,
(R)-4a, and (R)-5a, and their complementary achiral carboxylic
acid strands, 3d, 4d, and 5e.18 Various attempts to obtain crystals of
double-helical oligomers suitable for X-ray analysis including the
2-mers produced only amorphous solids. In addition, the 1H NMR
spectra of the longer duplexes became significantly broadened,
although the resonances of the NH protons remained at the low
magnetic field of ca. 12-14 ppm, showing that the salt bridges were
retained after duplex formation. Therefore, the double-helix for-
mation of the longer oligomers was investigated mainly by CD and
absorption spectroscopies (Figure 4A) except for 3-mers (for
is attributed to the double-helical structure of (R)-2a 2d. The
3
double-helix formation between (R)-2a and 2d was also sup-
ported by cold-spray ionization (CSI) mass spectrometry
(Figure S1A, Supporting Information). The CD spectra of (R)-
2a 2d and (S)-2a 2d showed intense mirror image CD signals
3
3
1
variable-temperature H NMR spectra for 3-mers, see the text
below 380 nm, whereas (R)-2a and (S)-2a exhibited very weak
Cotton effects (Figure 3B). The significant enhancement of the
Cotton effects for (R)-2a 2d and (S)-2a 2d, in particular, in the
below and Figures S5-S10, Supporting Information). The Cotton
effect patterns and intensities in the Pt(II) acetylide complex
regions around 300-400 nm were significantly dependent on
3
3
trans-Pt(II) acetylide complex region (ca. 300-380 nm), reveals
that (R)-2a 2d and (S)-2a 2d mostly adopt an excess single-
their molecular length. Among them, the 3-mer ((R)-3a 3d)
3
3
3
handed double-helical structure as in the case of the diacetylene
analogues (A and B in Figure 1).11a,b The association constant
(Ka) between (R)-2a and 2d in CDCl3 was estimated to be (5.1
( 2.2) ꢀ 108 M-1 at 25 °C by CD titration experiments (Figure
S2, Supporting Information);17 this Ka value is almost compar-
able to that of an analogous dimer duplex (A in Figure 1).
showed a rather complicated CD spectrum different from that of
the 2-mer (R)-2a 2d. Surprisingly, a further increase in the
3
molecular length to 4-mer ((R)-4a 4d) and 5-mer ((R)-5a 5e)
3
3
produced inversion of the Cotton effect signs in the Pt(II) acetylide
chromophore regions as compared to those of the 2-mer. The (R)-
4a 4d and (R)-5a 5e duplexes exhibited intense Cotton effects in
3
3
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Scheme 3. Synthesis of Edge-Chiral Amidine Strandsa
a Reagents and conditions: (a) TBAF/THF; (b) (R)-1a-PtCl, CuI (cat.), Et2NH/CHCl3; (c) 1f-PtCl, CuI (cat.), Et2NH/CHCl3.
the region of 300-400 nm due most likely to the double-helical
conformation with a helix-sense bias. These results suggest that the
preferred-handed helical sense of the 4- and 5-mers may be
opposite to that of the 2-mer, despite the fact that they all have
the same (R)-phenylethyl groups at the amidine residues (for more
detailed studies on the temperature effects on their CD spectral
patterns and intensities, see below). As previously reported, such an
inversion of the Cotton effects did not take place for the diacety-
lene-linked fully organic double-helical oligomers.11g
converts to the double helix at low concentrations, as illustrated in
Figure 4E. We note that such a remarkable concentration-depen-
dent CD spectral change was never observed for other smaller
duplexes of 2-mer -4-mer except for the edge-chiral amidine-
bound 4-mer ((R)-4b 4d) in CHCl3 at 25 °C (Figure 5).
3
Chiral Amplification in Double-Helix Formation of Edge-
or Center-Chiral Amidine Strands with Achiral Carboxylic
Acid Strands. Duplex formation of the edge-chiral 2-mer strand
bearing chiral and achiral amidine units ((R)-2b) with the com-
plementary achiral carboxylic acid 2-mer strand (2d) was confirmed
by CSI-mass spectrometry (Figure S1B, Supporting Information)
In order to gain insight into the mechanism of the Cotton effect
inversion depending on the molecular length, we measured the
concentration-dependent CD spectral changes of a series of the all-
chiral amidine-bound duplexes in CDCl3 at 25 °C. At concentra-
1
1
and further investigated by H NMR (Figure 6). The H NMR
spectrum of the amidine strand ((R)-2b) in CDCl3 (Figure 6a) was
tions higher than ca. 10-5 M, the CD intensity of (R)-5a 5e was
complicated as in the case of (R)-2a. Incontrast, (R)-2b 2d showed
3
3
a set of clear 1H NMR signals (Figure 6b), which were assigned to
found to dramatically decrease while maintaining its Cotton effect
pattern (Figure 4B and 4C). This sudden onset and rapid decrease
in the optical activity were accompanied by a slight red shift of λmax
by ca. 5 nm with a clear isosbestic point at 340 nm (Figure 4B),
one isomer by comparing to those of (R)-2a 2d (Figure 6c) and
3
2f 2d (Figure 6d) consisting of the chiral amidine 2-mer and achiral
3
amidine 2-mer complexed with the carboxylic acid 2-mer, respec-
tively. The resonances of the salt bridge N-H protons of the (R)-
which suggested that (R)-5a 5e may change its structure into a
3
2b 2d were observed as two sets of two doublets at 13.54 and 12.98
rather complex aggregate other than the discrete double helix at
high concentrations. Dynamic light scattering (DLS) measure-
ments support formation of a large aggregate, such as a supramo-
lecular double-helical oligomer with a hydrodynamic diameter
(DH) of ca. 300 nm when prepared at 20 μM in CHCl3
(Figure 4D). Upon dilution to 0.2 μM, the DH value gradually
decreased with time and no light scattering due to the aggregate
could be observed after 4 days. In addition, this dynamic structural
change was accompanied by an increase in the first Cotton effect
intensity at 358 nm, resulting in complete recovery of the CD
3
ppm and at 12.19 and 12.06 ppm, which were assigned to those of
the chiral and achiral amidine units, respectively. The nonequivalent
signals of the N-H, methine, and methyl protons of the amidine
groups again indicate the double-helical structure of (R)-2b 2d, as
3
inthecaseof(R)-2a 2d. The association constant of (R)-2b and 2d
3
((1.2 ( 0.2) ꢀ 108 M-1) estimated in CHCl3 at 25 °C by CD
titration experiments was comparable to that of (R)-2a and 2d
(Figure S3, Supporting Information),17 which means that re-
placement of the chiral amidine unit with the achiral one hardly
affects the stability of the double helices.
spectrum to that of (R)-5a 5e prepared at concentrations lower
3
than 10-5 M (Δε358 = 270 cm-1 M-1) after 18 days. These results
demonstrate that an equilibrium exists between the double helix
and supramolecular aggregates depending on the concentration,
and the latter is predominant at high concentrations which readily
The CD spectral pattern and intensity of (R)-2b 2d measured
3
at 25 °C are quite similar to those of (R)-2a 2d (Figure 7A),
3
suggesting that the 2-mers most probably adopt a double-helical
structure similar to each other with the same handedness
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Scheme 4. Synthesis of Center-Chiral Amidine Strandsa
a Reagents and conditions: (a) TBAF/THF; (c) 1f-PtCl, CuI (cat.), Et2NH/CHCl3.
and almost the same degree of helix-sense excess, i.e., the
(R)-phenylethyl groups on one of the amidine residues effec-
tively act as a helix-sense director to induce the same helical sense
in the next achiral amidine unit when complexed with 2d
(Figure 8). The chiral/achiral amidine strands longer than
2-mer, (R)-3b, (R)-3c, (R)-4b, (R)-5b, and (R)-5c, were then
mixed with the complementary achiral carboxylic acid strands in
CHCl3 to afford a series of duplexes, (R)-3b 3d, (R)-3c 3d,
Scheme 5. Synthesis of Achiral Carboxylic Acid Strandsa
3
3
(R)-4b 4d, (R)-5b 5e, and (R)-5c 5e, respectively, which also
3
3
3
had a helix-sense bias, as apparent from their CD induction
(Figure 7B-D). As observed for the all-chiral amidine-bound
5-mer duplex ((R)-5a 5e), the 5-mers of (R)-5b 5e and (R)-
3
3
5c 5e bearing one chiral amidine unit at the terminus and center,
3
respectively, also displayed a strong concentration dependence in
their double-helix formations (Figure 5). Interestingly, among
the other oligomer duplexes, only the edge-chiral amidine-bound
4-mer duplex ((R)-4b 4d) exhibited a concentration depen-
3
dence in the double-helix formation, as opposed to the all-chiral
amidine-bound 4-mer duplex, which suggests that the double-
helix formation over supramolecular aggregations is sensitive to
the sequences of the chiral/achiral amidine strands to a certain
extent. Therefore, the following CD and absorption measure-
ments for (R)-4b 4d, (R)-5b 5e, and (R)-5c 5e were per-
3
3
3
formed at concentrations as low as 10-6 M.
Although the all-chiral amidine-bound 3-mer ((R)-3a 3d)
3
exhibited a complicated CD spectral pattern different from those
of the corresponding 2-, 4-, and 5-mers (see Figure 4A), the edge-
((R)-3b 3d) and center-chiral ((R)-3c 3d) amidine-bound
3
3
3-mers showed a rather simple and similar positive first Cotton
effect in the Pt(II) acetylide chromophore regions with negligible
absorbance changes (Figure 7B), suggesting that they may adopt
a double helix with the same handedness. The edge- and center-
chiral amidine-bound 4-mer and 5-mer duplexes also showed
apparent CDs, but their spectral patterns in the Pt(II) linker
regions changed from a split-type to nonsplit one, while largely
maintaining the positive first Cotton effect (Figure 7C and 7D).
In addition, an appreciable difference in the CD intensity
depending on the position of the chiral amidine unit was
observed for the 5-mers.
Though less quantitative, the CD intensities corresponding to
the main-chain chromophore regions most likely reflect the helix-
sense excess of the helical oligomers when their CD and
absorption spectral patterns are almost identical, thereby allow-
ing a comparison between the helix-sense biases of the oligomers
a Reagents and conditions: (a) TBAF/THF; (d) 1d-PtCl, CuI (cat.),
Et2NH/CHCl3; (e) 1e-PtCl, CuI (cat.), Et2NH/CHCl3.
with the same chain lengths but different chiral/achiral amidine
sequences, because the CD signals of the Pt(II) linker regions do
not overlap those of the chiral phenylethyl chromophore region
and their chemical structures are quite similar to each other
except for the number of chiral/achiral amidine residues. The
chiral/achiral hybrid 3-mer duplexes with a chiral unit content
less than that of (R)-2b 2d (50%), (R)-3b 3d, and (R)-3c 3d
3
3
3
(33%), also showed appreciable Cotton effects whose intensities
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Figure 3. (A) Partial 1H NMR (500 MHz) spectra of (a) (R)-2a (0.50 mM) in CDCl3 at 25 °C and (b) (R)-2a 2d (0.50 mM). (B) CD and absorption
3
spectra of (R)-2a, (S)-2a, (R)-2a 2d, and (S)-2a 2d (0.10 mM) in CDCl3 at 25 °C.
3
3
were slightly greater than that of the all-chiral amidine-bound
optically active duplex oligomers, which may be closely related to
the ability of the chiral amidine residues to transfer its chirality to
the double-stranded oligomer backbones in solution. Because
double helix ((R)-3a 3d) (Figures 7B and 8), although different
3
CD spectral patterns hampered the quantitative discussion on
the amplification of helical chirality. The edge-chiral amidine-
longer duplexes, (R)-4b 4d and all the 5-mer duplexes, precipi-
3
bound 4-mer duplex ((R)-4b 4d), having a chiral unit content of
tated at low temperatures in CHCl3 and also in CH2Cl2, toluene
was chosen as the measuring solvent which enabled CD measure-
ments of all the duplexes at temperatures as low as -80 °C in the
same solvent. However, we found unusual solvent and tempera-
ture effects on the chiroptical properties of the duplexes except for
the 2-mers, which showed almost no solvent- and temperature-
dependent CD and absorption spectral changes.19 The Cotton
effect patterns of the longer duplexes (3-mer-5-mer) reversibly
changed with lowering temperatures, and their intensities tended
to lower in toluene at 25 °C accompanied by inversion of the CD
signatures for some oligomers, indicating the dynamic chiroptical
properties of the longer double helices (Figures 9 and S4,
Supporting Information).20
3
only 25%, also exhibited as an intense CD as that of the all-chiral
amidine-bound 4-mer duplex ((R)-4a 4d), implying that the
3
chirality of the terminus amidine unit is transferred to the
subsequent achiral amidine units when complexed with the
complementary achiral carboxylic acid strand (4d), resulting in
an excess of the one-handed double helix (Figures 7C and 8). In
contrast, the CD intensities for the chiral/achiral hybrid 5-mer
duplexes ((R)-5b 5e and (R)-5c 5e) (the chiral amidine con-
3
3
tent = 20%) decreased by comparison to that of the all-chiral
amidine-bound 5-mer double helix ((R)-5a 5e), indicating less
3
efficiency in the chirality transfer during the double-helix forma-
tion, especially for the edge-chiral amidine-bound 5-mer ((R)-
5b 5e). It should be noted that each complementary carboxylic
The Cotton effect signs of the all-chiral amidine 3-mer ((R)-
3
acid strand is totally achiral, which demonstrates that the chirality
transfer or amplification of the chirality indeed takes place along
the double-helix formation, although its efficiency is highly
dependent on the sequence and oligomer length.
3a 3d) were unexpectedly inverted in toluene (Figure 9A), and
3
the CD intensities of the first Cotton effects (Δεfirst) of all the
3-mers monotonically increased in the negative direction with
decreasing temperature (Figure 9A-C) but did not reach a
plateau value even at -80 °C as indicated by the plots of the
Δεfirst values versus temperature (Figure 9D). At low tempera-
tures, the CD spectral patterns for the edge- and center-chiral
3-mer duplexes changed to a split-type one like those of the
2-mers. These changes in their CD spectra were accompanied by
a slight increase in their absorbance, suggesting that conforma-
tional changes took place at low temperatures. As a consequence,
it is difficult to determine the handedness and to quantify the
helical sense excesses and the extent of the amplification of helical
chirality of the edge- and center-chiral 3-mer duplexes based on
the CD profile of the all-chiral 3-mer duplex. However, the fact
Thus, the chirality amplification in the 5-mers seems to be
highly affected by the sequences of the chiral and achiral amidine
units, in other words, the position of the chiral amidine unit
(Figures 7D and 8). A preferred-handed helical conformation in
the double helices may be more efficiently induced by the chiral
amidine unit inserted into the middle part of the longer oligo-
mers than that at the terminal part. A similar preference of one-
handedness was observed for the PNA-PNA duplexes having an
L-amino acid residue in the center of an achiral PNA strand.7
Next, we performed variable-temperature CD measurements in
order to obtain information on the dynamic properties of the
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Figure 4. (A) CD and absorption spectra of (R)-2a 2d, (R)-3a 3d, (R)-4a 4d, and (R)-5a 5e (CDCl3, 1.0 μM, 25 °C). (B) CD and absorption
3
3
3
3
spectra of (R)-5a 5e prepared at various concentrations (1-25 μM). (C) Δε values at 358 nm (Δε358) plotted against the concentrations of (R)-5a 5e
3
3
(25-0.05 μM). (D) Time course of the changes in the Δε358 and DH estimated by DLS measurements of a solution of (R)-5a 5e prepared at 20 μM and
3
subsequently diluted to 0.2 μM. The dotted line represents the Δε358 value of (R)-5a 5e measured at 2.0 μM at 25 °C. (E) Schematic illustration for the
3
formation of a double helix and a possible large aggregate of (R)-5a and 5e depending on the concentrations.
that the temperature-dependent CD intensity change for the
duplex ((R)-3b 3d) (Figure S9, Supporting Information). In
contrast, the broad salt bridge NH proton signals for the center-
3
center-chiral duplex ((R)-3c 3d) was comparable to that of the
3
all-chiral 3-mer duplex ((R)-3a 3d) and larger than that for the
chiral duplex ((R)-3c 3d) slightly sharpened within the tem-
3
3
edge-chiral 3-mer duplex ((R)-3b 3d) (Figure 9D) suggests that
perature range from 0 to -30 °C (Figure S10, Supporting
3
the double-helical structure with a chiral unit at the middle
position may form a more excess one-handed double helix than
that with a chiral unit at the end at low temperatures.
Information), suggesting that (R)-3c 3d may possess a more
3
stable and regular helical structure relative to (R)-3b 3d at low
3
temperatures. More significant changes in the variable-tempera-
ture H NMR spectra were observed for the terminal TMS
Variable-temperature 1H NMR spectra of 3-mers in the
temperature range between -50 and 55 °C (Figures S5-S10,
Supporting Information) revealed that the all-chiral amidine
1
proton resonances for (R)-3b 3d and (R)-3c 3d, which split into
3
3
broad complicated multiple signals at -30 and -50 °C (Figures
S8-S10, Supporting Information). These results indicate the
presence of several helical conformations under dynamic equilib-
rium that may be responsible for their rather complicated CD
spectral changes with temperature. Again, the changes in the TMS
proton signals at low temperature were significant for the edge-
3-mer ((R)-3a 3d) maintained its duplex structure stabilized
3
by the salt bridge formation over the full range of temperatures
investigated as supported by the apparent salt bridge NH proton
resonances (Figures S5 and S8, Supporting Information),
whereas the corresponding NH proton resonances for (R)-
3b 3d and (R)-3c 3d became significantly broadened at high
chiral 3-mer duplex ((R)-3b 3d), implying more complicated
3
3
3
temperature (Figures S6 and S7, Supporting Information, re-
spectively) and even at low temperature for the edge-chiral 3-mer
helical conformations relative to (R)-3c 3d as supported by the
3
molecular dynamics (MD) simulation results (see below).
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Figure 5. Plots of molar circular dichroism at the first Cotton effect (Δεfirst) against the concentration of the double-stranded helical oligomers in
CHCl3 at 25 °C; (R)-5a 5e (360 nm), (R)-5b 5e (358 nm), (R)-5c 5e (362 nm), (R)-4a 4d (350 nm), (R)-4b 4d (357 nm), (R)-3a 3d (343 nm),
3
3
3
3
3
3
(R)-3b 3d (346 nm), (R)-3c 3d (345 nm), (R)-2a 2d (354 nm), and (R)-2b 2d (357 nm).
3
3
3
3
Figure 6. Partial 1H NMR (500 MHz, CDCl3, 25 °C) spectra of (a) (R)-2b (0.50 mM), (b) (R)-2b 2d (0.50 mM), (c) (R)-2a 2d (0.10 mM), and (d)
3
3
2f 2d (0.10 mM).
3
As for the 4-mers, both the all-chiral and the edge-chiral
Supporting Information). In particular, almost no CD was
observed in the Pt(II) linker regions for the edge-chiral 5-mer
4-mers ((R)-4a 4d and (R)-4b 4d) also underwent a consider-
3
3
able change in their CD signals in toluene associated with
inversion of the Cotton effect signs, although the absorbance
spectra showed almost no change during the CD signal inversion
(Figure S4A and 4B, Supporting Information). The first positive
Cotton effects remained unchanged independent of the tem-
peratures, while the CD signal at the second Cotton effect
gradually increased in the negative direction with the decreasing
temperature. A comparison of plots of the CD intensities versus
temperature (Figure 9E) by taking into account the negligible
absorbance change for the 4-mers indicates that the edge-chiral
duplex ((R)-5b 5e) at 25 °C in toluene (Figure S4D, Supporting
3
Information), most probably because of a reversal in the helical
sense due to a solvent effect;20 a positive first Cotton effect in
CHCl3 might change to the opposite, negative Cotton effect in
toluene. In fact, a decrease in the temperature resulted in a further
increase in the CD intensity in the negative direction, although
the CD intensity was still weak as compared to those of the other
5-mers. The all-chiral 5-mer duplex ((R)-5a 5e) maintained its
3
split-type CD pattern regardless of the temperature, while the
second Cotton effect intensity increased with the decreasing
temperature accompanied with a remarkable red shift (Figure
S4C, Supporting Information). On the other hand, a different
behavior was observed for the center-chiral 5-mer duplex ((R)-
(R)-4b 4d might possess a double-helical structure similar to
3
that of the (R)-4a 4d, but a helical sense excess of the edge-chiral
3
(R)-4b 4d may be lower than that of the all-chiral (R)-4a 4d to
3
3
some extent.
5c 5e); the CD signals at the first and second Cotton effects
3
The variable-temperature CD profiles for the 5-mer duplexes
seem to be more complicated (Figures 9F and S4C-E,
decreased almost by one-half as the temperature was lowered
from 25 to -80 °C. We noted that these CD spectral changes
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Figure 7. CD and absorption spectra of double-stranded helical oligomers: (A) 2-mers (0.1 mM), (B) 3-mers (0.067 mM), (C) 4-mers (2.5 μM), and
(D) 5-mers (1.0 μM) in CHCl3 at 25 °C.
were accompanied by slight increases in their absorbance,
indicating that structural changes may not have occurred for all
5-mer duplexes. On the basis of the variable-temperature CD
spectral changes of all 5-mer duplexes in toluene (Figure 9F)
together with their CD spectra in CHCl3 (Figure 7D), it can be
concluded that the chirality of the amidine residue either at the
center or the terminus is certainly transferred to the achiral
amidine units but its efficiency may be better when the chiral
amidine is placed in the center of the amidine strand. A similar
tendency was observed for the 3-mer duplexes.
carboxylate remain in contact (6.717-7.471 Å) for all the 3-mer
duplexes at 300-400 K independently of their sequences,
whereas the achiral amidinium-carboxylate salt bridges of (R)-
3b 3d and (R)-3c 3d significantly increased in length, becom-
3
3
ing definitely longer than the adjacent chiral amidinium-car-
boxylate salt bridge lengths at 300-400 K. More importantly, for
the edge-chiral amidine 3-mer ((R)-3b 3d), the terminal achiral
3
amidinium-carboxylate salt bridge partially dissociates into a
single hydrogen bond (Figure S11B, Supporting Information)
and its length further elongated (8.982-9.815 Å) as compared
with the central one (7.105-7.890 Å) (Table S1, Supporting
Information) except in case at 400 K. In addition, one of the two
terminal achiral amidinium-carboxylate salt bridges of (R)-
Molecular Dynamics Simulations of 3-mer Duplexes. To
gain information regarding the helical structures of longer
oligomer duplexes, we performed MD calculations for a series
of 3-mers ((R)-3a 3d, (R)-3b 3d, and (R)-3c 3d) using the
3c 3d (7.164-8.552 Å) was considerably shorter than the other
3
3
3
3
Universal Force Field.21 The initial structures were generated on
the basis of the structural motif of duplex A determined by single-
crystal X-ray analysis (Figure 1)11a followed by the trans-Pt(II)
acetylide linkage insertion.11b The triethylphosphine ligands of
(R)-3a 3d, (R)-3b 3d, and (R)-3c 3d were replaced by tri-
(7.844-9.986 Å) at 300-350 K, while maintaining its double
hydrogen bonds. All of these MD simulations suggest that the salt
bridges composed of chiral amidines appear to be more rigid and
stable than those of the achiral amidines and the achiral amidine-
bound salt brides at the strand ends are more flexible than the
others, resulting in partial dissociation into single hydrogen
bond. Of particular note is the significantly greater flexibility of
the terminal achiral amidinium-carboxylate salt bridge of (R)-
3
3
3
methylphosphine for facilitating the calculations. The MD
calculations were run for the 3-mers for 1 or 10 ns at constant
volume and temperature (300, 350, and 400 K) (NVT MD using
the Hoover temperature thermostat) with a step size of 1 fs.
Figure S11, Supporting Information, shows representative snap-
shots of the 3-mers along 0.5-1 ns at 125 ps intervals. During the
MD simulations for 1 ns at 300-400 K and 10 ns at 300 K,
transitional conformations such as helical inversion and dissocia-
tion into single strands were not observed, suggesting that a
helical conformation may certainly be a favorable conformation
for the 3-mer duplexes independent of the chiral/achiral amidine
sequences. However, we noticed remarkable changes in the salt
bridges of the achiral amidinium-carboxylates depending on
their positions (edge or center) (Figure S11 and Table S1, Sup-
porting Information). The salt bridges of the chiral amidinium-
3b 3d relative to the corresponding central achiral amidinium-
3
carboxylate salt bridge.
Such key structural features of the 3-mers with different
chiral/achiral amidine sequences obtained by the MD simula-
tions appear to be useful in explaining the significant changes in
1
the variable-temperature H NMR spectra (Figures S5-S10,
Supporting Information) and the temperature-dependent CD
spectral changes (Figure 9) for the 3-mers, which may reflect
conformational heterogeneity in the 3-mer duplexes most
likely due to greater flexibility at the strand ends relative to
the center parts, in particular for (R)-3b 3d and (R)-3c 3d,
3
3
and this speculation may be applicable to other longer oligomer
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Figure 8. CD intensities of the first Cotton effect of the double helices in CHCl3: (R)-2a 2d (0.1 mM, 354 nm); (R)-2b 2d (0.1 mM, 357 nm); (R)-
3
3
3a 3d (6.7 μM, 343 nm); (R)-3b 3d (6.7 μM, 346 nm); (R)-3c 3d (6.7 μM, 345 nm); (R)-4a 4d (2.5 μM, 350 nm); (R)-4b 4d (2.5 μM, 357 nm);
3
3
3
3
3
(R)-5a 5e (1.0 μM, 360 nm); (R)-5b 5e (1.0 μM, 358 nm); (R)-5c 5e (1.0 μM, 362 nm).
3
3
3
duplexes, leading to unexpected CD and spectral changes with
temperature.
Because of the significant changes in the CD spectral patterns
and intensities at various temperatures in different solvents for
the longer duplexes, quantitative evaluation of the chirality
transfer abilities of chiral amidine residues to the achiral ones
along the duplex backbones is impossible, but qualitative con-
siderations about the structural and chiroptical properties and
chiral amplification in their double-helix formations could be
possible on the basis of the detailed systematic experimental
results together with the MD simulation results for the 3-mers;
the chiral/achiral alternative 2-mer duplex most likely possesses
an excess one-handedness comparable to that of the all-chiral
amidine 2-mer, since both of the 2-mers exhibited a similar
Cotton effect pattern and intensity independent of the solvents
and temperature accompanied by negligible absorbance changes,
leading to the conclusion that chiral information at the chiral
amidine unit probably transfers to the next achiral amidine unit in
an efficient fashion. A preferred-handed helical sense excess in
the longer duplexes may be more efficiently induced by the chiral
amidine unit inserted into the middle part of the oligomers than
that at the terminal part. A plausible explanation for this may lie in
the Pt(II)-acetylide linkages that likely generate a greater
flexibility of the Pt(II)-linked duplexes relative to the fully
organic, diacetylene-linked duplexes (A in Figure 1).22 The
MD simulations suggest that the chiral amidinium-carboxylate
salt bridges may be more rigid and stable than the achiral
amidinium-carboxylate ones. In particular, the achiral amidi-
nium-carboxylate salt bridges at the strand ends may be much
more flexible than the others, resulting in conformational hetero-
geneity, which likely reflects the complicated changes in the
variable-temperature 1H NMR and CD spectra for longer
oligomer duplexes as mentioned above.23
’ CONCLUSIONS
We successfully synthesized a series of chiral and chiral/achiral
hybrid amidine oligomers with a different sequence and their
complementary achiral carboxylic acid oligomers bearing the
Pt(II)-acetylide linkages from 2-mer to 5-mer in a stepwise
manner utilizing the monochloroplatinum intermediates. The
all-chiral amidine oligomers formed intertwined double helices
with a helical sense bias when complexed with their complemen-
tary carboxylic acid oligomers, as evidenced by the distinct
Cotton effects in the absorption regions of the Pt(II) acetylide
linkages (ca. 300-380 nm), resulting from the chiral phenylethyl
groups on the amidine units, which induced a preferred-handed
helical conformation. The Cotton effect signs were unexpectedly
dependent on the molecular length, and among the prepared
oligomer duplexes, the 2-mer duplexes exhibited an opposite first
Cotton effect sign in CHCl3 at 25 °C, suggesting an opposite-
handed double-helical structure compared to those of the longer
oligomer duplexes. A supramolecular double-helical aggregation
took place in relatively highly concentrated solutions for the
5-mer duplexes and the edge-chiral 4-mer duplex. The chiral/
achiral hybrid amidine oligomers also formed similar double
helices in the presence of the complementary carboxylic acid
oligomers, thus showing induced CDs, whose CD patterns and
signs were similar to each other when the molecular lengths are
the same. Variable-temperature CD experiments of the all-chiral
and chiral/achiral oligomer duplexes in a different solvent
demonstrate that the Pt(II)-linked duplexes are dynamic and
their chiroptical properties are highly sensitive to solvents and
temperature as well as molecular lengths and sequences.
In addition, the present study also implies that even fully
chiral-amidine duplex oligomers may not have a complete
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Figure 9. CD and absorption spectra of (R)-3a 3d (A), (R)-3b 3d (B), and (R)-3c 3d (C) in toluene (12.5 μM) at various temperatures. Plots of
3
3
3
Δεfirst of (R)-3a 3d, (R)-3b 3d, and (R)-3c 3d (D), Δεsecond of (R)-4a 4d and (R)-4b 4d (E), and Δεfirst of (R)-5a 5e, (R)-5b 5e, and (R)-5c 5e
(F) against temperature.
3
3
3
3
3
3
3
3
one-handed helical conformation with a regular structure ex-
cept for the 2-mers. Due to the flexibility around the Pt(II)
linkers and the duplex ends, a possible reversal in helical sense at
the achiral amidine units at the terminus during duplex forma-
tion could not be completely excluded. Apparently, a further
study on the structural analysis of the Pt(II)-linked duplexes by
X-ray is essential to determine the exact helical structure and to
obtain more direct evidence dealing with amplification of the
helical chirality. Finally, we believe, however, that the present
studies would be valuable for the design and synthesis of a
wide variety of analogous multistranded helical oligomers and
polymers with more stable helical conformations based on
amidine-carboxylate salt bridges as unique and specific motifs,
providing more sophisticated complementary helical architec-
tures with novel functions.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details in the
b
synthesis and characterization of the oligomeric strands and the
double helices; CSI-mass spectra of (R)-2a 2d and (R)-2b 2d,
3
3
CD titration results of (R)-2a with 2d and (R)-2b and 2d in
CHCl3, variable-temperature CD and absorption spectra of
1
4-mers and 5-mers in toluene, variable-temperature H NMR
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spectra of 3-mers in CDCl3, and MD simulation results of
3-mers. This material is available free of charge via the Internet
at http://pubs.acs.org.
Synth. Org. Chem., Jpn. 2007, 65, 1121–1133. (e) Furusho, Y.; Yashima,
E. Chem. Rec. 2007, 7, 1–11. (f) Amemiya, R.; Yamaguchi, M. Org.
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Polym. Sci., Part A: Polym. Chem. 2009, 47, 5195–5207. (i) Haldar, D.;
Schmuck, C. Chem. Soc. Rev. 2009, 38, 363–71.
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Corresponding Author
yashima@apchem.nagoya-u.ac.jp
Present Addresses
§Department of Chemistry, Graduate School of Science, Osaka
City University.
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University.
’ ACKNOWLEDGMENT
This work was supported in part by Grant-in-Aid for Scientific
Research (S) from the Japan Society for the Promotion of
Science (JSPS) and the Japan Science and Technology Agency
(JST). We thank Dr. Yoshie Tanaka (JST), Toshihide Hasegawa
(JST), and Wataru Makiguchi (Nagoya University) for their help
in the synthesis of the starting materials. We also thank Shinzo
Kobayashi and Hidekazu Yamada (Nagoya University) for their
help in the variable-temperature CD and NMR measurements.
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(22) Diacetylene-linked all-chiral (R)-amidine 2-, 3-, and 4-mers
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plementary diacetylene-linked carboxylic acid strands in CHCl3 as
supported by the no temperature-dependent CD and absorption
spectral changes and the X-ray crystal structural analysis for the 2-mer.
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by size-exclusion chromatography, leading to a unique chain-length-
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(23) Similar conformational heterogeneity has been proposed in
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PNA strand; see ref 7f.
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(18) The 5-mer (5e) with 1-octynyl chains was employed because of
the poor solubility of the 5-mer (5d) in CHCl3, which hampered any
further investigation.
(19) In contrast, an analogous 2-mer duplex composed of all-achiral
amidine and carboxylic acid strands bearing (R)- or (S)-2-diphenylpho-
sphino-20-methoxy-1,10-binaphthyl (MOP) and triphenylphosphine li-
gands instead of the triethylphosphine ones at the Pt(II) linkages,
respectively, showed a dramatic solvent effect, and its CD intensity
significantly increased with the decreasing temperature. In addition, the
Cotton effect signs in CHCl3 were almost inverted in toluene at low
temperatures, probably because of the steric repulsion caused by the
bulky phosphine ligands that may readily assist with the interconversion
between the diastereomeric right- and left-handed double helices in
solution. See ref 11e.
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