Synthesis of helically twisted [1 + 1]macrocycles assisted by amidinium-carboxylate salt bridges and control of their chiroptical properties

Article abstract of DOI:10.1039/c2ob27054d

A series of optically active, helically twisted [1 + 1]macrocycles connected via o-, m-, and p-linkages (o-2, m-2, and p-2) was prepared from the corresponding linear duplexes stabilized by complementary amidinium-carboxylate salt bridges bearing two arms with terminal vinyl groups at both ends through the ring-closing metathesis reaction in the good yields of 67, 92, and 96%, respectively. The chiroptical properties of the macrocycles were dependent on the linker geometries and could be controlled by acid-base interactions and zinc coordination, the changes in which were detected by their CD and absorption spectral changes and fluorescence colors.

Full text of DOI:10.1039/c2ob27054d

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Synthesis of helically twisted [1 + 1]macrocycles
assisted by amidinium–carboxylate salt bridges and
control of their chiroptical properties†
Cite this: DOI: 10.1039/c2ob27054d
Yuji Nakatani, Yoshio Furusho and Eiji Yashima*
A series of optically active, helically twisted [1 + 1]macrocycles connected via o-, m-, and p-linkages (o-2,
m-2, and p-2) was prepared from the corresponding linear duplexes stabilized by complementary amidi-
nium–carboxylate salt bridges bearing two arms with terminal vinyl groups at both ends through the
ring-closing metathesis reaction in the good yields of 67, 92, and 96%, respectively. The chiroptical
properties of the macrocycles were dependent on the linker geometries and could be controlled by acid–
base interactions and zinc coordination, the changes in which were detected by their CD and absorption
spectral changes and fluorescence colors.
Received 22nd October 2012,
Accepted 19th November 2012
DOI: 10.1039/c2ob27054d
www.rsc.org/obc
and an achiral carboxylic acid strand bearing long arms with
terminal vinyl groups at both ends through the ring-closing
Introduction
Macrocycles with
a
preferred-handed twisted structure metathesis (RCM) reaction,8 by which the intra-strand RCM
showing an optical activity have attracted considerable interest reactions predominantly took place, thus producing
a
in the past two decades in organic, inorganic, supramolecular, mechanically interlocked [2]catenane (Fig. 1A).9 By taking
and analytical chemistries,1 because of their promising appli- advantage of this strategy, we now describe the synthesis of
cations in many areas as chiral materials for chiral recognition, three new optically active, helically twisted [1 + 1]macrocycles
sensing, and separation of enantiomers as well as asymmetric connected via o-, m-, and p-linkages (o-2, m-2, and p-2) utilizing
catalysis.1c,2 Macrocycles are also regarded as some of the most the chiral amidinium–carboxylate salt bridges (Fig. 1B) and
useful components for the formation of topologically intri- the effects of the linker geometries on the stabilities of the
guing interlocked molecules, such as catenanes and rotax- helical conformations of the macrocycles and the control of
anes.3 Although
a
large number of helically twisted their chiroptical properties by acid–base interactions together
macrocycles with optical activities have been developed for with zinc coordination by measuring the absorption, circular
this purpose, most of which rely on steric effects4 and metal dichroism (CD), fluorescence, and 1H NMR.
coordination,1c,f,5 optically active macrocycles with a switch-
able chiroptical property are quite rare.1a,6
Previously, we have reported the rational design and syn-
Results and discussion
Syntheses and chiroptical properties of [1 + 1]macrocycles
thesis of a series of double-stranded helical oligomers and
polymers with optical activities, of which the strands consist of
crescent-shaped m-terphenyl backbones bearing complemen-
tary chiral amidine and achiral carboxy groups.7 The twist
sense of the double helices is regulated by the chiral amidi-
nium–carboxylate salt bridges. This chiral salt bridge-based
recognition motif was further applied to the efficient synthesis
of an optically active [2]catenane consisting of complementary
macrocyclic components derived from a chiral amidine strand
The syntheses of three optically active [1 + 1]macrocycles were
carried out according to Schemes 1 and 2 (see also ESI†). The
optically active amidines with two short arms bearing terminal
vinyl groups at both ends, i.e., the o-1a, m-1a, and p-1a,
were synthesized by the Sonogashira coupling between the
m-terphenyl amidine with two terminal acetylene groups (3a)
and the o-, m-, and p-iodobenzoate derivatives with 4-pentenyl
side chains (o-4, m-4, and p-4). The m-terphenyl-bound car-
boxylic acids with the identical 4-pentenyl side chains, o-1b,
m-1b, and p-1b, were also prepared in a similar manner. The
1H NMR spectra of equimolar mixtures of o-1a and o-1b, m-1a
and m-1b, and p-1a and p-1b showed signals for the NH
protons (Ha) at the low magnetic field of δ = 13.47, 13.47, and
Department of Molecular Design and Engineering, Graduate School of Engineering,
Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan.
E-mail: yashima@apchem.nagoya-u.ac.jp; Fax: +81-52-789-3185; Tel: +81-52-789-4495
†Electronic supplementary information (ESI) available: Experimental details and
additional spectroscopic data. See DOI: 10.1039/c2ob27054d
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Scheme 1 (A) Synthesis of [1 + 1]macrocycles (o-2, m-2, and p-2). Reagents
and conditions: (a) [PdCl2(PPh3)2], CuI, Et3N/THF, r.t.; (b) Grubbs’ catalyst
(1st generation), toluene, r.t. and (B) structures of 3a’·3b’ and 3a’’·3b’’.
Fig. 1 Structures of (A) [2]catenane and (B) [1 + 1]macrocycles and schematic
illustration of reversible structural changes between double helical and
non-helical macrocycles using an acid/base or Zn2+/cryptand [2.2.1] system.
macrocycle was detected by an ESI-MS analysis because of two
13.46 ppm, which indicated the formation of the duplexes, short arms that are unable to allow intramolecular cyclization,
o-1a·o-1b, m-1a·m-1b, and p-1a·p-1b, through the salt bridges, which unambiguously supported the selective intermolecular
respectively (c in Fig. 2A–C). The duplex solutions in toluene [1 + 1]macrocycle formations, thereby producing o-2, m-2, and
were treated with a catalytic amount of the 1st generation of p-2 (Fig. S2†).
Grubbs’ catalyst to give the corresponding macrocycles after
The [1 + 1]macrocycles, o-2, m-2, and p-2, consist of three
chromatographic purification in 67, 92, and 96% yields, isomers with respect to the internal olefin geometries, trans–
respectively. The RCM reactions resulted in the disappearances trans, trans–cis, and cis–cis isomers. Although it was not poss-
of the signals of the terminal methylene and methine protons, ible to completely separate these isomers, those of m-2 and p-2
and instead, the internal olefin protons (Hc and Ht) appeared could be partially separated by flash chromatography. The ole-
1
in their H NMR spectra (d in Fig. 2A–C). The macrocyclic for- finic proton resonances of m-2 and p-2 appeared as two signals
mations were also revealed by electron-spray ionization mass in their 1H NMR spectra in CDCl3 due to the cis and trans geo-
spectrometry (ESI-MS); the ESI-MS spectra of the CHCl3– metries, which also resulted in two sets of aromatic resonances
MeOH (1/1, v/v) solutions of o-2, m-2, and p-2 showed signals (d in Fig. 2B and C). As anticipated, the differences in the
for the mono-cationic species ([o-2 + H]+, [m-2 + H]+, and [p-2 + chemical shifts of the p-2 aromatic protons are not significant
H]+) at m/z = 1547.66, 1547.64, and 1547.61, respectively, of because p-2 most likely possesses a relaxed ring conformation
1
which the isotopic patterns were in good agreement with the as evidenced by the H NMR spectra of a series of p-2 isomers
simulated ones (Fig. S1†).
with different trans/cis ratios obtained by chromatographic
A [2]catenane can be regarded as an alternative possible fractionation (Fig. S3†), whereas the m-linked aromatic proton
structure formed during the RCM reactions, thus generating resonances of an isolated pure isomer of m-2 (trans–trans or
two complementary small macrocycles mechanically inter- cis–cis isomer) (g–j protons in e (Fig. 2B)) showed large upfield
locked with each other.9 o-1b was then allowed to react with shifts probably because of the ring current of the aromatic
the Grubbs’ catalyst because the two terminal olefins of o-1b ring of the other linker due to its high strain. Based on compu-
are located most closely to each other among the three o-1b, ter modeling, this isomer was reasonably assigned to the
m-1b, and p-1b strands. However, no trace amount of such a trans–trans isomer because it has a more highly strained
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Fig. 2 (A) Partial 1H NMR (500 MHz, 25 °C) spectra of (a) the amidine (o-1a), (b) the carboxylic acid (o-1b), (c) the duplex (o-1a·o-1b), (d) the o-[1 + 1]macrocycle
(o-2) in CDCl3 (trans–trans : cis–trans : cis–cis = 43 : 43 : 14), and (e) o-2 in DMSO-d6. (B) Partial 1H NMR (500 MHz, CDCl3, 25 °C) spectra of (a) the amidine (m-1a),
(b) the carboxylic acid (m-1b), (c) the duplex (m-1a·m-1b), (d) the m-[1 + 1]macrocycle (m-2) (trans : cis = 50 : 50), and (e) the (trans, trans)-m-[1 + 1]macrocycle ((t, t)-
m-2)). (C) Partial 1H NMR (500 MHz, CDCl3, 25 °C) spectra of (a) the amidine (p-1a), (b) the carboxylic acid (p-1b), (c) the duplex (p-1a·p-1b), and (d) the p-[1 + 1]
macrocycle (p-2) (trans : cis = 58 : 42).
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structure than that of the (cis, cis)-isomer (Fig. S9†). Therefore, active (R)-1-phenylethyl substituents on the amidine groups9
the trans/cis ratios of m-2 as well as p-2 were estimated to be because the corresponding (R)-amidine linear strands (o-1a,
50/50 and 58/42, respectively, using the integral ratios of the m-1a, and p-1a) exhibited very weak CDs in the same regions
olefinic proton resonances.
(red lines in Fig. 3). Although their absorption and CD spectral
In contrast, the olefinic proton resonances along with the patterns and intensities were slightly different from each other
aromatic ones of o-2 were quite complicated (d in Fig. 2A). due to the difference in their linker structures, the trans/cis
Instead, the salt-bridged NH protons that were sensitive to the geometries at the linkers of the macrocycles were found to
olefin geometries split into three sets of signals, i.e., a doublet, hardly influence the chiroptical properties probably because of
a double-doublet, and a doublet from the lower magnetic field the strong salt-bridges that determine the predominantly one-
originating from the highly restricted o-linked macrocyclic con- handed twisted helical conformations of the macrocycles, so
formations. Among them, the double-doublet signal can be that the CD spectra of the as-prepared m-2 (trans/cis = 50/50)
assigned to the trans–cis isomer. In order to identify other and trans–trans m-2 were almost identical to each other
isomers, the 1H NMR spectrum of o-2 was measured in (Fig. S4†).
dimethyl sulfoxide-d6 (DMSO-d6) (e in Fig. 2A), since the salt
bridge formation is hampered in polar DMSO, thereby releas-
Stabilities of macrocyclic duplexes
ing the macrocyclic strain (a′ and a′′ protons in e (Fig. 2A)). The effects of the macrocyclic structures with different linkers
The salt-bridged NH protons appeared as two doublets as on the stabilities of the intramolecularly double helix for-
observed for m-2 and p-2, and that at the lower magnetic field mations assisted by the salt bridges were then investigated by
is assigned to the trans isomer based on the 1H NMR spectrum measuring their CD spectra in dimethylsulfoxide (DMSO), in
of the (t,t)-m-2 isomer. As a consequence, the trans–trans, which the salt bridge formation is hampered. It should be
trans–cis, and cis–cis ratios for o-2 were estimated to be 43, 43, noted that the macrocycles, m-2 and p-2, exhibited as intense
and 14%, respectively, and the trans/cis ratio was 65/35 (a1–a3 CDs in DMSO as those in CHCl3 at 0.1 mM, although the CD
protons in d (Fig. 2A)).
intensity of o-2 was reduced to 85% of that in CHCl3 (Fig. 3).
Fig. 3A–C display the CD spectra of the macrocycles with In sharp contrast, the corresponding linear model duplexes
different linkers, but the same chiral amidine residues, o-2, (o-1a·o-1b, m-1a·m-1b, and p-1a·p-1b) and a monomeric duplex
m-2, and p-2, in CHCl3 at 20 °C, which showed first negative (3a′·3b′) showed a very weak CD in DMSO similar to those of
(o-2–p-2) and second positive (m-2 and p-2) Cotton effects for the amidine strands, o-1a, m-1a, p-1a, and 3a′, respectively,
the absorptions of the m-terphenyl ligands between approxi- indicating that the linear duplexes underwent dissociation
mately 250 and 350 nm, thus indicating that the two m-terphe- into single strands in DMSO as anticipated (Fig. S5†). These
nyl groups bound together by the salt bridges were twisted in noticeable solvent effects on the CD spectra were ascribed to
one direction, probably the same right-handed double helices their macrocyclic structures, thereby leading to a remarkable
independent of the linker structures biased by the optically enhancement of their association constants (Ka) in the polar
DMSO.
As we previously reported,7a,n,9 the Ka values for the mono-
meric and dimeric duplexes, 3a′·3b′ (Fig. S5†) and 3a′′·3b′′
(Fig. S6†) at 25 °C in CHCl3 were estimated to be 2.82 × 106
1
M−1 and 6.43 × 1013 M−1, respectively, by the H NMR and CD
titrations. Therefore, the Ka values for the present macrocycles,
o-2, m-2, and p-2, could be assumed to be higher than 6.43 ×
1013 M−1 in CHCl3 by comparing the relative CD intensities of
the macrocycles in CHCl3 and DMSO to those of the model
dimer 3a′′·3b′′, whose CD intensity in CHCl3 was reduced to
67% in DMSO (Fig. S6†),7a,n and the stabilities of the intra-
molecular duplexes of the macrocycles likely decreased in the
following order: p-2 ≥ m-2 > o-2.
Chiral switching of [1 + 1]macrocycles
The switching between the intramolecular “double helical
structure” and “non-helical structure” states of the macrocycles
could be completely controlled by the sequential addition of
an acid and a base in an alternate manner. The addition of tri-
fluoroacetic acid (TFA), as a salt-bridge competitor, to CHCl3
solutions of the macrocycles (0.1 mM) caused a gradual
decrease in the Cotton effects, and the CD spectra became the
Fig. 3 CD and absorption spectra of (A) o-2, (B) m-2, and (C) p-2 in CHCl3
same as those of the TFA salts of the linear amidine strands
(o-1a, m-1a, and p-1a) in the presence of 30 equiv. of TFA
(0.1 mM) (blue) and DMSO (0.1 mM) at 20 °C (dashed light blue) and (A) o-1a,
(B) m-1a, and (C) p-1a in CHCl3 (0.1 mM) at 20 °C (red).
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by the formation of the Zn2+ complex through coordination to
the amidine residues.9
The [1 + 1]macrocycles have conjugated m-terphenyl units
and emitted light in a different manner depending on the
linker structures when irradiated at 300 (m-2) and 313 nm (o-2
and p-2) (Fig. 5D–F). The addition of Zn2+ ions to a solution of
m-2 caused a significant enhancement and a large red shift in
its fluorescence, leading to a color change from faint purple to
bright bluish yellow (Fig. 5E and H). A similar fluorescence be-
havior was observed for an analogous topological isomer of [2]-
catenane composed of complementary m-linked macrocyclic
rings in the presence of Zn2+ ions.9 In contrast, the fluo-
rescence intensity of the [1 + 1]macrocycle, p-2, significantly
decreased upon the addition of Zn2+ ions accompanied by a
negligible shift in its fluorescence (Fig. 5F and I), whereas the
o-2 exhibited changes in its emission and fluorescence color
before and after the addition of Zn2+ ions (Fig. 5D and G). The
CD and fluorescent spectra of 2 were completely restored after
the addition of the cryptand [2.2.1], which trapped the Zn2+
ion from 2, indicating that the salt bridges were restored
(Fig. 5A–F). These results indicated that the [1 + 1]macrocycles,
in particular o-2, can be used as a novel photoluminescent
zinc sensor.10
Fig. 4 CD and absorption spectra of (A) o-2, (B) m-2, and (C) p-2 in CDCl3
(0.1 mM) at 20 °C before (blue) and after the addition of 5 and 30 equiv. of TFA
(dashed violet and red, respectively) followed by further neutralization with 30
equiv. of iPr2NEt (dashed light blue). (D) Plots of the Δε values of o-2 and p-2 at
335 nm (blue and red, respectively), and m-2 at 325 nm (green) in CHCl3
(0.1 mM) upon sequential addition of TFA and i-Pr2NEt in an alternate manner.
Conclusions
(Fig. 4 and Fig. S5†). We noted that the linear model duplexes
(o-1a·o-1b, m-1a·m-1b, and p-1a·p-1b) were completely disso-
ciated into single strands in the presence of 1 equiv. of TFA in
CHCl3 as evidenced by the similar CD spectral changes
(Fig. S5†), supporting the remarkable stabilities of the double
helical structures of the macrocycles. The neutralizations by
the further additions of equal amounts of diisopropylethyl-
amine (iPr2NEt) completely restored the CD spectra, indicating
that the macrocycles again folded into the preferred-handed
double helical structures as a result of the restorations of the
salt bridges (dashed light blue lines in Fig. 4A–C). These cycles
could be repeated three times by the sequential addition of an
acid and a base in an alternating manner, as shown in Fig. 4D.
In the presence of 20 equiv. of TFA, the CD intensities of
o-2, m-2, and p-2 at 0.1 mM were significantly reduced as
shown in Fig. S7† (B–D), but recovered to 60, 75, and 90% of
the original values when diluted with CHCl3 to 0.01 mM,
whereas those of the corresponding linear duplexes with 20
equiv. of TFA remained the same after dilution, suggesting the
re-folding into duplexes with an excess handedness that only
took place for the macrocycles under dilute conditions.
In summary, we have designed and synthesized a series of
optically active, helically twisted [1 + 1]macrocycles utilizing
amidinium–carboxylate salt bridges as a versatile structural
motif to control the twisting motion of the macrocycles by
acid–base interactions and zinc coordination. These changes
could be detected by their CD and fluorescence colors. The
present methodology based on the complementary salt
bridges affording chiral conjugated macrocycles with switch-
able chiroptical and photoluminescent properties may provide
a novel sensor for detecting the chirality of chiral molecules
bearing an acid/base functionality and/or a metal containing
group.2c,2e
Experimental
General remarks
All starting materials and dehydrated solvents were purchased
from Aldrich (Milwaukee WI), Wako Pure Chemical Industries
(Osaka, Japan), and Tokyo Kasei Kogyo (TCI, Tokyo, Japan) and
used without future purification unless otherwise noted. Tri-
ethylamine (Et3N) was dried over KOH pellets and distilled
onto KOH under nitrogen. Deuteriochloroform (CDCl3, 99.8
atom%D) was obtained from Aldrich. Compounds 3a7h and
3b7h (Scheme 1) were prepared according to the previously
reported methods. The silica gel (SiO2, BW-300) and the
aminopropyl-modified silica gel (NH-SiO2, NH-DM1020) were
purchased from Fuji Silysia Chemical (Kasugai, Japan). The
NMR spectra were measured using a Varian UNITY INOVA
The switches between the helical and non-helical states of
the macrocycles were also achieved by the sequential addition
of Zn(ClO4)2 and cryptand [2.2.1] in an alternate manner,
resulting in similar changes in their CD spectra (Fig. 5A–C).
These cycles could be also repeated three times. The CD
spectra of the macrocycles after the addition of 2 equiv. of the
Zn2+ ion became almost the same as those in the presence of
30 equiv. of TFA, suggesting that the salt bridges were broken
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Fig. 5 CD and absorption spectra of (A) o-2, (B) m-2, and (C) p-2 in CH2Cl2–THF (10/1, v/v, 0.01 mM) at 20 °C before (blue) and after the addition of 2 equiv. of
Zn(ClO4)2 (red), followed by subsequent removal of Zn2+ ion with 2 equiv. of cryptand [2.2.1] (dashed light blue), respectively. Fluorescence spectra of (D) o-2 (λex
=
313 nm), (E) m-2 (λex = 300 nm), and (F) p-2 (λex = 313 nm) in CH2Cl2–THF (10/1, 0.01 mM) at ambient temperature before (blue) and after the addition of 2 equiv.
of Zn(ClO4)2 (red), followed by subsequent removal of Zn2+ ions with 2 equiv. of cryptand [2.2.1] (dashed light blue), respectively. Photographs of solutions of (G)
o-2, (H) m-2, and (I) p-2 in CH2Cl2–THF (10/1, v/v) under irradiation at 254 nm. Fluorescence spectra of 2 gradually changed with time after the addition of 2 equiv.
of Zn(ClO4)2 within 12 h (Fig. S8†), and the CD, absorption, and fluorescence spectra of 2 with Zn(ClO4)2 after 12 h are shown.
ionization (ESI) mass spectra were recorded using a JEOL
JMS-T100CS mass spectrometer.
o-4. N,N′-Dicyclohexylcarbodiimide (DCC, 3.30 g, 16.3 mmol)
was added to a solution of the compound 5 (1.30 g, 15.0 mmol)
and 2-iodobenzoic acid (o-6, 3.90 g, 16.0 mmol) in CHCl3
(40.0 mL) at 0 °C. After warming to ambient temperature,
4-(N,N-dimethylamino)pyridine (DMAP, 91.5 mg, 0.750 mmol)
was added to the solution, which was stirred at ambient temp-
Scheme 2 Synthesis of o-4, m-4, and p-4.
erature for 2 days. After filtration, the filtrate was evaporated to
dryness, and the residue was purified by flash column chrom-
atography (SiO2, n-hexane–EtOAc = 1/1 (v/v)) to afford the com-
500AS spectrometer operating at 500 MHz for 1H. Chemical
shifts are reported in parts per million (δ) downfield from
pound o-4 (3.82 g, 82% yield) as a clear, colorless liquid.
1H NMR (500 MHz, CDCl3): δ 7.99 (dd, J = 7.8, 1.1 Hz, 1H,
tetramethylsilane (TMS) as the internal standard in CDCl3.
The absorption and CD spectra were measured in a 0.1 or
1.0 cm quartz cell using a JASCO V-560 spectrophotometer and
a JASCO J-820 spectropolarimeter, respectively. The photolumi-
nescence spectra were measured in a 1.0 cm quartz cell using
ArH), 7.79 (dd, J = 7.8, 1.7 Hz, 1H, ArH), 7.41 (td, J = 7.8,
1.1 Hz, 1H, ArH), 7.15 (td, J = 7.8, 1.7 Hz, 1H, ArH), 5.85 (ddt,
J = 17.1, 10.4, 6.7 Hz, 1H, CH2CHvCH2), 5.08 (ddt, J = 17.1,
1.7, 1.6 Hz, 1H, CHvCHZHE), 5.03–5.00 (m, 1H, CHvCHEHZ),
4.36 (t, J = 6.6 Hz, 2H, OCH2C4H7), 2.26–2.21 (m, 2H,
CH2CHvCH2), 1.93–1.86 (m, 2H, OCH2CH2C3H5).
a
JASCO FP-6500 spectrofluorometer. The electron-spray
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o-1a. CuI (3.76 mg, 20.0 μmol) was added to a solution of 7.66–7.62 (m, 4H, ArH), 7.53 (d, J = 8.4 Hz, 4H, H3,5,3′′,5′′ of
the compound o-4 (0.252 g, 0.800 mmol) and bis(triphenylpho- amidine), 7.48 (d, J = 7.7 Hz, 2H, H4′,6′ of amidine), 7.41–7.35
sphine)palladium(II) dichloride (14.0 mg, 20.0 μmol) in Et3N (m, 3H, H4′,5′,6′ of acid), 7.35–7.25 (m, 8H, ArH), 7.18–7.01 (m,
(4.0 mL) and THF (8.0 mL) at ambient temperature for 4 h. To 6H, m- and p-H of Ph), 6.72 (d, J = 7.5 Hz, 4H, o-H of Ph), 6.67
the reaction mixture was added dropwise a solution of com- (d, J = 8.4 Hz, 4H, H2,6,2′′,6′′ of amidine), 5.82–5.72 (m, 4H,
pound 3a (0.106 g, 0.200 mmol) in Et3N (2.0 mL) and THF CH2CHvCH2), 5.03–4.91 (m, 8H, CHvCH2), 4.40–4.28 (m, 8H,
(4.0 mL) at ambient temperature over a period of 1 h, and then OCH2C4H7), 3.85–3.76 (m, 2H, CHN), 2.22–2.12 (m, 8H,
the mixture was stirred for a further 24 h. After the reaction CH2CHvCH), 1.92–1.78 (m, 8H, CHvCHCH2CH2), 0.65 (d, J =
mixture was evaporated to dryness, the residue was purified by 6.8 Hz, 6H, CH3CHN).
column chromatography (NH-SiO2, Et2O–n-hexane = 1/3 to 1/0
o-2. The amidine o-1a (18.1 mg, 20.0 μmol) and the car-
(v/v), then NH-SiO2, n-hexane–CHCl3 = 4/1 to 2/1 (v/v)) to afford boxylic acid o-1b (14.0 mg, 20.0 μmol) were dissolved in dry
the amidine o-1a (24.3 mg, 13% yield) as a clear, colorless toluene (195 mL), and the solution was deoxygenated by freeze–
paste. 1H NMR (500 MHz, CDCl3, o-1a (1.0 mM), CH3CO2H pump–thaw cycles for 3 times. To this was added a solution of
(15 mM), 25 °C): δ 12.79 (br s, 2H, N–H), 7.99 (dd, J = 8.0, the 1st generation Grubbs’ catalyst (11.5 mg, 14.0 μmol) in
1.4 Hz, 2H, ArH), 7.79 (t, J = 7.9 Hz, 1H, H5′), 7.67 (dd, J = 7.2, toluene (5.0 mL), and the reaction mixture was stirred at
1.4 Hz, 2H, ArH), 7.55 (d, J = 7.9 Hz, 2H, H4′,6′), 7.52 (ddd, ambient temperature for 24 h under Ar. After the solvent was
J = 8.0, 7.5, 1.4 Hz, 2H, ArH), 7.41 (ddd, J = 7.5, 7.2, 1.4 Hz, 2H, evaporated to dryness, the residue was purified by column
ArH), 7.34 (d, J = 8.5 Hz, 4H, H3,5,3′′,5′′), 7.30–7.21 (m, 6H, m- chromatography (NH-SiO2, EtOAc–n-hexane = 2/1 (v/v), then
and p-H of Ph), 7.04 (d, J = 7.0 Hz, 4H, o-H of Ph), 6.73 NH-SiO2, CHCl3) to afford the o-[1 + 1]macrocycle o-2 (20.4 mg,
(d, J = 8.5 Hz, 4H, H2,6,2′′,6′′), 5.81 (ddt, J = 17.0, 10.3, 6.6 Hz, 67% yield) as a clear, colorless paste. The o-[1 + 1]macrocycle
2H, CH2CHvCH2), 5.06–5.01 (m, 2H, CHvCHZHE), 5.01–4.97 o-2 consists of trans–trans, trans–cis, and cis–cis isomers and the
(m, 2H, CHvCHEHZ), 4.39 (t, J = 6.6 Hz, 4H, OCH2C4H7), 3.97 trans/cis ratio was estimated to be 65 : 35 on the basis of its
(q, J = 6.8 Hz, 2H, CHN), 2.26–2.21 (m, 4H, CH2CHvCH2), 2.11 1H NMR spectrum (see (d) in Fig. 2A). 1H NMR (500 MHz,
(s, 3H, CH3CO2), 1.95–1.89 (m, 4H, OCH2CH2C3H5), 0.74 (d, J = CDCl3, 25 °C); [(trans–trans, trans–cis, cis–cis) = (43%, 43%,
6.8 Hz, 6H, CH3CHN); HRMS (ESI, CHCl3–MeOH (1/1, v/v), 14%)]: δ 13.49 (d, J = 7.6 Hz, 2H, N–H [43% trans–trans]), 13.42
positive): calcd for [M + H]+ = C63H57N2O4: m/z = 905.4318, (d, J = 7.6 Hz, 2H, N–H [21.5% trans of trans–cis]), 13.40 (d, J =
found: m/z = 905.4313.
7.7 Hz, 2H, N–H [21.5% cis of trans–cis]), 13.30 (d, J = 7.7 Hz, 2H,
o-1b. CuI (18.8 mg, 0.100 mmol) was added to a solution of N–H [14% cis–cis]), 7.97–7.84 (m, 4H, ArH), 7.83–7.67 (m, 9H,
the compound o-4 (1.26 g, 4.00 mmol) and bis(triphenylpho- H5′ of amidine, H2,3,5,6,2′′,3′′,5′′,6′′ of acid), 7.64–7.45 (m, 8H, ArH,
sphine)palladium(II) dichloride (70.2 mg, 0.100 mmol) in Et3N H3,5,3′′,5′′ of amidine), 7.45–7.29 (m, 9H, ArH, H4′,6′ of amidine,
(9.0 mL) and THF (81 mL) at ambient temperature for 3 h. To H4′,5′,6′ of acid), 7.29–7.11 (m, 10H, ArH, m- and p-H of Ph), 6.80
the reaction mixture was added dropwise a solution of com- (d, J = 7.5 Hz, 8H, o-H of Ph, H2,6,2′′,6′′ of amidine from trans–
pound 3b (0.322 g, 1.00 mmol) in THF (30 mL) at ambient trans and trans–cis), 6.58 (d, J = 7.8 Hz, 4H, H2,6,2′′,6′′ of amidine
temperature over a period of 1 h, and then the mixture was from cis–cis), 5.26–5.06 (m, 4H, CH2CHvCHCH2), 4.31–4.00 (m,
stirred for a further 24 h. After the reaction mixture was evap- 8H, CO2CH2CH2), 3.86–3.75 (m, 2H, CHN), 2.16–1.80 (m, 16H,
orated to dryness, the residue was purified by column chrom- CO2C2H4CH2CHvCH, CO2CH2CH2CH2), 0.67–0.59 (m, 6H,
atography (SiO2, CHCl3–MeOH = 1/0 to 24/1 (v/v)) to afford the CH3CHN); HRMS (ESI, MeOH, positive): calcd for [M + Na]+
=
carboxylic acid o-1b (88.3 mg, 13% yield) as a clear, colorless
paste. 1H NMR (500 MHz, CDCl3, r.t.): δ 7.99 (d, J = 7.8, 1.1 Hz,
C
106H86N2O10Na: m/z = 1569.6180, found: m/z = 1569.6194.
m-4. DCC (3.30 g, 16.3 mmol) was added to a solution of
2H, ArH), 7.79 (d, J = 7.3 Hz, 2H, ArH), 7.62 (d, J = 8.2 Hz, 4H, the compound 5 (1.30 g, 15.0 mmol) and 3-iodobenzoic acid
ArH), 7.56 (t, J = 7.2 Hz, 1H, ArH), 7.50 (t, J = 6.9 Hz, 2H, ArH), (m-6, 3.90 g, 16.0 mmol) in CHCl3 (40.0 mL) at 0 °C. After
7.45 (d, J = 8.2 Hz, 4H, ArH), 7.42–7.37 (m, 4H, ArH), 5.80 (ddt, warming to ambient temperature, DMAP (91.5 mg,
J = 17.0, 10.3, 6.9 Hz, 2H, CH2CHvCH2), 5.05–4.99 (m, 2H, 0.750 mmol) was added to the solution, which was stirred at
CHvCHZHE), 4.99–4.96 (m, 2H, CHvCHEHZ), 4.38 (t, J = ambient temperature for 3 days. After filtration, the filtrate was
6.6 Hz, 4H, OCH2C4H7), 2.24–2.18 (m, 4H, CH2CHvCH2), evaporated to dryness, and the residue was purified by flash
1.92–1.85 (m, 4H, OCH2CH2C3H5); HRMS (ESI, CHCl3–MeOH column chromatography (SiO2, n-hexane–EtOAc = 1/1 (v/v)) to
(1/1, v/v), negative): calcd for [M − H]− = C47H37O6: m/z = afford the compound m-4 (4.22 g, 89% yield) as a clear, color-
1
697.2590, found: m/z = 697.2572.
less liquid. H NMR (500 MHz, CDCl3): δ 8.37 (dd, J = 1.7, 1.5
o-1a·o-1b. The amidine o-1a (4.53 mg, 5.00 μmol) and the Hz, 1H, ArH), 8.00 (ddd, J = 7.8, 1.5, 1.1 Hz, 1H, ArH), 7.88
carboxylic acid o-1b (3.49 mg, 5.00 μmol) were dissolved in (ddd, J = 7.8, 1.7, 1.1 Hz, 1H, ArH), 7.18 (t, J = 7.8, Hz, 1H,
CHCl3 (5.0 mL). The resultant solution was concentrated ArH), 5.85 (ddt, J = 17.1, 10.4, 6.7 Hz, 1H, CH2CHvCH2), 5.08
in vacuo to afford the complex o-1a·o-1b (7.91 mg, 98% yield) (ddt, J = 17.1, 1.7, 1.6 Hz, 1H, CHvCHZHE), 5.04–5.01 (m, 1H,
1
as a clear, colorless paste. H NMR (500 MHz, CDCl3, 25 °C): CHvCHEHZ), 4.33 (t, J = 6.6 Hz, 2H, OCH2C4H7), 2.24–2.19
δ 13.47 (d, J = 7.8 Hz, 2H, N–H), 7.95–7.88 (m, 4H, ArH), 7.80 (m, 2H, CH2CHvCH2), 1.91–1.84 (m, 2H, OCH2-CH2C3H5).
(d, J = 8.3 Hz, 4H, H2,6,2′′,6′′ of acid), 7.76 (d, J = 8.3 Hz, 4H,
m-1a. CuI (3.76 mg, 20.0 μmol) was added to a solution of
H3,5,3′′,5′′ of acid), 7.73 (t, J = 7.7 Hz, 1H, H5′ of amidine), the compound m-4 (0.252 g, 0.800 mmol) and bis
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(triphenylphosphine)palladium(II) dichloride (14.0 mg, H4′,5′,6′ of acid), 7.31–7.24 (m, 4H, ArH), 7.17–7.06 (m, 6H, m-
20.0 μmol) in Et3N (4.0 mL) and THF (8.0 mL) at ambient and p-H of Ph), 6.79 (d, J = 7.3 Hz, 4H, o-H of Ph), 6.67 (d, J =
temperature for 1 h. To the reaction mixture was added drop- 8.3 Hz, 4H, H2,6,2′′,6′′ of amidine), 5.86–5.76 (m, 4H,
wise a solution of compound 3a (0.106 g, 0.200 mmol) in Et3N CH2CHvCH2), 5.07–4.98 (m, 8H, CHvCH2), 4.30–4.27 (m, 8H,
(2.0 mL) and THF (4.0 mL) at ambient temperature over a OCH2C4H7), 3.84–3.78 (m, 2H, CHN), 2.20–2.13 (m, 8H,
period of 1 h, and then the mixture was stirred for a further CH2CHvCH), 1.86–1.79 (m, 8H, CHvCHCH2CH2), 0.66 (d, J =
28 h. After the reaction mixture was evaporated to dryness, the 6.8 Hz, 6H, CH3CHN).
residue was purified by column chromatography (NH-SiO2,
m-2. The amidine m-1a (63.4 mg, 70.0 μmol) and the car-
Et2O–n-hexane = 1/3 to 1/0 (v/v), then NH-SiO2, n-hexane– boxylic acid m-1b (48.9 mg, 70.0 μmol) were dissolved in dry
CHCl3 = 4/1 to 2/1 (v/v)) to afford the amidine m-1a (59.7 mg, toluene (690 mL), and the solution was deoxygenated by freeze–
1
33% yield) as a white solid. H NMR (500 MHz, CDCl3, m-1a pump–thaw cycles for 3 times. To this was added a solution of
(1.0 mM), CH3CO2H (15 mM), 25 °C): δ 13.22 (br s, 2H, N–H), the 1st generation Grubbs’ catalyst (40.4 mg, 49.0 μmol) in
8.20 (s, 2H, ArH), 8.02 (d, J = 7.8 Hz, 2H, ArH), 7.80 (t, J = 7.7 toluene (10 mL), and the reaction mixture was stirred at
Hz, 1H, H5′), 7.71 (d, J = 7.8 Hz, 2H, ArH), 7.57 (d, J = 7.7 Hz, ambient temperature for 6 h under Ar. After the solvent was
2H, H4′,6′), 7.45 (t, J = 7.8, Hz, 2H, ArH), 7.33–7.20 (m, 10H, evaporated to dryness, the residue was purified by column
H3,5,3′′,5′′, m- and p-H of Ph), 7.04 (d, J = 7.6 Hz, 4H, o-H of Ph), chromatography (NH-SiO2, EtOAc–n-hexane = 2/1 (v/v), then
6.73 (d, J = 8.3 Hz, 4H, H2,6,2′′,6′′), 5.87 (ddt, J = 17.3, 10.4, 6.7 NH-SiO2, CHCl3) to afford m-[1 + 1]macrocycle m-2 (99.4 mg,
Hz, 2H, CH2CHvCH2), 5.09 (d, J = 17.1 Hz, 2H, CHvCHZHE), 92% yield) as a white solid. The m-[1 + 1]macrocycle m-2 con-
5.03 (d, J = 10.4 Hz, 2H, CHvCHEHZ), 4.36 (t, J = 6.5 Hz, 4H, sists of trans–trans, trans–cis, and cis–cis isomers and the trans/
1
OCH2C4H7), 3.98–3.93 (m, 2H, CHN), 2.27–2.22 (m, 4H, cis ratio was estimated to be 50 : 50 on the basis of its H NMR
CH2CHvCH2), 2.11 (s, 3H, CH3CO2), 1.94–1.88 (m, 4H, spectrum (see (d) in Fig. 2B). 1H NMR (500 MHz, CDCl3, 25 °C);
OCH2CH2C3H5), 0.74 (d, J = 6.8 Hz, 6H, CH3CHN); HRMS (ESI, δ 13.53–13.49 (m, 2H, N–H from trans), 13.48–13.44 (m, 2H,
CHCl3–MeOH (1/1, v/v), positive): calcd for [M + H]+
C63H57N2O4: m/z = 905.4318, found: m/z = 905.4314.
=
N–H from cis), 8.21–8.19 (m, 2H, ArH of amidine from cis),
8.16–8.14 (m, 2H, ArH of acid from cis), 8.04–8.02 (m, 2H, ArH
m-1b. CuI (3.78 mg, 20.0 μmol) was added to a solution of of amidine from trans), 7.96–7.93 (m, 2H, ArH of acid from
the compound m-4 (0.252 g, 0.800 mmol) and bis(triphenyl- trans), 7.92–7.88 (m, 4H, ArH from cis), 7.84–7.78 (m, 8H, ArH
phosphine)palladium(II) dichloride (14.0 mg, 20.0 μmol) in from trans, H2,6,2′′,6′′ of acid), 7.77–7.68 (m, 9H, ArH from cis,
Et3N (1.8 mL) and THF (16.2 mL) at ambient temperature for H5′ of amidine, H3,5,3′′,5′′ of acid), 7.58–7.49 (m, 10H, ArH from
2 h. To the reaction mixture was added dropwise a solution of trans, H3,5,3′′,5′′,4′,6′ of amidine), 7.46–7.37 (m, 3H, H4′,5′,6′ of
compound 3b (64.5 mg, 0.200 mmol) in THF (7.0 mL) at acid), 7.32–7.27 (m, 4H, ArH from cis), 7.25–7.10 (m, 10H, ArH
ambient temperature over a period of 1 h, and then the from trans, m-H of Ph, p-H of Ph from trans), 7.07–7.03 (m, 2H,
mixture was stirred for a further 27 h. After the reaction p-H of Ph from cis), 6.88–6.79 (m, 4H, o-H of Ph), 6.76–6.67 (m,
mixture was evaporated to dryness, the residue was purified by 4H, H2,6,2′′,6′′ of amidine), 5.55–5.51 (m, 4H, CH2CHvCHCH2
column chromatography (SiO2, CHCl3) to afford the carboxylic [50% cis]), 5.51–5.48 (m, 4H, CH2CHvCHCH2 [50% trans]),
acid m-1b (39.4 mg, 28% yield) as a white solid. 1H NMR 4.38–4.19 (m, 8H, CO2CH2CH2), 3.86–3.79 (m, 2H, CHN),
(500 MHz, CDCl3, r.t.): δ 8.21 (t, J = 1.5 Hz, 2H, ArH), 7.98 2.31–2.16 (m, 8H, CO2C2H4CH2CHvCH), 1.87–1.77 (m, 8H,
(ddd, J = 7.7, 1.5, 1.3 Hz, 2H, ArH), 7.70 (ddd, J = 7.7, 1.5, CO2CH2CH2CH2), 0.67–0.62 (m, 6H, CH3CHN); HRMS (ESI,
1.3 Hz, 2H, ArH), 7.63 (d, J = 8.3 Hz, 4H, ArH), 7.55 (t, J = 7.7 MeOH, positive): calcd for [M + Na]+ = C106H86N2O10Na: m/z =
Hz, 1H, ArH), 7.44 (d, J = 8.3 Hz, 4H, ArH), 7.41 (d, J = 7.7 Hz, 1569.6180, found: m/z = 1569.6172.
2H, ArH), 7.40 (t, J = 7.7 Hz, 2H, ArH), 5.78 (ddt, J = 17.1, 10.3,
The trans–trans isomer was isolated from the mixture by
6.7 Hz, 2H, CH2CHvCH2), 5.08 (ddt, J = 17.1, 1.7, 1.6 Hz, 2H, flash chromatography (NH-SiO2, EtOAc–n-hexane = 1/1 to 2/1
CHvCHZHE), 5.04–5.00 (m, 2H, CHvCHEHZ), 4.34 (t, J = 6.6 (v/v)), in ca. 12% yield and its 1H NMR spectrum was measured
1
Hz, 4H, OCH2C4H7), 2.24–2.20 (m, 4H, CH2CHvCH2), (see (e) in Fig. 2B). H NMR of (t,t)-m-2: δ 13.50 (d, J = 8.9 Hz,
1.91–1.85 (m, 4H, OCH2CH2C3H5); HRMS (ESI, CHCl3–MeOH 2H, N–H), 8.04–8.02 (m, 2H, ArH of amidine), 7.94–7.93 (m,
(1/1, v/v), negative): calcd for [M − H]− = C47H37O6: m/z = 2H, ArH of acid), 7.84–7.78 (m, 4H, ArH), 7.83 (d, J = 8.3 Hz,
697.2590, found: m/z = 697.2581.
4H, H2,6,2′′,6′′ of acid), 7.77 (t, J = 7.7 Hz, 1H, H5′ of amidine),
m-1a·m-1b. The amidine m-1a (9.06 mg, 10.0 μmol) and the 7.69 (d, J = 8.3 Hz, 4H, H3,5,3′′,5′′ of acid), 7.59–7.49 (m, 10H,
carboxylic acid m-1b (6.98 mg, 10.0 μmol) were dissolved in ArH, H3,5,3′′,5′′,4′,6′ of amidine), 7.46–7.38 (m, 3H, H4′,5′,6′ of
CHCl3 (5.0 mL). The resultant solution was concentrated acid), 7.25–7.10 (m, 10H, ArH, m- and p-H of Ph), 6.87 (d, J =
in vacuo to afford the complex m-1a·m-1b (15.9 mg, 99% yield) 6.8 Hz, 4H, o-H of Ph), 6.74 (d, J = 8.4 Hz, 4H, H2,6,2′′,6′′ of
1
as a white solid. H NMR (500 MHz, CDCl3, 25 °C): δ 13.47 (d, amidine), 5.51–5.48 (m, 4H, CH2CHvCHCH2 [trans]),
J = 8.7 Hz, 2H, N–H), 8.22–8.21 (m, 2H, ArH), 8.18–8.16 (m, 4.34–4.20 (m, 8H, CO2CH2CH2), 3.86–3.80 (m, 2H, CHN),
2H, ArH), 7.93–7.87 (m, 4H, ArH), 7.79 (d, J = 8.4 Hz, 4H, 2.32–2.22 (m, 8H, CO2C2H4CH2CHvCH), 1.87–1.78 (m, 8H,
H2,6,2′′,6′′ of acid), 7.74 (t, J = 7.8 Hz, 1H, H5′ of amidine), 7.72 CO2CH2CH2CH2), 0.63 (d, J = 6.8 Hz, 6H, CH3CHN); HRMS
(d, J = 8.4 Hz, 4H, H3,5,3′′,5′′ of acid), 7.69–7.63 (m, 4H, ArH), (ESI, MeOH, positive): calcd for [M + Na]+ = C106H86N2O10Na:
7.53–7.49 (m, 6H, H3,5,3′′,5′′, 4′,6′ of amidine), 7.43–7.35 (m, 3H, m/z = 1569.6180, found: m/z = 1569.6168.
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p-4. DCC (3.30 g, 16.3 mmol) was added to a solution of the 1.92–1.86 (m, 4H, OCH2CH2C3H5); HRMS (ESI, MeOH, nega-
compound 5 (1.30 g, 15.0 mmol) and 4-iodobenzoic acid (p-6, tive): calcd for [M − H]− = C47H37O6: m/z = 697.2590, found:
3.90 g, 16.0 mmol) in CHCl3 (40.0 mL) at 0 °C. After warming m/z = 697.2566.
to ambient temperature, DMAP (91.5 mg, 0.750 mmol) was
p-1a·p-1b. The amidine p-1a (9.06 mg, 10.0 μmol) and the
added to the solution, which was stirred at ambient tempera- carboxylic acid p-1b (6.98 mg, 10.0 μmol) were dissolved in
ture for 3 days. After filtration, the filtrate was evaporated to CHCl3 (5.0 mL). The resultant solution was concentrated
dryness, and the residue was purified by flash column chrom- in vacuo to afford the complex p-1a·p-1b (15.8 mg, 98% yield)
1
atography (SiO2, n-hexane–EtOAc = 4/1 (v/v)) to afford the com- as a white solid. H NMR (500 MHz, CDCl3, 25 °C): δ 13.46 (d,
pound p-4 (4.31 g, 91% yield) as a clear, colorless liquid. 1H J = 8.8 Hz, 2H, N–H), 7.93–7.90 (m, 8H, ArH), 7.80 (d, J =
NMR (500 MHz, CDCl3): δ 7.82–7.79 (m, 2H, ArH), 7.76–7.73 8.4 Hz, 4H, H2,6,2′′,6′′ of acid), 7.74 (t, J = 7.7 Hz, 1H, H5′ of
(m, 2H, ArH), 5.84 (ddt,
CH2CHvCH2), 5.07 (ddt,
J
J
=
=
17.1, 10.3, 6.7 Hz, 1H, amidine), 7.72 (d, J = 8.4 Hz, 4H, H3,5,3′′,5′′ of acid), 7.61–7.54
17.1, 1.9, 1.7 Hz, 1H, (m, 8H, ArH), 7.53–7.49 (m, 6H, H3,5,3′′,5′′,4′,6′ of amidine),
CHvCHZHE), 5.03–5.00 (m, 1H, CHvCHEHZ), 4.33 (t, J = 6.5 7.44–7.36 (m, 3H, H4′,5′,6′ of acid), 7.13 (dd, J = 7.5, 7.3 Hz, 4H,
Hz, 2H, OCH2C4H7), 2.24–2.18 (m, 2H, CH2CHvCH2), m-H of Ph), 7.03 (t, J = 7.5 Hz, 2H, p-H of Ph), 6.77 (d, J =
1.91–1.84 (m, 2H, OCH2CH2C3H5).
7.3 Hz, 4H, o-H of Ph), 6.66 (d, J = 8.3 Hz, 4H, H2,6,2′′,6′′ of
p-1a. CuI (18.8 mg, 0.100 mmol) was added to a solution of amidine), 5.88–5.79 (m, 4H, CH2CHvCH2), 5.09–4.99 (m, 8H,
the compound p-4 (1.26 g, 4.00 mmol) and bis(triphenylpho- CHvCH2), 4.33–4.29 (m, 8H, OCH2C4H7), 3.84–3.77 (m, 2H,
sphine)palladium(II) dichloride (70.2 mg, 0.100 mmol) in Et3N CHN), 2.23–2.17 (m, 8H, CH2CHvCH), 1.89–1.82 (m, 8H,
(20 mL) and THF (40 mL) at ambient temperature for 5 h. To CHvCHCH2CH2), 0.66 (d, J = 6.8 Hz, 6H, CH3CHN).
the reaction mixture was added dropwise a solution of com-
p-2. The amidine p-1a (90.5 mg, 0.100 mmol) and the car-
pound 3a (528 mg, 1.00 mmol) in Et3N (20 mL) and THF boxylic acid p-1b (69.9 mg, 0.100 mmol) were dissolved in dry
(40 mL) at ambient temperature over a period of 1 h, and then toluene (195 mL), and the solution was deoxygenated by
the mixture was stirred for a further 36 h. After the reaction freeze–pump–thaw cycles for 3 times. To this was added a sol-
mixture was evaporated to dryness, the residue was purified by ution of the 1st generation Grubbs’ catalyst (57.5 mg,
column chromatography (NH-SiO2, Et2O–n-hexane = 1/1 to 2/1 69.9 μmol) in toluene (5 mL), and the reaction mixture was
(v/v)) to afford the amidine p-1a (633 mg, 70% yield) as a white stirred at ambient temperature for 9 h under Ar. After the
solid. 1H NMR (500 MHz, CDCl3, p-1a (1.0 mM), CH3CO2H solvent was evaporated to dryness, the residue was purified by
(15 mM), 25 °C): δ 13.21 (br s, 2H, N–H), 8.05–8.02 (m, 4H, column chromatography (NH-SiO2, EtOAc–n-hexane = 2/1 (v/v),
ArH), 7.80 (t, J = 7.8 Hz, 1H, H5′), 7.61–7.58 (m, 4H, ArH), 7.56 then NH-SiO2, CHCl3) to afford p-[1 + 1]macrocycle p-2
(d, J = 7.8 Hz, 2H, H4′,6′), 7.34–7.25 (m, 10H, H3,5,3′′,5′′, m- and (149.1 mg, 96% yield) as a white solid. The p-[1 + 1]macrocycle
p-H of Ph), 7.05 (d, J = 7.2 Hz, 4H, o-H of Ph), 6.74 (d, J = p-2 consists of trans–trans, trans–cis, and cis–cis isomers and
8.4 Hz, 4H, H2,6,2′′,6′′), 5.86 (ddt, J = 17.1, 10.4, 6.7 Hz, 2H, the trans/cis ratio was estimated to be 58 : 42 on the basis of its
CH2CHvCH2), 5.08 (ddt,
J =
17.1, 1.9, 1.7 Hz, 2H, 1H NMR spectrum (see (d) in Fig. 2C). 1H NMR (500 MHz,
CHvCHZHE), 5.05–5.01 (m, 2H, CHvCHEHZ), 4.35 (t, J = 6.6 CDCl3, 25 °C): δ 13.61–13.55 (m, 2H, N–H), 7.86–7.79 (m, 12H,
Hz, 4H, OCH2C4H7), 3.95 (q, J = 6.8 Hz, 2H, CHN), 2.26–2.21 ArH H2,6,2′′,6′′ of acid), 7.78–7.74 (m, 1H, H5′ of amidine),
(m, 4H, CH2CHvCH2), 2.11 (s, 3H, CH3CO2), 1.92–1.86 (m, 7.70–7.65 (m, 4H, H3,5,3′′,5′′ of acid), 7.54–7.46 (m, 8H, ArH),
4H, OCH2CH2C3H5), 0.73 (d, J = 6.8 Hz, 6H, CH3CHN); HRMS 7.45–7.36 (m, 9H, H4′,6′ of amidine, H3,5,3′′,5′′ of amidine from
(ESI, CHCl3–MeOH (1/1, v/v), positive): calcd for [M + H]+
C63H57N2O4: m/z = 905.4318, found: m/z = 905.4310.
=
cis, H4′,5′,6′ of acid), 7.28–7.25 (m, 4H, H3,5,3′′,5′′ of amidine from
trans), 7.18–7.13 (m, 6H, m, p-H of Ph), 6.87–6.81 (m, 4H, o-H
p-1b. CuI (18.8 mg, 0.100 mmol) was added to a solution of of Ph), 6.74–6.71 (m, 4H, H2,6,2′′,6′′ of amidine), 5.53–5.50 (m,
the compound p-4 (1.26 g, 4.00 mmol) and bis(triphenylpho- 4H, CH2CHvCHCH2 [42% cis]), 5.49–5.43 (m, 4H,
sphine)palladium(II) dichloride (70.2 mg, 0.100 mmol) in Et3N CH2CHvCHCH2 [58% trans]), 4.40–4.26 (m, 8H, CO2CH2CH2),
(9.0 mL) and THF (81 mL) at ambient temperature for 5 h. To 3.90–3.84
(m,
2H,
CHN),
2.40–2.31
(m,
8H,
the reaction mixture was added dropwise a solution of com- CO2C2H4CH2CHvCH from cis), 2.25–2.14 (m, 8H,
pound 3b (322 mg, 1.00 mmol) in THF (30 mL) at ambient CO2C2H4CH2CHvCH from trans), 1.95–1.74 (m, 8H,
temperature over a period of 1 h, and then the mixture was CO2CH2CH2CH2), 0.72–0.67 (m, 6H, CH3CHN); HRMS (ESI,
stirred for a further 36 h. After the reaction mixture was evap- MeOH, positive): calcd for [M + Na]+ = C106H86N2O10Na: m/z =
orated to dryness, the residue was purified by column chrom- 1569.6180, found: m/z = 1569.6141.
atography (SiO2, CHCl3–MeOH = 1/0 to 49/1 (v/v)) to afford the
1
carboxylic acid p-1b (516 mg, 74% yield) as a white solid. H
NMR (500 MHz, CDCl3, r.t.): δ 8.04–8.02 (m, 4H, ArH),
7.62–7.59 (m, 8H, ArH), 7.57 (t, J = 8.1 Hz, 1H, ArH), 7.48–7.45
(m, 4H, ArH), 7.42 (d, J = 8.1 Hz, 2H, ArH), 5.86 (ddt, J = 17.1,
Acknowledgements
10.3, 6.7 Hz, 2H, CH2CHvCH2), 5.08 (ddt, J = 17.1, 1.7, 1.6 Hz, This work was supported in part by Grant-in-Aids for Scientific
2H, CHvCHZHE), 5.04–5.01 (m, 2H, CHvCHEHZ), 4.35 (t, J = Research (S) from the JSPS (E.Y.) and for Scientific Research on
6.6 Hz, 4H, OCH2C4H7), 2.26–2.20 (m, 4H, CH2CHvCH2), Innovative Areas, “Emergence in Chemistry” (20111010) from
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the MEXT (Y.F.). Y.N. expresses his thanks for a JSPS Research
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