A foldable cyclic oligomer: Chiroptical modulation through molecular folding upon complexation and a change in temperature

Article abstract of DOI:10.1021/jo501883m

A foldable cyclic oligomer 1 consisting of three terephthalamide units spaced with a 3-fold o-phenylene unit presented a dynamic pair of enantiomeric forms through molecular folding, to which the external chirality on a ditopic guest [(S,S)-2 or (R,R)-2]

Full text of DOI:10.1021/jo501883m

Article
pubs.acs.org/joc
A Foldable Cyclic Oligomer: Chiroptical Modulation through
Molecular Folding upon Complexation and a Change in Temperature
Ryo Katoono,* Yuki Tanaka, Kenshu Fujiwara, and Takanori Suzuki*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
ABSTRACT: A foldable cyclic oligomer 1 consisting of three
terephthalamide units spaced with a 3-fold o-phenylene unit
presented a dynamic pair of enantiomeric forms through molecular
folding, to which the external chirality on a ditopic guest [(S,S)-2
or (R,R)-2] was supramolecularly transferred to prefer a particular
sense of dynamic helicity [(M,M)-/(P,P)-1 and (M,M,P)-/
(P,P,M)-1]. In the macrocycle, the terephthalamide units acted
as exotopic binding sites to fold into helical forms upon
complexation. The internal chirality associated with a host
[(R,R,R,R,R,R)-1b] had no preference in a helical sense in the
absence of a guest. Instead, the internal chirality was responsible
for the signal modulation that it was cooperatively or competitively
transferred in response to the external chirality on a guest (S,S)-2 or (R,R)-2. During the diastereomeric complexation, a
particular sense of dynamic helicity was favored due to cooperative transmission of chirality when the helical preference was
matched between the host and guest. Alternatively, the host complexed with an antipodal guest underwent a drastic change in
conformation upon a change in temperature.
Scheme 1. (a) A Foldable Cyclic Oligomer Consisting of a
Shape-Persistent Unit and a Folding Unit (Exotopic Binding
Site) and (b) Dynamic Interconversion between a
Nonhelical (Anti) Form and Helical (Syn) Forms of a
Terephthalamide Unit
INTRODUCTION
■
Change in conformation of a host molecule in response to
recognition of a guest molecule is one of the central issues to
study signal transduction and amplification.1 Such a dynamic
host molecule is designed to accompany some spectral
modulation upon the change in conformation.2 In an advanced
system, a host molecule gives a specific response to an analyte,
e.g., each of the enantiomeric guests, through a specific change
in conformation.3 Circular dichroism (CD) signals are useful to
find a change in conformation of a molecule to be chiral.4
There has been particular interest in foldamers5,6 with a goal of
inducing a change in conformation from random to helical
forms in response to a change in the environment, such as
temperature5a−c or solvent,5c−f as well as with the addition of a
guest.7,8 They are designed to prefer a helical form under a
specific condition due to well-defined intramolecular inter-
actions, but adopt a random conformation under other
conditions.
We considered how a foldable oligomer acts in a cyclic
structure that either is highly flexible or does not have a specific
programmed intramolecular interaction among repeating
components. We were interested in a foldable cyclic oligomer
consisting of two components that are alternatively arranged to
form a cyclic structure (Scheme 1a). One component is a
shape-persistent chromophoric unit that enables detection of a
change in conformation by spectroscopy. The other component
is a flexible part that can transform with the addition of a guest.
In such a macrocycle, the molecule could show various patterns
of folding rather than folding into a single pair of right- or left-
handed helices. To promote various types of folding, which are
important in terms of signal modulation, it would be better to
adopt an exotopic type of recognition of a guest rather than an
endotopic recognition such as the encapsulation of a guest in a
cavity presented by a single pair of right- or left-handed
helices.8 To generate an exotopic binding site upon folding, we
Received: August 15, 2014
Published: September 29, 2014
© 2014 American Chemical Society
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used a terephthalamide derivative (Scheme 1b). A syn-form
terephthalamide unit can capture a ditopic guest at the two
amide carbonyls through the formation of hydrogen bonds.9 In
a syn-form, two helical forms are present, in terms of the
direction of twisting of the two amide groups, while an anti-
form is no longer helical due to a local center of symmetry.10
We envisioned a trimeric macrocycle, in which three shape-
persistent o-phenylene units, often used in the design of helical
molecules,11−13 and dynamic terephthalamide units are linked
through triple bonds (Scheme 2). A helically foldable
through molecular folding upon complexation and could prefer
a particular sense of dynamic helicity through supramolecular
transmission of the external chirality of a chiral ditopic guest,9
such as (R,R)-2 and (S,S)-2 (Figure 1). We considered how the
Scheme 2. Chemical Structures of 1 and Dynamic Helicity
[(M)/(P), (M,M)/(P,P), or (M,M,P)/(P,P,M)] Generated
through Molecular Folding at a Terephthalamide Unit(s)
Figure 1. Chemical structures of chiral ditopic guests (R,R)-2 and
(S,S)-2,9a and substructures 3 and 4a9b/4b.
internal chirality could be intramolecularly transferred in a
macrocycle (R,R,R,R,R,R)-1b with a chiral auxiliary (R) on each
amide nitrogen. There was no preferred helical sense in the
absence of a guest (described later). However, it should act as a
chiral handle to prefer a particular sense of dynamic helicity
through the intramolecular transmission of chirality, once
dynamic helicity is generated in the macrocycle through
molecular folding upon complexation. We then investigated
the signal modulation upon transmission of the internal and
external chirality to dynamic helicity generated in the
macrocycle through molecular folding. We examined diaster-
eomeric complexation of (R,R,R,R,R,R)-1b with each of the
enantiomeric guests (R,R)-2 and (S,S)-2, while varying the
equivalent ratios of guest to host, and the temperature (Scheme
3), since an equilibrium is perturbed by such parameters. When
Scheme 3. Chiroptical Modulation by a Foldable Cyclic
Oligomer through Intramolecular (Signal 1) Transmission
of Chirality, and Cooperative (Signal 2) or Competitive
(Signal 3) Transmission of Chirality upon Complexation
and a Change in Temperature
terephthalamide unit with a particular sense of (M)- or (P)-
helicity is arranged by spacing with the V-structure, and it acts
as a binding site when it adopts a syn-form. Otherwise, it might
adopt a nonhelical anti-form and might act as just a linker unit.
In a folded macrocycle, replacement of the two neighboring V-
shaped units with each other, such as 1 and 2, or 2 and 3
depicted in Scheme 2, gives a mirror image, and the two forms
before and after replacement are considered to be an
enantiomeric pair [(M)/(P), (M,M)/(P,P), or (M,M,P)/
(P,P,M), etc.], which may be classified as dynamic helical
molecules13 rather than chiral triangular molecules.14 The
biasing of helicity would be controlled by a preference for a
particular sense of local dynamic helicity of the syn-form
terephthalamide unit(s). The control of helicity in a syn-form
would be enabled by the formation of a complex with a chiral
ditopic guest at the two amide carbonyls through the
supramolecular transmission of chirality, and/or by the
attachment of a chiral auxiliary to each amide nitrogen through
the intramolecular transmission of chirality.
the preference for a particular sense of dynamic helicity is
matched, both internal and external chirality would be
cooperatively transferred to produce strong CD signals. This
was true for a combination of (R,R,R,R,R,R)-1b and (S,S)-2.
Alternatively, each preference competed during transmission of
internal and external chirality in a complex of (R,R,R,R,R,R)-1b
with (R,R)-2, and resulted in production of different signals
from those obtained with (S,S)-2. The host underwent a drastic
change in conformation with a decrease in temperature to
accompany a drastic change in CD signals.
Thus, we designed a tristerephthalamide host 1a to
investigate whether or not it could give a dynamic helical pair
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RESULTS AND DISCUSSION
Preparation and H NMR Characterization of Trister-
■
1
ephthalamides 1a−c. We prepared hosts 1a and 1b [X = Y]
in one step through a 3-fold condensation reaction of a V-
shaped dianiline 5a/b and terephthaloyl chloride,15 and
prepared a derivative 1c with both chiral and achiral
substituents on the amide nitrogens [X = (R)-C*HMe(cHex)
and Y = nBu] through a condensation reaction of dianiline 5b
and an acid chloride (Scheme 4), which was derived from 1,2-
Scheme 4. Preparation of Tristerephthalamides 1a,
(R,R,R,R,R,R)-1b, and (R,R,R,R)-1c
1
Figure 2. (a) H NMR spectra (300 MHz) of 1a in the presence of
(R,R)-2 [0 (1a only), 1, and 2 equiv], and H NMR spectrum of
(R,R)-2. (b) Job plot for the complexation of 1a with (R,R)-2, using
continuous changes (Δδ = δ1a·2 − δ2) in the chemical shift for
phenylene (pale blue) or benzyl protons (pink) of 2 ([1] + [2] = 2
mM). All spectra were measured in CDCl3 at 303 K.
diethynylbenzene16 in a stepwise manner (Scheme S1 in the
Supporting Information). We also prepared a V-shaped
substructure 3, and double-armed substructures 4a9b/b (Figure
1), the latter of which prefers a nonhelical anti-form in the
absence of a guest and adopts helical arm-crossing syn-forms in
a 1:1 complex with a ditopic guest.9b
1
1
In the H NMR spectra of 1a and 1b, measured at room
(0.75 < χ2), which might indicate a further change in
conformation.
temperature, we observed a single set of averaged resonances
that was assigned to D3h for 1a or C3 for 1b (Figure S1 in the
Supporting Information). These observed symmetries should
be due to dynamic interconversion among conformation-
s,13a,b,17 because we observed decoalesced resonances in the
spectra of 1b measured at low temperatures (Figure S3a in the
Supporting Information). It seems reasonable if we consider
that the molecules should avoid a planar and triangular
structure with six trans-amides, as depicted in Scheme 2, due to
the cis-preference in N-alkylbenzanilides.18,19 In the spectrum of
1c, two sets of averaged resonances were present in a 1:2 ratio
as if we superimposed the two spectra of 1a and 1b.
We then monitored the complexation of 1a with each of an
enantiomeric pair of (R,R)-2 and (S,S)-2 by UV and CD
spectroscopy. The UV spectrum of 1a showed two major
absorptions that could be assigned to the diphenylacetylene
unit (290 nm) and longer conjugation through the o-phenylene
group (around 330 nm sh) (Figure 3a),21 and the latter was
attenuated in the presence of 2 (Figure 3b), which might reflect
a change in conformation such as reduction of effective
conjugation due to generation of twisting upon complexation.
Supramolecular Transmission of External Chirality to
Dynamic Helicity upon Complexation of 1a with a Chiral
Ditopic Guest 2. We first investigated the complexation of 1a
with a ditopic guest 2 by monitoring continuous changes in the
1
chemical shift by H NMR spectroscopy. We confirmed that
the host and guest formed a complex by an upfield shift for
both the phenylene protons of a terephthalamide unit in 1a and
the phenylene protons in 2 (Figure 2a). These upfield shifts
indicated that a ditopic guest was captured at the two amide
carbonyls. For some other protons in 1a, far from the binding
site, a small change in the chemical shift was also induced.20
A
Job plot, based on relatively large changes in the chemical shift
for guest protons, revealed that the stoichiometry was 1:2
(Figure 2b), which verified the presence of two syn-form
terephthalamide units in the macrocycle under the condition
([1] + [2] = 2 mM). The complexation-induced chemical shifts
broke the continuity when the guest was excessively added
Figure 3. (a) UV spectra of 1a (bold line), 3 (thin line), and 4a
(dashed line). (b) UV spectra of 1a (9.0 × 10−5 M) in the presence of
(R,R)-2 [0 (1a only, black line), 3, 6, and 12 equiv (blue lines)]. All
spectra were measured in CH2Cl2 at room temperature.
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The two major absorptions were commonly seen in the
spectrum of V-shaped substructure 3 (293 nm and 330 sh nm),
and only the former was found for a double-armed 4a (291
nm). In the CD spectrum of 1a, we found a pair of mirror
images with bisignated Cotton effects in the absorption region
of 1a [321 nm (Δε −15) and 286 (+11) for a solution of 1a in
the presence of (R,R)-2], which continuously increased with
the addition of up to 6 equiv of 2 (Figure 4a). When the guest
in a macrocyclic host by CD spectroscopy. When we gradually
added up to 3 equiv of a chiral guest (S,S)-2 to a solution of
(R,R,R,R,R,R)-1b, the Cotton effects changed continuously
[320 nm (Δε +40), 283 (−97), and 256 (+27)] (Figure 5a),
Figure 5. Continuous changes in the CD spectrum of (R,R,R,R,R,R)-
1b (1.1 × 10−4 M) upon complexation with (a) (S,S)-2 (red lines) or
(b) (R,R)-2 (blue lines) [0 (1b only, black line), 1, 2, and 3 equiv],
measured in CH2Cl2 at 293 K.
Figure 4. (a) Continuous changes in the CD spectrum of 1a (1 × 10−4
M) upon complexation with (R,R)-2 [blue lines, (i) 3, (ii) 6, and (iii)
12 equiv] or (S,S)-2 [red lines, (iv) 3, (v) 6, and (vi) 12 equiv]. (b)
CD spectra of (R,R,R,R,R,R)-1b (bold line), (R,R,R,R)-1c (thin dashed
line), and (R,R)-4b (bold dashed line). All spectra were measured in
CH2Cl2 at 293 K.
and the spectral shape of the induced effects was identical to
that for the complex of 1a with (S,S)-2 (Figure 4a). We
considered that the successful chiroptical enhancement was the
result of the cooperative transmission of the internal (R) and
external (S,S) chirality to dynamic helicity generated in the
complex. Alternatively, the Cotton effects fluctuated upon the
addition of (R,R)-2 (Figure 5b) and indicated a competitive
transmission of chirality to a flexible conformation in the
macrocycle. Also in the cases of using (R,R,R,R)-1c instead of
(R,R,R,R,R,R)-1b, we observed similar responses to each of the
enantiomers (Figure S5 in the Supporting Information). The
shape of the induced Cotton effects for a complex of (R,R,R,R)-
1c with (S,S)-2 (3 equiv) [318 nm (Δε +30), 282 (−48), and
257 (+13)] was common with that for complexes 1a/1b with
(S,S)-2. The result indicated that these hosts adopted a
common structure in each complex and every terephthalamide
unit with X or Y groups can act as a binding site or a linker unit.
Most notably, we found a remarkable difference in the
chiroptical response between the diastereomeric complexes
when we added greater amounts of each of the guests (up to 6
equiv) and changed the temperature (263−313 K) (Scheme 3).
For the complex of (R,R,R,R,R,R)-1b with (S,S)-2, the induced
Cotton effects were further enhanced with an increase in guest
equivalents (6 equiv), and with a decrease in temperature to
263 K, and attenuated with an increase in temperature to 313 K
(Figure 6a). This continuous change while maintaining the
spectral shape can be explained as follows: (1) a dynamic pair
of helical forms such as (M,M)-1b and (P,P)-1b is in
equilibrium, and the population of the major component
increases with a decrease in temperature,24 and (2) the
formation of complexed species is also favored with a decrease
in temperature.25
was further added (12 equiv), the induced Cotton effects were
reduced [321 nm (Δε −10) and 286 (+9)], and we considered
the change as a result of cancellation of local helicity in the
terephthalamide units [e.g., (M,M,P)/(P,P,M)]. The shapes of
the induced Cotton effects for the complexes of 1a with 2 were
similar to that for a 1:1 complex of the double-armed host 4a
with 2, where Cotton effects continuously increased with an
increase in equivalents of the guest throughout the addition
[312 nm (Δε +12) and 283 (−4)], although the sign was
reversed (Figure S4 in the Supporting Information).22 These
results showed that a dynamic helical pair was generated in a
syn-form terephthalamide unit (Scheme 2), and a particular
sense was preferred through the supramolecular transmission of
guest chirality. The chirality in 2 was transferred to the dynamic
helicity of the host to show their own preference under cyclic
or acyclic conditions.
Intramolecular Transmission of Internal Chirality
Associated with Hosts 1b and 1c. The CD spectra of
(R,R,R,R,R,R)-1b and (R,R,R,R)-1c were similar and showed
several negatively signed Cotton effects [341 nm (Δε −8), 318
(−11), 295 (−16), 280 (−4), and 265 (−14) for 1b; 342 nm
(Δε −7), 315 (−11), 302 (−12), 280 (+3), and 260 (−9) for
1c] (Figure 4b),23 and they were totally different from that of
1a in the presence of (R,R)-2 or (S,S)-2 (Figure 4a). A local
chiral auxiliary on the amide nitrogen has some effects even
though a molecule does not adopt a helical form, as shown by
the nonhelical structure of (R,R)-4b in the absence of a guest
(Figure 4b). Thus, we considered that the difference in the
shape of the Cotton effects was the result of a failure in
generation of helical forms through intramolecular transmission
of chirality (R) to 1b or 1c.
For a solution of (R,R,R,R,R,R)-1b in the presence of (R,R)-
2, the spectral shape changed discontinuously upon addition of
the guest up to 6 equiv (Figure 6b, black line) from those
obtained with less than 3 equiv (Figure 5b), and showed
ultimately a response similar to that of the complex with (S,S)-2
upon lowering the temperature (Figure 6b, purple line). These
changes demonstrated that the internal chirality (R) associated
with 1b could be predominantly transferred to dynamic helicity,
Cooperative and Competitive Transmission of Chir-
ality to Dynamic Helicity. We further investigated the intra-
and intermolecular transmission of chirality to dynamic helicity
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(282 mg, 32%) as a white solid. The former fraction containing 1a was
further purified by GPC to give 1a (71 mg) as a white solid in 8%
yield. An analytical sample of 1a was obtained as a white solid by
further purification through GPC, followed by recrystallization from
ethyl acetate.
1
Data of 1a [X = Y = nBu]: mp 199.5−202.5 °C; H NMR (300
MHz, CDCl3, TMS) δ = 7.48 (6H, dd, J = 3.3, 5.7 Hz),26 7.35 (12H,
d, J = 8.4 Hz), 7.26 (6H, dd, J = 3.3, 5.7 Hz),26 7.13 (12H, s), 6.91
(12H, d, J = 8.4 Hz), 3.85 (12H, br t), 1.55 (12H, quin, J = 7.5 Hz),
1.31 (12H, sext, J = 7.5 Hz), 0.87 (18H, t, J = 7.5 Hz) ppm; 13C NMR
(75 MHz, CDCl3) δ = 169.2, 143.1, 137.2, 132.4, 132.0, 128.2, 127.6,
125.2, 121.6, 92.5, 89.3, 50.1, 29.8, 20.1, 13.8 ppm; IR (KBr) 3055,
2956, 2926, 2871, 2211, 1650, 1601, 1561, 1511 cm−1; FD-LRMS m/z
(%) 1656.1 (4) [M + 5]+, 1655.1 (11) [M + 4]+, 1654.1 (31) [M +
3]+, 1653.1 (65) [M + 2]+, 1652.1 (100) [M + 1]+, 1651.1 (81) [M]+;
UV (CH2Cl2) λmax (log ε) 330sh (4.90), 290 (5.11), 276sh (5.06) nm;
FD-HRMS29 m/z calcd for C114H102N6O6 1650.78608 [M]+; found
1650.78573.
Figure 6. VT-CD spectra of (R,R,R,R,R,R)-1b (1.1 × 10−4 M) in the
presence of (a) (S,S)-2 or (b) (R,R)-2 (6 equiv), measured in CH2Cl2
at 263−313 K.
Preparation of (R,R,R,R,R,R)-1b [X = Y = (R)-C*HMe(cHex)].
To an ice-cooled solution of 8b (809 mg, 1.12 mmol) in MeOH/THF
(22 mL/22 mL) was added 60% NaH in oil (1.80 g, 45.0 mmol), and
the mixture was stirred at room temperature for 1 h and then diluted
with dichloromethane. The diluted solution was washed with water
and brine and then dried over MgSO4. After removal of a solid by
filtration, the filtrate was passed over a short column of Al2O3 eluted
with 1:2 dichloromethane/hexane and then concentrated to give 5b
(581 mg) as a yellow amorphous solid in 98% yield. The product was
immediately subjected to the next reaction without further purification
[deprotection of TFA].
once a helical form was sufficiently induced in the macrocycle
by complexation. Alternatively, it was competitive with the
supramolecular transmission of chirality (R,R) in the guest,
which would promote the opposite preference (Figure 4a), at
elevated temperatures or under lower equivalents of guest to
host (<3 equiv). During the complexation, the host underwent
a drastic change in conformation through molecular folding to
produce a drastic change in chiroptical signals upon a change in
temperature.
To a solution of 5b (229 mg, 0.433 mmol) in Et3N/toluene (0.6
mL/1 mL) was added terephthaloyl chloride (105 mg, 0.517 mmol) at
85 °C, and the mixture was stirred at that temperature for 4 h and then
diluted with chloroform. The diluted solution was washed with water
and brine, dried over MgSO4, and then purified by column
chromatography on SiO2 (1:5 ethyl acetate/chloroform) to give two
fractions: one was a mixture containing 1b, and the other gave 6b (103
mg, 35%) as a yellow solid. The former fraction containing 1b was
further purified by repeated preparative TLC on SiO2 (1:5 ethyl
acetate/chloroform), followed by GPC, to give 1b (9 mg) as a white
solid in 3% yield. An analytical sample of 6b was obtained as a white
solid by GPC and recrystallization from toluene.
CONCLUSION
■
We have demonstrated a foldable cyclic oligomer, in which a
shape-persistent unit and a folding unit are repeatedly arranged.
A helically folded (syn-form) terephthalamide unit provided a
dynamic pair of enantiomeric forms in the macrocycle, and the
helical preference was successfully controlled through supra-
molecular transmission of the guest chirality. In addition, the
guest chirality was modulated with the internal chirality through
cooperative or competitive transmission to dynamic helicity
generated by molecular folding. The external chirality (S,S) on
a guest was enhanced with the internal chirality (R) on a host.
For the combination of internal (R,R,R,R,R,R) and external
chirality (R,R), the internal chirality competed with the external
chirality upon transmission under conditions of lower
equivalents of guest to host or elevated temperatures, and the
internal chirality was predominantly transferred to dynamic
helicity once a helical form was sufficiently generated in the
complex. Thus, we demonstrated that a difference in the
structure of a guest triggered different signaling pathways.
Data of (R,R,R,R,R,R)-1b [X = Y = (R)-CH*Me(cHex)]: mp 202−204
°C (dec); [α]2D5 = −158.5 (c = 1.0 in CHCl3); H NMR (400 MHz,
1
CDCl3, TMS) [333 K] δ = 7.45 (6H, dd, J = 3.2, 5.6 Hz),26 7.34 (12H,
d, J = 8.4 Hz), 7.22 (6H, dd, J = 3.2, 5.6 Hz)26 7.08 (12H, s), 6.89
(12H, d, J = 8.4 Hz), 4.33 (6H, br s), 2.05 (6H, br d), 1.84−1.42
(30H, br m), 1.37−1.04 (24H, br m), 1.15 (18H, d, J = 7.2 Hz), 1.02−
0.89 (6H, br m) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.7, 141.6,
137.8, 132.1, 132.0, 129.5, 128.3, 127.9, 125.1, 122.0, 92.4, 89.5, 59.3,
41.4, 30.8, 30.3, 26.2, 26.0, 26.0, 16.7 ppm; IR (KBr) 3058, 2970, 2928,
2851, 2216, 1650, 1600, 1556, 1510 cm−1; FD-LRMS m/z (%)
1980.99 (3) [M + 6]+, 1980.02 (8) [M + 5]+, 1978.99 (20) [M + 4]+,
1977.99 (46) [M + 3]+, 1976.99 (82) [M + 2]+, 1975.99 (100) [M +
1]+, 1974.98 (62) [M]+; UV (CH2Cl2) λmax (log ε) 327sh (4.87), 287
(5.08), 272sh (5.02) nm; CD (CH2Cl2) λ 341 (Δε −8), 318 (−11),
295 (−16), 280 (−4), 265 (−14) nm; FD-HRMS29 m/z calcd for
C138H138N6O6 1975.06778 [M]+; found 1975.06423.
EXPERIMENTAL SECTION
■
Preparation of 1a [X = Y = nBu]. To an ice-cooled solution of 8a
(1.0 g, 1.6 mmol) in MeOH/THF (33 mL/33 mL) was added 60%
NaH in oil (0.65 g, 16 mmol), and the mixture was stirred at room
temperature for 1 h and then diluted with chloroform. The diluted
solution was washed with water and brine, dried over MgSO4, and
then purified by column chromatography on SiO2 (0.5:2.5:7
triethylamine/chloroform/hexane) to give 5a (0.67 g) as a brown
solid in 98% yield. The product was immediately subjected to the next
reaction without further purification [deprotection of TFA].
To a solution of 5a (673 mg, 1.60 mmol) in Et3N/toluene (3 mL/3
mL) was added terephthaloyl chloride (357 mg, 1.76 mmol) at 85 °C,
and the mixture was stirred at that temperature for 30 min and then
diluted with chloroform. The diluted solution was washed with water
and brine, dried over MgSO4, and then purified by column
chromatography on SiO2 (1:3 ethyl acetate/chloroform) to give two
fractions: one was a mixture containing 1a, and the other gave 6a3b
Data of (R,R)-6b [Z = (R)-CH*Me(cHex)]: mp 206−208 °C (dec);
[α]2D5 = −60.0 (c = 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3, TMS)
δ = 7.51 (2H, dd, J = 3.2, 6.0 Hz),26 7.35 (2H, dd, J = 3.2, 6.0 Hz),26
7.27 (4H, d, J = 8.4 Hz),26 7.08 (4H, s), 6.85 (4H, d, J = 8.4 Hz),26
4.34 (2H, br dq), 1.98 (2H, br d), 1.83−1.52 (10H, br m), 1.29−1.06
(8H, br m), 1.22 (6H, d, J = 6.8 Hz), 1.02−0.90 (2H, br m) ppm; 13C
NMR (100 MHz, CDCl3) δ = 169.5, 142.2, 137.9, 131.7, 130.0, 128.3,
128.2, 128.1, 126.9, 121.2, 93.6, 88.5, 60.5, 41.2, 30.7, 30.6, 26.2, 26.0,
25.9, 16.8 ppm; IR (KBr) 3053, 2970, 2932, 2850, 2216, 1644, 1599,
1556, 1510 cm−1; FD-LRMS m/z (%) 661.4 (5) [M + 3]+, 660.4 (17)
[M + 2]+, 659.4 (55) [M + 1]+, 658.4 (100) [M]+; UV (CH2Cl2) λmax
(log ε) 263 (4.58) nm; CD (CH2Cl2) λ 306 (Δε −2), 284 (+1), 272
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(0) nm; elemental analysis calcd (%) for C46H46N2O2 C 83.85, H 7.04,
N 4.25; found C 83.60, H 7.00, N 4.03.
TMS) δ = 7.54−7.50 (4H, m), 7.37 (4H, br d), 7.34−7.28 (6H, m),
7.01 (4H, br s), 6.84 (4H, br d), 4.47 (2H, br s), 2.09 (2H, br d),
1.85−1.53 (10H, br m), 1.33−1.07 (8H, br m), 1.12 (6H, d, J = 6.8
Hz), 1.05−0.91 (2H, br m) ppm; 13C NMR (100 MHz, CDCl3) δ =
170.1, 141.1, 137.9, 132.0, 131.6, 129.5, 128.4, 128.3, 127.5, 122.8,
121.9, 90.7, 88.5, 58.6, 41.4, 30.8, 30.3, 26.2, 26.0, 25.9, 16.7 ppm; IR
(KBr) 3060, 2970, 2932, 2851, 2221, 1649, 1594, 1555, 1509 cm−1;
FD-LRMS m/z (%) 739.39 (4) [M + 3]+, 738.39 (18) [M + 2]+,
737.38 (59) [M + 1]+, 736.38 (100) [M]+; UV (CH2Cl2) λmax (log ε)
306 (4.68), 290 (4.78), 273 (4.65) nm; CD (CH2Cl2) λ 312 (Δε
−13), 300 (−11), 284 (−4), 267 (−6) nm; elemental analysis calcd
(%) for C52H52N2O2 C 84.75, H 7.11, N 3.80; found C 84.60, H 7.05,
N 3.78.
Preparation of (R,R,R,R)-1c [X = (R)-C*HMe(cHex), Y = nBu].
To a refluxed solution of 13 (1.05 g, 0.763 mmol) and BnNEt3Cl (5
mg, 0.02 mmol) in CH2Cl2 (15 mL) was added SOCl2 (0.15 mL, 2.1
mmol), and the mixture was further refluxed for 1 h. After removal of
the solvent by evaporation, the residual solid (13′) was dried in vacuo
and dissolved in toluene (20 mL) [acid chloride preparation].
To a solution of 5b (412 mg, 0.779 mmol) and Et3N (1.1 mL, 7.9
mmol) in toluene (56 mL) was added the freshly prepared toluene
solution (20 mL) containing the acid chloride 13′ at 85 °C, and the
mixture was stirred at that temperature for 2 h and then diluted with
chloroform. The diluted solution was washed with water and brine,
dried over MgSO4, and then purified by column chromatography on
SiO2 (1:4 ethyl acetate/chloroform), preparative TLC on SiO2 (1:3
ethyl acetate/chloroform), and GPC to give 1c (150 mg) as a slightly
colored solid in 11% yield.
Preparation of 8a [Z = nBu]. To a solution of 716 (955 mg, 7.57
mmol) and 15a (6.18 g, 16.7 mmol) in Et3N (62 mL) were added
PdCl2(PPh3)2 (0.58 g, 0.83 mmol) and CuI (0.32 g, 1.7 mmol) under
an argon atmosphere, and the mixture was stirred at 40 °C for 16 h.
After removal of a solid by filtration through a Celite pad, the filtrate
was concentrated and dissolved in chloroform. The solution was
washed with water and brine, dried over MgSO4, and then purified by
column chromatography on SiO2 (chloroform) to give 8a (4.64 g) as a
brown oil in 100% yield. An analytical sample was obtained as a
colorless oil by further purification through GPC (chloroform,
detected by UV 254 nm and RI).
Data of (R,R,R,R)-1c [X = (R)-CH*Me(cHex), Y = nBu]: mp 190−
192 °C (dec); [α]2D6 = −113.3 (c = 1.0 in CHCl3); H NMR (400
1
MHz, CDCl3, TMS) δ = 7.59−7.40 (6H, br m), 7.40−7.29 (8H, br
m), 7.35 (4H, d, J = 8.0 Hz), 7.26−7.21 (6H, br m), 7.12 (4H, s), 7.07
(8H, br s), 6.92 (4H, d, J = 8.0 Hz), 6.88 (8H, br s), 4.44 (4H, br s),
3.85 (4H, br t), 2.07 (4H, br d), 1.88−1.45 (20H+4H, br m), 1.39−
0.78 (12H+20H, br m), 1.31 (4H, sext, J = 7.2 Hz), 0.88 (6H, t, J = 7.2
Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.8, 169.0, 143.1, 141.6
(br), 137.8, 137.8, 137.1, 132.4, 132.0 (br), 129.5 (br), 128.2, 127.8
(br), 127.5, 125.2, 122.0 (br), 121.6, 92.4, 89.5, 89.3, 59.2, 50.2, 41.5,
30.8, 30.3, 29.8, 26.2, 26.0, 26.0, 20.1, 16.7, 13.8 ppm; IR (KBr) 3052,
2928, 2851, 2216, 1650, 1600, 1559, 1510 cm−1; FD-LRMS m/z (%)
1871.94 (7) [M + 5]+, 1870.93 (19) [M + 4]+, 1869.93 (45) [M + 3]+,
1868.92 (81) [M + 2]+, 1867.92 (100) [M + 1]+, 1866.92 (68) [M]+;
UV (CH2Cl2) λmax (log ε) 327sh (4.89), 288 (5.10), 272sh (5.04) nm;
CD (CH2Cl2) λ 342 (Δε −7), 315 (−11), 302 (−12), 280 (+3), 260
(−9) nm; FD-HRMS29 m/z calcd for C130H126N6O6 1866.97388
[M]+; found 1866.97714.
Data of 8a [Z = nBu]: 1H NMR (400 MHz, CDCl3, TMS) δ = 7.60
(4H, d, J = 8.4 Hz), 7.59 (2H, dd, J = 3.6, 5.6 Hz),8 7.37 (2H, dd, J =
3.6, 5.6 Hz),8 7.19 (4H, d, J = 8.4 Hz), 3.74 (4H, t, J = 7.6 Hz), 1.55
(4H, quin, J = 7.6 Hz), 1.34 (4H, sext, J = 7.6 Hz), 0.91 (6H, t, J = 7.6
Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.5 (C(O)CF3),
139.0, 132.5, 131.9, 128.5, 128.5, 125.4, 124.2, 116.4 (CF3), 92.2, 89.9,
51.6, 28.9, 19.8, 13.6 ppm; IR (neat) 3060, 2961, 2938, 2875, 2221,
1697, 1602, 1510 cm−1; FD-LRMS m/z (%) 614.17 (8) [M + 2]+,
613.17 (38) [M + 1]+, 612.17 (100) [M]+; elemental analysis calcd
(%) for C34H30F6N2O2 C 66.66, H 4.94, N 4.57; found C 66.63, H
4.84, N 4.44.
Preparation of 3. To a solution of 5a (305 mg, 0.725 mmol),
DMAP (1 mg, 0.007 mmol), and Et3N (0.20 mL, 1.4 mmol) in
toluene (10 mL) was added benzoyl chloride (0.34 mL, 2.9 mmol),
and the mixture was stirred at 80 °C for 2 h. The reaction mixture was
treated with 1 N NaOH aq and extracted with diethyl ether. The
organic layer was washed with water and brine, dried over MgSO4, and
then purified by column chromatography on SiO2 (1:2 ethyl acetate/
hexane) to give 3 (397 mg) as a yellow amorphous solid in 87% yield.
An analytical sample of 3 was obtained as a white solid by
recrystallization from methanol, followed by GPC.
Preparation of 8b [Z = (R)-C*HMe(cHex)]. To a solution of 716
(2.09 g, 16.6 mmol) and 15b (15.5 g, 36.5 mmol) in Et3N (135 mL)
were added PdCl2(PPh3)2 (1.28 g, 1.83 mmol) and CuI (0.69 g, 3.6
mmol) under an argon atmosphere, and the mixture was stirred at 40
°C for 22 h. After removal of a solid by filtration through a Celite pad,
the filtrate was concentrated and dissolved in chloroform. The solution
was washed with water and brine, dried over MgSO4, and then purified
by column chromatography on SiO2 (4:1 chloroform/hexane) to give
8b (10.1 g) as a dark orange amorphous solid in 85% yield. An
analytical sample was obtained as a white solid by further purification
through GPC.
Data of 3: mp 134.0−134.5 °C; 1H NMR (400 MHz, CDCl3,
TMS) δ = 7.51 (2H, dd, J = 3.2, 5.6 Hz),26 7.36 (4H, d, J = 8.8 Hz),26
7.33−7.28 (6H, m), 7.25−7.16 (6H, m), 6.97 (4H, d, J = 8.8 Hz), 3.94
(4H, t, J = 7.6 Hz), 1.62 (4H, quin, J = 7.6 Hz), 1.38 (4H, sext, J = 7.6
Hz), 0.93 (6H, t, J = 7.6 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ =
170.1, 143.6, 136.0, 132.3, 131.8, 129.7, 128.7, 128.2, 127.8, 127.5,
125.4, 121.2, 92.6, 89.0, 50.1, 29.9, 20.1, 13.8 ppm; IR (KBr) 3055,
2959, 2928, 2865, 2211, 1649, 1600, 1560, 1510 cm−1; FD-LRMS m/z
(%) 631.3 (5) [M + 3]+, 630.3 (16) [M + 2]+, 629.3 (54) [M + 1]+,
628.3 (100) [M]+; UV (CH2Cl2) λmax (log ε) 330sh (4.41), 291 (4.68)
nm; FD-HRMS29 m/z calcd for C44H40N2O2 628.30898 [M]+; found
628.31138; elemental analysis calcd (%) for C44H40N2O2 C 84.04, H
6.41, N 4.46; found C 83.64, H 6.43, N 4.39.
Data of 8b [Z = (R)-C*HMe(cHex)]: mp 70.0−71.0 °C; [α]D26
=
1
−31.0 (c = 1.0 in CHCl3); H NMR (300 MHz, CDCl3, TMS) δ =
7.61−7.58 (4H, br), 7.59 (2H, dd, J = 3.3, 5.7 Hz), 7.37 (2H, dd, J =
3.3, 5.7 Hz),8 7.16 (4H, br d), 4.42 (2H, dq, J = 6.9, 10.2 Hz), 1.97
(2H, br d), 1.86−1.58 (8H, br m), 1.51−1.33 (2H, br m), 1.30−0.83
(10H, br m), 1.12 (6H, d, J = 6.9 Hz) ppm; 13C NMR (75 MHz,
CDCl3) δ = 156.8 (C(O)CF3), 136.0, 132.0, 131.9, 130.8, 129.5,
128.5, 125.4, 124.3, 116.4 (CF3), 92.3, 90.0, 59.8, 40.3, 30.7, 29.7, 26.1,
25.9, 25.8, 16.3 ppm; IR (KBr) 3059, 2981, 2932, 2853, 2221, 1694,
1602, 1510 cm−1; FD-LRMS m/z (%) 723.3 (4) [M + 3]+, 722.3 (15)
[M + 2]+, 721.3 (50) [M + 1]+, 720.3 (100) [M]+; elemental analysis
calcd (%) for C42H42F6N2O2 C 69.99, H 5.87, N 3.89; found C 69.70,
H 5.80, N 3.88.
Preparation of (R,R)-4b [Z = (R)-C*HMe(cHex)]. To a solution
of 9b (584 mg, 0.741 mmol) and phenylacetylene (0.18 mL, 1.6
mmol) in Et3N/THF (20 mL/20 mL) were added Pd(PPh3)4 (77 mg,
0.067 mmol) and CuI (27 mg, 0.14 mmol) under an argon
atmosphere at 40 °C, and the mixture was stirred for 20 h. After
removal of a solid by filtration through a Celite pad, the filtrate was
concentrated and purified by column chromatography on SiO2
(dichloromethane−1:10 ethyl acetate/dichloromethane) and GPC to
give 4b (429 mg) as a white solid in 79% yield. An analytical sample
was obtained as a white solid by recrystallization from ethanol.
Data of (R,R)-4b [Z = (R)-C*HMe(cHex)]: mp 209.0−209.5 °C;
Preparation of 9b [Z = (R)-C*HMe(cHex)]. To a solution of
14b3b (1.69 g, 5.12 mmol) in Et3N/THF (1 mL/35 mL) was added
terephthaloyl chloride (519 mg, 2.56 mmol), and the mixture was
refluxed for 22 h. After removal of the solvent, the residue was purified
by column chromatography on SiO2 (dichloromethane−1:20 ethyl
acetate/dichloromethane) to give 9b (1.42 g) as a white amorphous
solid in 70% yield. An analytical sample of 9b was obtained as a white
solid by washing in refluxed methanol and hexane, followed by
collection through filtration.
Data of 9b [Z = (R)-C*HMe(cHex)]: mp 173.5−175.0 °C; [α]D25
=
[α]2D5 = −180.5 (c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3,
−113.0 (c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3, TMS) δ =
1
1
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7.51 (4H, br d), 7.01 (4H, br s), 6.63 (4H, br d), 4.43 (2H, br s), 2.06
(2H, br d), 1.83−1.52 (10H, br m), 1.33−1.06 (8H, br m), 1.11 (6H,
d, J = 7.2 Hz), 1.04−0.89 (2H, br m) ppm; 13C NMR (100 MHz,
CDCl3) δ = 169.9, 141.0, 137.9, 137.7, 131.3, 127.7, 92.2, 58.8, 41.3,
30.7, 30.3, 26.2, 26.0, 25.9, 16.7 ppm; IR (KBr) 3055, 2928, 2849,
1646, 1581, 1504, 1483 cm−1; FD-LRMS m/z (%) 791.14 (2) [M +
3]+, 790.14 (9) [M + 2]+, 789.13 (42) [M + 1]+, 788.13 (100) [M]+;
elemental analysis calcd (%) for C36H42I2N2O2·(hexane)1/6 C 55.35, H
5.57, N 3.49; found C 55.18, H 5.30, N 3.24.
acidified with 1 N HCl aq, and washed with brine. The organic layer
was dried over MgSO4 and then concentrated to give 13 (238 mg) as a
yellow solid in 96% yield. The product was subjected to the next
reaction without purification.
Preparation of 15a [Z = nBu]. To a solution of 14a28 (4.95 g,
18.0 mmol) and Et3N (3.81 mL, 27.4 mmol) in CH2Cl2 (130 mL) was
added TFAA (3.35 mL, 24.0 mmol) at room temperature, and the
mixture was stirred for 2 h and then diluted with dichloromethane.
The diluted solution was washed with saturated NaHCO3 aq, dried
over MgSO4, and then purified by column chromatography on SiO2
(1:1 dichloromethane/hexane) to give 15a (6.62 g) as a pale yellow oil
in 99% yield. An analytical sample was obtained as a colorless oil by
further purification through GPC.
Preparation of 11. To a solution of 10′3c (111 mg, 0.232 mmol),
which was obtained by deprotection of TMS in 10,3c and 1627 (153
mg, 0.510 mmol) in Et3N/THF (5 mL/5 mL) were added Pd(PPh3)4
(54 mg, 0.047 mmol) and CuI (9 mg, 0.05 mmol) under an argon
atmosphere, and the mixture was stirred at 55 °C for 18 h. The
reaction mixture was diluted with chloroform, washed with water and
brine, dried over MgSO4, and then purified by column chromatog-
raphy on SiO2 (1:10 ethyl acetate/chloroform) to give 11 (166 mg) as
a pale yellow solid in 87% yield. An analytical sample was obtained as a
white solid by further purification through GPC.
1
Data of 15a [Z = nBu]: H NMR (400 MHz, CDCl3, TMS) δ =
7.77 (2H, d, J = 8.8 Hz),8 6.96 (2H, d, J = 8.8 Hz), 3.70 (2H, t, J = 7.6
Hz), 1.53 (2H, quin, J = 7.6 Hz), 1.32 (2H, sext, J = 7.6 Hz), 0.91 (3H,
t, J = 7.6 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.1 (C(
O)CF3), 138.6, 138.4, 130.1, 116.1 (CF3), 94.4, 51.3, 28.6, 19.6, 13.4
ppm; IR (neat) 3065, 2961, 2934, 2874, 1698, 1584, 1486 cm−1; FD-
LRMS m/z (%) 371.98 (19) [M + 1]+, 370.97 (100) [M]+; elemental
analysis calcd (%) for C12H13F3INO C 38.83, H 3.53, N 3.77; found C
38.74, H 3.34, N 3.81.
1
Data of 11: mp 183.0−184.0 °C; H NMR (400 MHz, CDCl3,
TMS) δ = 7.50−7.47 (2H × 2, m), 7.38 (4H, d, J = 8.4 Hz), 7.27−7.25
(2H × 2, m), 7.10 (4H, s), 6.90 (4H, d, J = 8.4 Hz), 3.87 (4H, t, J =
7.6 Hz), 1.56 (4H, br quin), 1.33 (4H, sext, J = 7.6 Hz), 0.89 (6H, t, J
= 7.6 Hz), 0.25 (18H, s) ppm; 13C NMR (100 MHz, CDCl3) δ =
169.2, 143.1, 137.1, 132.4, 132.3, 131.7, 128.2. 128.2, 128.0, 127.5,
125.7, 125.6, 121.7, 103.4, 98.7, 92.4, 89.2, 50.1, 29.8, 20.1, 13.8, 0.0
ppm; IR (KBr) 3058, 2959, 2926, 2870, 2221, 2152, 1634, 1603, 1563,
1511 cm−1; FD-LRMS m/z (%) 824.36 (3) [M + 4]+, 823.36 (11) [M
+ 3]+, 822.35 (34) [M + 2]+, 821.35 (73) [M + 1]+, 820.35 (100)
[M]+; elemental analysis calcd (%) for C54H56N2O2Si2 C 78.98, H
6.87, N 3.41; found C 78.72, H 6.85, N 3.34.
Preparation of 15b [Z = (R)-C*HMe(cHex)]. To a solution of
14b3b (11.05 g, 33.57 mmol) and Et3N (7.1 mL, 51 mmol) in CH2Cl2
(250 mL) was added TFAA (6.2 mL, 44 mmol) at room temperature,
and the mixture was stirred for 1 h and then diluted with
dichloromethane. The diluted solution was washed with saturated
NaHCO3 aq, dried over MgSO4, and then purified by column
chromatography on SiO2 (1:1 dichloromethane/hexane) and
recrystallization from ethanol to give 15b (13.63 g) as a white solid
in 96% yield.
Data of 15b [Z = (R)-CH*Me(cHex)]: mp 83.5−84.5 °C; [α]D25
=
Preparation of 12. Under an argon atomosphere, a mixture of 11
(396 mg, 0.482 mmol), THF (10 mL), MeOH (10 mL), and K2CO3
(133 mg, 0.964 mmol) was stirred at room temperature for 30 min
and then diluted with dichloromethane. The diluted solution was
washed with water and brine and then dried over MgSO4. After
removal of a solid by filtration, the filtrate was concentrated to give 11′
(324 mg) as a yellow solid in 99% yield, which was subjected to the
following reaction without purification [deprotection of TMS].
To a solution of 11′ (324 mg, 0.479 mmol) and 173b (588 mg, 1.20
mmol) in Et3N/THF (10 mL/10 mL) were added Pd(PPh3)4 (111
mg, 96.1 μmol) and CuI (18 mg, 95 μmol) under an argon
atmosphere, and the mixture was stirred at 55 °C for 14 h. The
reaction mixture was diluted with chloroform, washed with water and
brine, dried over MgSO4, and then purified by column chromatog-
raphy on SiO2 (chloroform−ethyl acetate/chloroform) to give 12 (648
mg) as a brown amorphous solid in 96% yield. An analytical sample
was obtained as a yellow solid by further purification through GPC.
Data of 12: mp 126.0−127.5 °C; [α]2D4 = −49.8 (c = 1.0 in CHCl3);
1H NMR (400 MHz, CDCl3, TMS) δ = 7.82 (4H, br d), 7.55−7.47
(2H × 2, br m), 7.43−7.25 (12H, br m), 7.36 (4H, d, J = 8.4 Hz), 7.13
(4H, s), 6.99 (4H, br d), 6.91 (4H, d, J = 8.4 Hz), 4.50 (2H, br s), 3.87
(4H, br t), 3.84 (6H, s), 2.15 (2H, br d), 1.88−1.63 (10H, br m), 1.57
(4H, br quin), 1.38−1.11 (8H, br m), 1.33 (4H, sext, J = 7.6 Hz), 1.22
(6H, d, J = 7.2 Hz), 1.09−0.95 (2H, br m), 0.89 (6H, t, J = 7.6 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ = 169.7, 169.1, 166.1, 142.9,
141.4, 141.2, 137.1, 132.9, 132.2, 132.0, 131.9, 131.9, 130.3, 129.4,
128.9, 128.2, 128.1, 128.0, 127.4, 125.1, 125.0, 122.0, 121.4, 92.4, 92.3,
89.3, 89.1, 59.2, 52.0, 49.9, 41.2, 30.7, 30.2, 29.7, 26.1, 25.9, 25.9, 20.0,
16.7, 13.6 ppm; IR (KBr) 3052, 2929, 2851, 2216, 1725, 1649, 1600,
1559, 1510 cm−1; FD-LRMS m/z (%) 1406.62 (7) [M + 4]+, 1405.62
(22) [M + 3]+, 1404.61 (56) [M + 2]+, 1403.61 (100) [M + 1]+,
1402.61 (95) [M]+; FD-HRMS m/z calcd for C94H90N4O8
1402.67586 [M]+; found 1402.67838; elemental analysis calcd (%)
for C94H90N4O8 C 80.43, H 6.46, N 3.99; found C 77.97, H 6.25, N
3.82.
1
−27.5 (c = 1.0 in CHCl3); H NMR (400 MHz, CDCl3, TMS) δ =
7.75 (2H, br d), 6.92 (2H, br d), 4.41 (1H, dq, J = 6.8, 10.2 Hz), 1.94
(1H, br d), 1.85−1.59 (4H, br m), 1.45−1.33 (1H, br m), 1.27−1.06
(4H, br m), 1.09 (3H, d, J = 6.8 Hz), 1.01−0.88 (1H, br m) ppm; 13C
NMR (100 MHz, CDCl3) δ = 156.7 (C(O)CF3), 138.2, 138.0,
135.7, 132.5, 131.2, 116.4 (CF3), 95.0, 59.5, 40.2, 30.6, 29.7, 26.0, 25.9,
25.7, 16.3 ppm; IR (KBr) 3097, 2987, 2935, 2845, 1685, 1577, 1486
cm−1; FD-LRMS m/z (%) 427.1 (2) [M + 2]+, 426.1 (19) [M + 1]+,
425.0 (100) [M]+; elemental analysis calcd (%) for C16H19F3INO C
45.19, H 4.50, N 3.29; found C 45.06, H 4.28, N 3.04.
ASSOCIATED CONTENT
* Supporting Information
■
S
Supplementary figures (NMR/CD spectra in the presence/
absence of a guest and energy-minimized structures for 1a′),
supplementary scheme, and 1H/13C NMR spectra of new
compounds (1, 3, 4b, 6b, 8, 9b, 11, 12, and 15). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Tel: (+)81-11-706-3396. Fax: (+)81-11-706-2714. E-mail:
katoono@sci.hokudai.ac.jp. E-mail:
■
*Tel: (+)81-11-706-3396. Fax: (+)81-11-706-2714. E-mail:
tak@sci.hokudai.ac.jp
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Kolinski, M.; Plazinska, A.; Jozwiak, K. Curr. Med. Chem.
2012, 19, 1155−1163. (b) Kremer, C.; Lutzen, A. Chem.Eur. J.
̈
2013, 19, 6162−6196.
Preparation of 13. To a solution of 12 (252 mg, 0.179 mmol) in
THF/MeOH (3.6 mL/12 mL) was added a solution of LiOH·H2O
(38 mg, 0.91 mmol) in water (1.2 mL), and the mixture was stirred at
room temperature for 5 h. The mixture was diluted with ethyl acetate,
(2) (a) Wolf, C.; Bentley, K. W. Chem. Soc. Rev. 2013, 42, 5408−
5424. (b) Canary, J. W.; Dai, Z.; Mortezaei, S. Compr. Chirality 2012,
8, 600−624.
10224
dx.doi.org/10.1021/jo501883m | J. Org. Chem. 2014, 79, 10218−10225

The Journal of Organic Chemistry
Article
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dx.doi.org/10.1021/jo501883m | J. Org. Chem. 2014, 79, 10218−10225