Homochiral and heterochiral associations observed in crystals of ArSO2-(Aib)5-OMe

Article abstract of DOI:10.1039/d0ce01267j

The molecular conformations, packing structures and intermolecular interactions of homopentapeptides from achiral α-aminoisobutyric acid (Aib), ArSO2-(Aib)5-OMe (Ar = p-tolyl, p-bromophenyl and p-methoxyphenyl), have been investigated by single-crystal X-

Full text of DOI:10.1039/d0ce01267j

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Homochiral and heterochiral associations
observed in crystals of ArSO2-(Aib)5-OMe†
Cite this: CrystEngComm, 2020, 22,
8353
Hidemasa Hikawa,
Ayaka Takahashi, Shoko Kikkawa,
Ayaka Suzuki,
*
Yoshiki Takahashi, Naruka Sato, Misaki Okayasu
and Isao Azumaya
The molecular conformations, packing structures and intermolecular interactions of homopentapeptides
from achiral α-aminoisobutyric acid (Aib), ArSO2-(Aib)5-OMe (Ar p-tolyl, p-bromophenyl and
=
p-methoxyphenyl), have been investigated by single-crystal X-ray diffraction analysis. The peptides were
folded in 310-helical conformations consisting of two or three consecutive ten-atom intramolecular
hydrogen-bonded β-turns of type III or III′. In the packing mode, left-handed (M) and right-handed (P) 310
-
Received 29th August 2020,
Accepted 28th October 2020
helical molecules formed linear network structures with head-to-tail type intermolecular hydrogen bonds.
Two types of network structures consisting of homochiral sequences (⋯M⋯M⋯M⋯ or ⋯P⋯P⋯P⋯) and
heterochiral sequences (⋯M⋯P⋯M⋯P⋯) were obtained depending on the functional groups or
substituents of the peptides. Interestingly, peptide 1a which has a p-tolyl group crystallized differently when
using a different crystallization medium.
DOI: 10.1039/d0ce01267j
rsc.li/crystengcomm
afforded a crystal with no voids or solvent, in the space group
Introduction
Pbca.5 However, chirality in the helical assembly of the
Helical biopolymers and synthetic polymers are attracting
increasing interest in numerous research fields due to their
unique properties and variety of applications. Oligopeptides
are well-known as bio-based polymeric materials, and
introduction of unnatural amino acids such as
α-aminoisobutyric acid (Aib) into backbones enables the
creation of novel functionalities by their unique structures.1
Aib-rich peptides show a high propensity to form secondary
structural elements, in particular 310- and α-helical structures,
due to the reduction of the accessible region in the
conformational space in the presence of two methyl groups
attached to the α-carbon atom. Furthermore, enantiomeric
left- and right-handed helical conformations are equally
populated in the achiral Aib homopeptides.2 In 1978, Balaram
et al. reported that the X-ray derived crystal structure of Aib
homopentapeptide, Ts-(Aib)5-OMe,3 adopted a defined 310-
helical conformation stabilized by three intramolecular
hydrogen bonds and a network of head-to-tail intermolecular
hydrogen bonds.4 In 1981, Balaram also reported that a
crystalline peptide, i.e., homochiral or heterochiral
association observed in crystals of Ts-(Aib)5-OMe, was not
mentioned in their reports.6 Furthermore, the mechanism of
the formation of the channel structure in the crystal has not
been explained in detail since there have been only a few
investigations into Aib homooligopeptides.
Based on this interesting phenomenon, we explored
whether the packing structures of Aib oligopeptides could be
controlled by the substituents or the recrystallization
conditions. We herein report a solid-state conformational
analysis of the complete homopentapeptides constructed by
the achiral Aib residue having the general formula ArSO2-
(Aib)5-OMe (Ar
=
p-tolyl 1, p-bromophenyl 2, and
p-methoxyphenyl 3). X-ray crystallographic analysis was
employed to characterize the intramolecular hydrogen-
bonding network, and to evaluate the ϕ and ψ torsion angles
in the 310-helical conformations. The crystal packing
structures of these molecules were dramatically different and
interesting from the viewpoint of supramolecular assemblies,
including the formation of channel structures and chiral
association of the molecules, whereas the conformations of
the helical structures were very similar.
¯
triclinic crystal (space group: P1) of Ts-(Aib)5-OMe with
hydrophobic channels was obtained in aqueous methanol
with LiClO4, whereas crystallization from methanol alone
Experimental
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan. E-mail: isao.azumaya@phar.toho-u.ac.jp
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for the new compounds. CCDC 2022589–2022593. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0ce01267j
All of the starting materials and solvents were purchased from
Sigma-Aldrich Japan (Tokyo, Japan), FUJIFILM Wako Pure
Chemical Co. (Osaka, Japan), KANTO CHEMICAL CO., Inc.
(Tokyo, Japan) and TCI Co., Ltd. (Tokyo, Japan). All
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commercially available reagents and solvents were used
without further purification. A CHROMATOREX Q-PACK SI50
(Fuji Silysia Chemical, Ltd., Japan) was used for flash column
chromatography. All melting points were determined using
resulting mixture was stirred at room temperature for 3 days
under argon. The reaction mixture was poured into
dichloromethane (100 mL), washed with 5% KHSO4 aq. (110 mL
× 3), 5% NaHCO3 aq. (110 mL × 3), and brine (110 mL), dried
over Na2SO4, and concentrated in vacuo to give the crude
product (2.02 g, 3.84 mmol, 79%). The crude product was
purified using column chromatography (silica gel, CHCl3/MeOH)
to give the desired product 20 (1.83 g, 71%) as a white solid.
1
Yanaco micro melting point apparatus without correction. H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a JEOL ECS400 spectrometer. IR spectra were measured with
a JASCO FT/IR-4100 spectrometer. Mass spectra were obtained
using a JEOL JMS-700 MStation mass spectrometer.
Typical procedure for ester hydrolysis
Peptide synthesis
To a solution of Ts-(Aib)4-OMe, 20 (1.81 g, 3.43 mmol) in THF
(26 mL) was added to LiOH·H2O (0.448 g, 10.6 mmol) in H2O
(13 mL), and the resulting mixture was stirred at 50 °C for 3
h. After adding LiOH·H2O (0.224 g, 5.3 mmol), THF (13 mL)
and H2O (6.0 mL), the resulting mixture was stirred at 50 °C
for 1.5 h. After the removal of THF in vacuo, the aqueous
solution was extracted with Et2O (150 mL × 3) and acidified
to pH 2 by addition of concentrated hydrochloric acid. The
resulting product was dissolved in AcOEt (100 mL), washed
with brine (150 mL), and concentrated in vacuo. The resulting
precipitate was collected by filtration to give Ts-(Aib)4-OH 21
(1.83 g, 3.58 mmol, quant.) as a white solid, which was used
directly in further steps without any purification.
Syntheses of Balaram's pentapeptide Ts-(Aib)5-OMe 1 and
new pentapeptides ArSO2-(Aib)5-OMe (Ar = p-bromophenyl 2
and p-methoxyphenyl 3) were carried out by conventional
solution-phase methods using
a fragment condensation
strategy with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC) hydrochloride and 1-hydroxybenzotriazole (HOBt) as
coupling reagents via synthetic pathway A (Scheme 1). First,
the
coupling
reaction
of
N-tert-butoxycarbonyl-α,α-
dimethylglycine 4 with methyl 2-aminoisobutyric acid 5 in
the presence of EDC/HOBt afforded dipeptide 6, which was
hydrolyzed using LiOH·H2O to give the corresponding
product 7. After repeating the condensation and hydrolysis
reactions, pentapeptide 12 was obtained. Next, deprotection
of the tert-butoxycarbonyl group under acidic conditions gave
the corresponding amine 13, which was coupled with
benzenesulfonyl chlorides to afford the desired pentapeptides
1–3. Alternatively, after the preparation of sulfonamide 14
from sulfonyl chlorides and Aib substrate 5, desired penta-
peptide 1 was obtained by repeating the condensation
reaction and hydrolysis via synthetic pathway B.
Typical procedure for the preparation of sulfonamides
A
mixture of H-(Aib)5-OMe 13 (48.1 mg, 0.105 mmol),
p-toluenesulfonyl chloride (20.1 mg, 0.105 mmol), triethylamine
(120 μL, 0.86 mmol), and 4-dimethylaminopyridine (2.5 mg,
0.02 mmol) in dichloromethane (1 mL) was stirred at room
temperature for 4 h under argon. The reaction mixture was
poured into dichloromethane (30 mL), then washed with 2 M
HCl aq. (30 mL), water (30 mL), 5% NaHCO3 aq. (20 mL), and
brine (30 mL), dried over Na2SO4, and concentrated in vacuo to
give the crude product (35.1 mg, 0.0574 mmol, 55%). The
resulting compound was recrystallized in n-hexane/EtOAc to give
the desired product 1 (22.1 mg, 0.0362 mmol, 35%) as a
white solid.
Typical procedure for the coupling reaction using EDC/HOBt
To the mixture of Ts-(Aib)3-OH 19 (2.07 g, 4.86 mmol), H-Aib-
OMe·HCl 5 (0.74 g, 4.86 mmol), HOBt·H2O (0.74 g, 4.86 mmol),
and EDC·HCl (1.12 g, 5.8 mmol) in dichloromethane (32 mL), N,
N-diisopropylethylamine (0.85 mL, 4.86 mmol) was added. The
Scheme 1 Preparation of pentapeptides 1–3. Reaction conditions: (a) EDC·HCl (1.2 equiv.), HOBt·H2O (1 equiv.), i-Pr2NEt (1 equiv.), CH2Cl2, rt, 2–3
d; (b) LiOH·H2O (3–6 equiv.), THF, H2O, rt or 50 °C, 2 h; (c) 4 M HCl/AcOEt, rt, 4 h; (d) ArSO2Cl, Et3N (8 equiv.), DMAP (0.2 equiv.), CH2Cl2, rt, 4–5 h.
8354 | CrystEngComm, 2020, 22, 8353–8361
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Ts-(Aib)5-OMe 1 (ref. 4)
data were integrated, and the absorption correction was
calculated using the Rigaku CrystalClear, CrysAlisPro program
package. The structures were solved by SHELXT version 2014/5
and refined by full-matrix least-squares fitting on F2 (SHELXL
versions 2014/7 and 2018/3).7 All non-hydrogen atoms were
refined anisotropically. All N–H hydrogen atoms of the
sulfonamides were found by difference Fourier synthesis. The
other hydrogen atoms were located on the calculated positions.
The crystal data and the structure refinements are summarized
in Tables 1 and S1.† Crystallographic data have been deposited
with the Cambridge Crystallographic Data Center as
supplementary publication numbers CCDC 2022589–2022593.
mp 230–235 °C; IR (KBr) (cm−1): 3337, 1738, 1667, 1651,
1
1526; H NMR (400 MHz, CDCl3): δ 1.36 (s, 6H), 1.48 (s, 6H),
1.51 (s, 6H), 1.53 (s, 6H), 2.46 (s, 3H), 3.69 (s, 3H), 5.47 (br s,
1H), 7.01 (br s, 1H), 7.25 (br s, 1H), 7.33–7.39 (m, 3H), 7.46
(br s, 1H), 7.74 (d, J = 6.4 Hz, 2H); 13C-NMR (100 MHz,
DMSO-d6): δ 21.5, 24.8, 25.2, 25.3, 25.5, 25.8, 52.1, 55.3, 56.2,
56.5, 56.7, 59.2, 79.7, 126.7, 130.1, 140.8, 143.3, 173.6, 174.4,
175.0, 175.3; MS (FAB): m/z 612 [M + H]+; HRMS-FAB: m/z [M
+ Na]+ calcd for C28H45N5O8SNa 634.2887, found 634.2888.
ArSO2-(Aib)5-OMe (Ar = p-bromophenyl) 2
Following the typical procedure for the preparation of
sulfonamides, the reaction of H-(Aib)5-OMe 13 (68.8 mg, 0.15
mmol) with p-bromobenzenesulfonyl chloride (39.4 mg, 0.154
mmol) afforded crude product 2 (53.6 mg, 0.0794 mmol,
53%), which was recrystallized in n-hexane (2 mL)/CHCl3 (1
mL) to give the pure product 2 (25.3 mg, 0.0375 mmol, 25%)
as a white solid. mp 271–277 °C; IR (KBr) (cm−1): 3424, 3357,
Results and discussion
Conformations of pentapeptides 1–3 in the crystalline state
The pentapeptides 1–3 produced suitable single crystals 1a–c,
2, and 3 for X-ray crystallographic analysis via the slow
evaporation of the relevant solvents at room temperature
[crystals 1a (MeOH/toluene), 1b (MeOH/EtOAc) and 1c
(chloroform/THF) of peptide 1; crystal 2 (MeOH/THF) of
peptide 2, and crystal 3 (MeOH/toluene) of peptide 3]. The
crystal structure and diffraction parameters of 1a–c, 2, and 3,
and known crystals A–B reported by Balaram are summarized
in Table 1. The relevant backbone and side torsion angles
and the intra- and intermolecular hydrogen bond parameters
of 1a–c, 2, and 3 are listed in Tables 2 and 3.
1
3322, 1736, 1673, 1651, 1537; H NMR (400 MHz, DMSO-d6):
δ 1.24 (s, 6H), 1.31 (s, 12H), 1.35 (s, 6H), 1.35 (s, 6H), 3.53 (s,
3H), 7.31 (br s, 1H), 7.39 (br s, 1H), 7.50 (br s, 1H), 7.79 (d, J
= 8.9 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 8.02 (br s, 1H), 8.19 (br
s, 1H); 13C-NMR (100 MHz, CD3OD): δ 23.7, 23.9, 24.1, 24.3,
24.6, 51.2, 55.7, 56.4, 56.5, 56.6, 59.0, 127.0, 128.1, 132.2,
142.3, 175.0, 175.2, 175.5, 175.8; MS (FAB): m/z 676 [M + H]+,
678 [M + H + 2]+; HRMS-FAB: m/z [M + Na]+ calcd for C27H42-
N5O8S79BrNa 698.1835, found 698.1836.
Crystal structure of 1a. Crystal 1a of pentapeptide 1
bearing the p-tolyl group was obtained in MeOH/toluene
¯
solution. The crystal belongs to the triclinic space group P1
and contains enantiomeric left-handed (M) and right-handed
(P) helical conformations in the unit cell (Fig. 1a). Disordered
toluene molecules filled the channel space (pore diameter: 4.9
Å), which consisted of helical enantiomers along the direction
perpendicular to the helical axis (Fig. 1b). The edge aromatic
hydrogen atoms on the electron-deficient tosyl ring interacted
with toluene molecules via intermolecular edge-to-face CH/π
aromatic interactions8 [the H to ring-centroid distance is 3.15
Å; the perpendicular distance from the H to the π-plane is
3.00 Å; the point of intersection of this perpendicular to the
plane is offset by 0.97 Å from the ring centroid; the
interacting aromatic rings adopt an orthogonal (85°) edge-
tilted-T arrangement] (Fig. 1c). The mean ϕ and ψ torsion
angles for the Aib residues (1–4) are +52.6° and +29.3° for the
left-handed helical conformation (Fig. 1d), which are close to
those for the ideal 310-helix conformations (+57° and +30°,
respectively).9 Reversal of the torsion angle signs was
observed at the C-terminal Aib(5) residues (ϕ5 = −47.8°, ψ5 =
−47.4°), which is frequently observed in 310-helical Aib. The
deviations of the ω angles for the Aib residues (1–5) from the
ideal value for the trans planar peptide bonds (180°) are small
(the average value is 4.6°). Three intramolecular i ← i + 3 type
hydrogen bonds with three consecutive type III′ β-turns were
found in the 310-helical molecules. They were located between
N(3)–H of Aib(3) and the SO oxygen atom in the SO2 group
[N(3)⋯O(SO2) = 3.01 Å], between N(4)–H of Aib(4) and O(1) of
ArSO2-(Aib)5-OMe (Ar = p-methoxyphenyl) 3
Following the typical procedure for the preparation of
sulfonamides, the reaction of H-(Aib)5-OMe 13 (46.1 mg, 0.10
mmol) with p-methoxybenzenesulfonyl chloride (26.9 mg,
0.130 mmol) afforded crude product 3 (36.4 mg, 0.058 mmol,
58%), which was recrystallized in n-hexane (2 mL)/CHCl3 (1
mL) to give the desired product 3 (27.2 mg, 0.0434 mmol,
43%) as a white solid. mp 227–235 °C; IR (KBr) (cm−1): 3350,
1
1728, 1668, 1652, 1520; H NMR (400 MHz, DMSO-d6): δ 1.22
(s, 6H), 1.31 (s, 12H), 1.35 (s, 6H), 1.36 (s, 6H), 3.53 (s, 3H),
3.84 (s, 3H), 7.13 (d, J = 8.9 Hz, 2H), 7.34 (br s, 1H), 7.38 (br
s, 1H), 7.56 (br s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.93 (br s, 1H),
8.03 (br s, 1H); 13C-NMR (100 MHz, DMSO-d6): δ 24.8, 25.2,
25.3, 25.5, 25.8, 52.1, 55.3, 56.2, 56.5, 56.7, 59.1, 114.9, 128.9,
135.2, 162.7, 173.6, 174.4, 175.0, 175.1, 175.3; MS (FAB): m/z
628 [M + H]+; HRMS-FAB: m/z [M + Na]+ calcd for C28H45N5O9-
SNa 650.2836, found 650.2836.
X-ray crystallography
Single crystals were mounted on
a loop for the X-ray
measurements. Diffraction data were collected on an X-ray
diffractometer (Rigaku XtaLAB P200) equipped with a rotating
anode X-ray source (with multi-layer mirror monochromated
Mo-Kα, α = 0.71075 Å, and Cu-Kα, α = 1.54187 Å) and a hybrid
photon counting detector (PILATUS 200 K) at 93 K. The frame
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Table
2
Torsion angles (ω, ϕ, and ψ) as determined by X-ray
crystallographic analysis
1a
128.9(1)
45.6(2)
35.8(2)
173.1(1)
57.2(2)
29.0(2)
1b
113.9(1)
58.3(2)
26.9(2)
1c
2
3
ω0
ϕ1
ψ1
ω1
ϕ2
ψ2
ω2
ϕ3
ψ3
ω3
ϕ4
ψ4
ω4
ϕ5
ψ5
ω5
95.9(3)
70.2(4)
30.2(4)
−83.7(3)
−68.8(3)
−33.3(3)
87.4(2)
61.4(2)
37.6(2)
171.9(2)
55.6(2)
33.1(2)
177.6(2)
58.5(2)
20.7(2)
−179.2(1)
172.5(3)
53.5(4)
−168.9(2)
−60.9(3)
−16.3(3)
173.0(2)
−48.2(3)
−35.2(3)
−180.0(2)
−51.9(3)
−42.6(3)
−178.3(2)
52.0(3)
47.4(2)
39.9(2)
171.2(1)
57.7(2)
32.3(2)
176.4(1)
64.2(2)
34.4(4)
179.7(1)
59.3(2)
16.3(2)
176.3(3)
54.6(4)
34.2(4)
−170.1(2)
177.1(3)
60.1(4)
−174.6(2)
48.2(2)
53.8(2)
31.9(2)
36.2(2)
24.3(2)
27.2(4)
174.0(1)
−47.8(2)
−47.4(2)
−179.9(2)
168.8(1)
−48.2(2)
−40.7(2)
176.4(2)
−170.5(3)
−50.9(4)
−51.9(4)
−175.3(3)
179.3(2)
−48.9(2)
−48.1(2)
−177.6(2)
34.2(3)
179.6(2)
Aib(1) [N(4)⋯O(1) = 2.96 Å], and between N(5)–H in Aib(5)
and O(2) in Aib(2) [N(5)⋯O(2) = 2.94 Å]. Despite that the cell
dimensions of 1a containing toluene molecules were different
from those of known crystal A grown in aqueous MeOH
containing 0.5 equivalents LiClO4, this crystal also belongs to
¯
the triclinic space group P1 (see Table 1).
The helices are linked in head-to-tail alignments along the
backbone by a network of intermolecular hydrogen bonds
between N(1)–H of Aib(1) and O(4′) of Aib(4′) in neighboring
Table 3 Intra- and intermolecular H-bond parameters
d (Å)
Acceptor D⋯A
Angle (°)
D–H⋯A
Symmetry
operations
Donor
1a
N(3)–H O(SO2)
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
1b
3.012(2) 149.76(10) x, y, z
2.961(2) 163.91(10) x, y, z
2.938(2) 168.77(10) x, y, z
2.785(2) 175(2)
x, −1 + y, z
N(3)–H O(SO2)
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
1c
2.969(2) 156.16(10) x, y, z
3.048(2) 151.71(9)
3.034(2) 163.85(9)
2.784(2) 168(2)
x, y, z
x, y, z
x, 1.5 − y, −1/2 + z
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
2
2.92(4)
2.980(3) 144.2(18)
2.761(4) 167.1(2)
151.6(2)
x, y, z
x, y, z
x, 1/2 − y, −1/2 + z
N(3)–H O(SO2)
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
3
3.052(3) 167.89(15) x, y, z
3.070(3) 169.23(13) x, y, z
2.867(3) 135.26(14) x, y, z
2.928(3) 172(4)
−1/2 + x, 1.5 − y, 1/2 + z
N(3)–H O(SO2)
N(4)–H O(1)
N(5)–H O(2)
N(1)–H O(4′)
2.958(2) 161(2)
2.962(2) 164(2)
2.964(2) 169(2)
2.761(2) 169(2)
x, y, z
x, y, z
x, y, z
x, −1 + y, z
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Fig. 2 (a) Packing of crystal 1a for the left-handed 310-helix (yellow)
and right-handed 310-helix (blue) along the a-axis (side). The network
of intramolecular hydrogen bonds is indicated by sky blue lines, and
intermolecular hydrogen bonds are indicated by magenta lines. (b)
Intermolecular CH/π interactions are indicated by orange lines.
1b were consistent with those of crystal B grown in MeOH
alone reported by Balaram (Table 2). The average values of
the torsion angles ϕ and ψ for the residues (1–4) were +56.9°
and +30.9° for the left-handed helix, which are comparable to
those observed for 310-helices in the Aib homopeptides.
Reversed signs of the torsion angles were observed at the
C-terminal Aib(5) residues (ϕ5 = −48.2°, ψ5 = −40.7°). The
intramolecular hydrogen bonding pattern for the molecules
was typical for a 310-helix consisting of i ← i + 3 type
hydrogen bonds, which were found between N(3)–H and
O(SO2) [N(3)⋯O(SO2) = 2.97 Å], between N(4)–H and O(1)
[N(4)⋯O(1) = 3.05 Å], and between N(5)–H and O(2) [N(5)
⋯O(2) = 3.03 Å]. The molecules were linked by a network of
intermolecular hydrogen bonds between N(1)–H of Aib(1) and
O(4′) of Aib(4′) in neighboring molecules [N(1)⋯O(4′) = 2.78
Å]. However, the packing mode for 1b dramatically changed
compared to that for crystal 1a. The two left-handed (M) and
right-handed (P) 310-helical molecules were alternately
connected head-to-tail by intermolecular hydrogen bonds
along the b-axis, resulting in heterochiral chains that
consisted of alternating enantiomers, i.e., ⋯M⋯P⋯M⋯P⋯
(Fig. 3). No intermolecular hydrogen bonds were observed
between the heterochiral chains.
Fig. 1 (a) X-ray diffraction structure of crystal 1a for the left-handed
310-helix (yellow) and right-handed 310-helix (blue) along the a-axis.
The toluene molecule is shown in grey. The hydrogen atoms have
been removed for simplicity. (b) Channel structure along the direction
perpendicular to the helical axis. Toluene molecules were removed. C
atoms are shown in grey, N in light blue, O in red, H in light gray and S
in yellow. (c) Intermolecular edge-to-face CH/π aromatic interactions
highlighted by orange lines. (d) Left-handed (M) 310-helix viewed
perpendicular to the helical axis (side) and along the helical axis (top)
with the intramolecular hydrogen-bonding interactions present in the
solid-state highlighted by sky blue lines.
molecules [N(1)⋯O(4′) = 2.79 Å]. Interestingly, the one-
handed enantiomers were aligned along the b-axis and
connected through the hydrogen bonding network, i.e.,
⋯M⋯M⋯M⋯ or ⋯P⋯P⋯P⋯, resulting in homochiral
chains of the peptides (Fig. 2a). Furthermore, the crystal
packing showed the presence of intermolecular CH/π
interactions between the C–H bond of the methyl in the
p-tolyl group and the phenyl ring (CH⋯π-plane = 3.15 Å)
(Fig. 2b). Therefore, the enantiomeric helical chain units
faced each other by intermolecular CH/π interactions,
whereas intermolecular hydrogen bonds were not observed
between the opposite enantiomeric networks.
Crystal structure of 1b. The crystal 1b, which was obtained
in MeOH/EtOAc solution, belongs to the orthorhombic space
group Pbca and contains left-handed (M) and right-handed
(P) 310-helical molecules. The void space in the unit cell was
small and not capable of including any solvent molecules.
The space group, cell dimensions, and packing structure of
Crystal structure of 1c. The crystal 1c obtained in
chloroform/tetrahydrofuran belongs to the monoclinic
space group P21/c. The crystal contains left-handed (M)
and right-handed (P) 310-helices in the unit cell with no
void spaces, and chloroform and tetrahydrofuran molecules
existed as crystal solvents. Intermolecular oxygen–halogen
interactions were observed between the Cl atom of
chloroform and the oxygen atom of the SO2 group, where
the Cl⋯O distance of 3.00 Å is less than the sum of the
respective van der Waals radii (3.27
Å
for Cl⋯O)
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C-terminal Aib(5) residues (ϕ5 = 52.0°, ψ5 = 34.2°). Three
intramolecular hydrogen bonds of the i ← i + 3 type were
found between N(3)–H and O(SO2) [N(3)⋯O(SO2) = 3.05 Å],
between N(4)–H and O(1) [N(4)⋯O(1) = 3.07 Å], and between
N(5)–H and O(2) [N(5)⋯O(2) = 2.87 Å]. In the packing mode,
the two left-handed (M) and right-handed (P) 310-helical
molecules were alternately connected head-to-tail by
intermolecular hydrogen bonds along the helical axis,
resulting in heterochiral chains that consisted of alternating
Fig. 3 Packing of 1b for the left-handed 310-helix (yellow) and
right-handed
310-helix (blue) viewed perpendicular to the helical
axis. The network of intramolecular hydrogen bonds is indicated by
sky blue lines, and intermolecular hydrogen bonds are indicated by
magenta lines.
enantiomers,
i.e.,
⋯M⋯P⋯M⋯P⋯
(Fig.
5).
No
intermolecular hydrogen bonds were observed between the
heterochiral chains.
(Fig. 4a).10 The average values of the torsion angles ϕ and
ψ for the residues (1–4) were +59.6° and +31.5° for the
left-handed helices. Reversed signs of the torsion angles
Crystal structure of 3. Crystals of pentapeptide 3 bearing
the p-methoxyphenyl group were obtained in a MeOH/toluene
solution. The crystals belong to the triclinic system and space
were observed at the C-terminal Aib(5) residues (ϕ5
=
¯
−50.9°, ψ5 = −51.9°). Two intramolecular hydrogen bonds
of the i ← i + 3 type were found between N(4)–H and
O(1) [N(4)⋯O(1) = 2.93 Å] and between N(5)–H and O(2)
[N(5)⋯O(2) = 2.98 Å]. The two left-handed (M) and right-
handed (P) 310-helical molecules were alternately connected
head-to-tail by intermolecular hydrogen bonds along the
b-axis, resulting in heterochiral chains that consisted of
alternating enantiomers, i.e., ⋯M⋯P⋯M⋯P⋯ (Fig. 4b).
Crystal structure of 2. The crystals of pentapeptide 2
bearing the p-bromophenyl group were obtained in a MeOH/
THF solution. The crystals belong to the monoclinic space
group P21/n and contain left-handed (M) and right-handed
(P) 310-helices in the unit cell. The crystal may include some
disordered solvent molecules. Removal of the solvent
molecules and subsequent refinement were executed using
SQUEEZE, a part of the PLATON program.11 The mean values
of the ϕ and ψ torsion angles for the Aib residues (1–4) were
−57.5° and −31.9° for the right-handed helical conformation.
Reversal of the torsion angle signs was observed at the
group P1. The unit cell consists of left-handed (M) and right-
handed (P) helical molecules (Fig. 6a). Disordered toluene
molecules filled the channel spaces (pore diameter: 6.5 Å),
which consisted of helical enantiomers along the direction
perpendicular to the helical axis (Fig. 6b), and the edge
aromatic hydrogen atoms of the p-methoxyphenyl group
interacted with toluene molecules via intermolecular edge-to-
face CH/π aromatic interactions [the H to ring-centroid
distance is 2.97 Å; the perpendicular distance from the H to
π-plane is 2.96 Å; the point of intersection of this
perpendicular to the plane is offset by 0.24 Å from the ring
centroid; the interacting aromatic rings adopt orthogonal
(47°) edge-tilted-T arrangements] (Fig. 6c). The mean ϕ and ψ
torsion angles for the amino acid residues (1–4) were +57.3°
and +30.9° for the left-handed helical conformation. Reversal
of the torsion angle signs was observed at the C-terminal
Aib(5) residues (ϕ5
=
−48.9°, ψ5
=
−48.0°). Three
intramolecular i ← i + 3 type hydrogen bonds were found in
the 310-helical molecules. They were located between N(3)–H
of Aib(3) and the SO oxygen atom of the SO2 group [N(3)
⋯O(SO2) = 2.96 Å], between N(4)–H of Aib(4) and O(1) of
Aib(1) [N(4)⋯O(1) = 2.96 Å], and between N(5)–H of Aib(5)
and O(2) of Aib(2) [N(5)⋯O(2) = 2.96 Å]. In the packing mode,
the left-handed (M) and right-handed (P) 310-helical
molecules each formed homochiral sequences as straight
chains, which were linked in a head-to-tail fashion via
intermolecular hydrogen bonds along the backbone, i.e.,
⋯M⋯M⋯M⋯ or ⋯P⋯P⋯P⋯ (Fig. 6d), which was almost
the same packing mode as crystal 1a. Furthermore, the
crystal packing showed the presence of an intermolecular
CH/π interaction between the C–H bond of the methoxy
Fig. 4 (a) Halogen bond between the Cl atom of chloroform and the
oxygen atom of the SO2 group is shown by a red line in the crystal
structure of 1c. The hydrogen atoms were removed for simplicity. C
atoms are shown in gray, N in light blue, O in red and Cl in green. (b)
Packing of 1c for the left-handed 310-helix (yellow) and right-handed
Fig. 5 Packing of 2 for the left-handed 310-helix (yellow) and right-
handed 310-helix (blue) viewed perpendicular to the helical axis. The
network of intramolecular hydrogen bonds is indicated by sky blue lines,
and intermolecular hydrogen bonds are indicated by magenta lines.
310-helix (blue) viewed perpendicular to the helical axis. The network
of intramolecular hydrogen bonds is indicated by sky blue lines, and
intermolecular hydrogen bonds are indicated by magenta lines.
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chain units faced each other by an intermolecular CH/π
interaction, whereas intermolecular hydrogen bonds were not
observed between the opposite enantiomeric networks.
The investigation of molecular conformations, packing
structures and intermolecular interactions in Aib penta-
peptides 1–3 indicated that two remarkably different types of
intermolecular hydrogen bonding network structures such as
homochiral sequences (⋯M⋯M⋯M⋯ or ⋯P⋯P⋯P⋯) and
heterochiral sequences (⋯M⋯P⋯M⋯P⋯) were formed in
the solid state. Notably, dramatic changes were caused by
switching the crystallization solvents, forming the
homochiral chains in crystal 1a. These results have given us
mechanistic insights into the formation of crystal 1a as
follows: 1)
a
homochiral chain (⋯M⋯M⋯M⋯ or
⋯P⋯P⋯P⋯) forms between the enantiomers with the same
handedness via intermolecular hydrogen bonds along the
b-axis, followed by weakly interacting opposite enantiomeric
helical chain units facing each other that contain toluene
molecules by intermolecular CH/π interactions, 2) two-
dimensional layers form along the a-axis through self-
assembly with adjacent 1D chain units, and 3) self-assembly
of the 2D layers along the c-axis occurs (Fig. 7). At this time,
we have only obtained racemic compounds that contain
equal amounts of both enantiomeric helices in the unit cell.
However, if one-handed enantiomeric 2D molecular networks
are formed through axially chiral self-assemblies of
homochiral 1D chains, homochiral associations of 2D sheets
would occur to give conglomerate crystals.12 To the best of
our knowledge, there is no example of chiral crystallization
of achiral oligopeptides, while the formation of
Fig. 6 (a) Crystal structure of 3 for the left-handed 310-helix (yellow)
and right-handed 310-helix (blue) viewed down the a-axis. (b) Channel
structure. The toluene molecules were removed for clarity. (c)
Intermolecular edge-to-face aromatic–aromatic interaction is
highlighted by green lines. (d) Packing of crystal
3
viewed
perpendicular to the helical axis. The intramolecular hydrogen bonds
are indicated by sky blue lines. The intermolecular hydrogen bonds are
indicated by magenta lines. (e) Intermolecular CH/π interactions are
indicated by orange lines.
Fig. 7 Proposed mechanism for the formation of crystal 1a. (a)
Homochiral 1D chains via hydrogen bonds along the b-axis. (b) 2D
layers along the a-axis form. (c) Assemblies of the 2D layers along
the c-axis.
group and the phenyl ring (the H to ring-centroid distance is
3.31 Å) (Fig. 6e).9 Therefore, each of the enantiomeric helical
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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Fig. 8 Channel-shaped network structures of 1a and 3 highlighting
the left-handed 310-helix (yellow), right-handed 310-helix (blue), and
toluene molecules (gray) as a space-filling model. The orange columns
indicate the channel-shaped network structure.
conglomerates from mixed enantiomers has been observed
in numerous molecules. Therefore, the homochiral
association observed in the crystals is attractive for producing
chiral crystals from achiral compounds.13
Crystals 1a and
3 formed channel-shaped network
structures consisting of enantiomeric helical molecules
with toluene molecules (Fig. 8). Our results suggest that
the preference for the different packing structures could
be finely tuned by several factors such as the
substituents of the pentapeptides and the nature of the
solvents used for crystallization, via intermolecular
hydrogen bonds and CH–π interactions, thus offering
attractive packing arrangements in the development of
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3 M. T. Leplawy, D. S. Jones, G. W. Kenner and R. C.
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6 The crystal structures of Z-(Aib)n-OR have been reported, see:
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Conclusions
Aib pentapeptides 1–3 formed networks of 310-helical
molecules with linear head-to-tail type intermolecular
hydrogen bonds. In this study, we demonstrated two
remarkably different types of network structures: homochiral
and heterochiral 1D chains consisting of enantiomeric 310-
helices in the solid-state. Furthermore, crystals 1a and 3
formed channel-shaped network structures, whose inner
spaces were occupied by toluene as a guest molecule. The
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form intermolecular hydrogen bonds or CH–π interactions.
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11 In the crystal of 2, highly disordered or partially occupied
solvent molecules located in two independent voids, which
were probably water molecules, were unable to be modeled.
Reflection contributions from this solvent molecule were
fixed and added to the calculated structure factors using the
12 K. Katagiri, T. Sakai, M. Hishikawa, H. Masu, M. Tominaga,
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