Diastereomeric Right- and Left-Handed Helical Structures with Fourteen (R)-Chiral Centers

Article abstract of DOI:10.1002/chem.201705306

The relationship between chiral centers and the helical-screw control of their peptides has already been reported, but it has yet to be elucidated in detail. A chiral four-membered ring α,α-disubstituted α-amino acid with a (R,R)-butane-2,3-diol acetal moiety at the γ-position, but no α-chiral carbon, was synthesized. X-ray crystallographic analysis unambiguously revealed that its homo-chiral heptapeptide formed right-handed (P) and left-handed (M) 3₁₀-helical structures at a ratio of 1:1. They appeared to be enantiomeric at the peptide backbone, but diastereomeric with fourteen (R)-configuration chiral centers. Conformational analyses of homopeptides in solution also indicated that diastereomeric (P) and (M) helices existed at approximately equal amounts, with a slight preference toward right-handedness, and they quickly interchanged at room temperature. The circumstances of chiral centers are important for the control of their helical-screw direction.

Full text of DOI:10.1002/chem.201705306

A Journal of
Accepted Article
Title: Diastereomeric Right- and Left-Handed Helical Structures with
Fourteen (R)-Chiral Centers
Authors: Ryo Eto, Makoto Oba, Atsushi Ueda, Tsubasa Uku,
Mitsunobu Doi, Yosuke Matsuo, Takashi Tanaka, Yosuke
Demizu, Masaaki Kurihara, and Masakazu Tanaka
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201705306
Link to VoR: http://dx.doi.org/10.1002/chem.201705306
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Diastereomeric Right- and Left-Handed Helical Structures with
Fourteen (R)-Chiral Centers
Ryo Eto,[a] Makoto Oba,[a] Atsushi Ueda,[a] Tsubasa Uku,[a] Mitsunobu Doi,[b] Yosuke Matsuo,[a] Takashi
Tanaka,[a] Yosuke Demizu,[c] Masaaki Kurihara,[d] and Masakazu Tanaka*[a]
Abstract: The relationship between chiral centers and the helical-
screw control of their peptides has already been reported, but it has
yet to be elucidated in detail. A chiral four-membered ring -
disubstituted -amino acid with a (R,R)-butane-2,3-diol acetal moiety
at the -position, but no -chiral carbon, was synthesized. X-ray
crystallographic analysis unambiguously revealed that its homo-chiral
heptapeptide formed right-handed (P) and left-handed (M) 310-helical
structures at a ratio of 1 to 1. They appeared to be enantiomeric at
the peptide backbone, but diastereomeric with fourteen (R)-
Furthermore, the whole one-handed helical secondary structures
of polymers may be controlled by side-chain chiral centers or non-
covalent chiral molecules.[9] On the other hand, the bicyclic amino
acid (R,R)-Ab5,6=c hexapeptide assumed diastereomeric right-
handed (P) and left-handed (M) helices with twelve chiral centers
at the side chain.[10] Furthermore, in homopeptides composed of
the six-membered ring amino acid (R,R)-Ac6c4BD with a chiral
acetal moiety, helical-screw control appeared to be very weak,
and their structures were unclear[11,12] (Figure 1).
configuration chiral centers.
Conformational analyses of
In the present study, we designed the four-membered ring
dAA[13] (R,R)-Ac4c3BD to study the relationship between chiral
centers and peptide helical-screw control. The (R,R)-Ac4c3BD has
a chiral (R,R)-butane-2,3-diol acetal moiety at the -position, and
the distance between side-chain chiral centers and the peptide
backbone is still far, but becomes shorter than that of the (R,R)-
Ac6c4BD peptide. A cyclobutane ring is not strictly coplanar but
may be regarded as pseudo-coplanar. Thus, two methyl
substituents at the acetal in (R,R)-Ac4c3BD lie in one face of the
peptide bond plane, and may affect the torsion angles of its amino
acid residue,[4] while the steric repulsion of substituents at the i
and i+3 amino acid residues on the helical one-turn may affect the
helical-screw bias.[7] We examined the preferred conformation of
(R,R)-Ac4c3BD homopeptides and revealed that they formed
almost equal amounts of right-handed (P) and left-handed (M)
helices.
homopeptides in solution also indicated that diastereomeric (P) and
(M) helices existed at approximately equal amounts, with a slight
preference toward right-handedness, and they quickly interchanged
at room temperature. The circumstances of chiral centers are
important for the control of their helical-screw direction.
Helical structures are chiral, and may form right-handed (P)
and/or left-handed (M) structures, which have a mirror image
relationship (enantiomeric). The helices of peptides and peptide
segments in proteins are typically right-handed because of the -
chiral centers of L--amino acid residues.[1] The control of the
helical-screw sense of foldamers,[2] including peptides,
peptidomimetics, and polymers, has been reported, and few chiral
centers or only one chiral center may control the helical-screw
sense with a preference for one-handedness. For example, the
helical-screw directions of peptides (or peptide segments) based
on achiral ,-disubstituted -amino acids (dAAs) were shown to
be controlled by a single chiral amino acid,[3,4] by a chiral side-
chain bridge,[5] and by the non-covalent domino effect of a small
chiral molecule.[6]
Toniolo and co-workers,[7] and we[8]
independently reported that the side-chainchiral centers of the
five-membered ring amino acid (S,S)-Ac5cdOM or three-membered
ring amino acid exclusively controlled the helical-screw directions
of their homo-chiral peptides without an -chiral center.
Figure 1. Chemical structures of chiral cyclic amino acids.
[a]
R. Eto, Dr. M. Oba, Dr. A. Ueda, T. Uku, Dr. Y. Matsuo, Prof. T.
Tanaka, Prof. M. Tanaka*
The (R,R)-Ac4c3BD was synthesized as follows (Scheme 1).
The treatment of acetone with Br2 in MeOH, followed by the
exchange of the resulting dimethyl acetal with ethylene glycol
gave 2,2-ethylenedioxy-1,3-dibromoacetone 1 in 71% yield.
According to Pigou’s procedures,[14] a four-membered ring was
constructed by the alkylation of diisopropyl malonate with 1 and
NaH to give the diester 2 in 50% yield. The alkaline hydrolysis of
an ester in 2, followed by the Curtius rearrangement with
diphenylphosphoryl azide (DPPA) and workup with BnOH
afforded the achiral amino acid 3 in 24% yield. The removal of
ethylene acetal, followed by acetalization with (R,R)-butane-2,3-
diol produced the chiral amino acid Cbz-{(R,R)-Ac4c3BD}-OiPr (4)
in 66% yield.[15] The alkaline hydrolysis of 4 gave the C-terminal
free amino acid 5, while the hydrogenolysis of 4 gave an N-
Graduate School of Biomedical Sciences
Nagasaki University
Nagasaki 852-8521 (Japan)
E-mail: matanaka@nagasaki-u.ac.jp
Prof. M. Doi
Osaka University of Pharmaceutical Sciences, Osaka 569-1094
(Japan)
Dr. Y. Demizu
National Institute of Health Sciences
Tokyo 158-8501 (Japan)
[b]
[c]
[d]
Prof. M. Kurihara
Graduate School of Pharmaceutical Sciences
International University of Health and Welfare
Ohtawara 324-8501 (Japan)
Supporting information (SI) for this article is given via a link at the
end of the document.
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terminal free amino acid ester. (R,R)-Ac4c3BD homo-chiral
homopeptides (up to the octapeptide 12) were prepared by
stepwise one amino acid elongation from the C terminus using
not affect 1H NMR spectra in the region of 0.25–1.0 mM; however;
some N–H proton signals at a concentration of 5.0 mM shifted to
a lower magnetic field, which may be due to intermolecular
interactions (Figure S3).
solution-phase
methods
with
1-[{1-(cyano-2-ethoxy-2-
oxoethylideneaminooxy)dimethylamino-
morpholinomethylene}]methanaminium
(COMU) as a coupling reagent.
The NOESY NMR spectrum of 12 in CDCl3 solution showed
the partially sequential correlation dNN from the amide N(3)–H to
N(7)–H, indicative of the helical conformation in the peptide
segment (Figure S4).[8b,17] The 1H NMR spectrum of 12 measured
at room temperature showed eight N–H proton signals at the 
6.04–8.18 region, suggesting that the peptide adopted a single
preferred conformer or several conformers in fast exchange.
Thus, we measured 1H NMR spectroscopies at lowered
temperatures. The 1H NMR spectra of 12 measured at six
different temperatures (−30~+20°C) indicated that each N–H
proton signal observed at 20°C split into two peaks at a ratio of 56
to 44 at lowered temperatures (Figure 2). These results
suggested that the octapeptide 12 adopted two conformers and
interconversion between them was faster than the relevant T1
timescale of 1H NMR spectroscopy at room temperature.[18] We
measured the NOESY NMR spectrum of 12 at −10°C in order to
examine the dNN (i, i+1) correlations of each split N–H signal;
however; dNN (i, i+1) correlations were not observed, whereas dNN’
(i, i) correlations were noted between two splitting N(i)–H signals
(Figure S5).
hexafluorophosphate
Scheme 1. Synthesis of (R,R)-Ac4c3BD and its homo-chiral peptides.
The FT-IR absorption spectra of Cbz-{(R,R)-Ac4c3BD}n-OiPr
(n = 1~8) were measured in CDCl3 solution (Figure S1).
Absorption bands were observed at 3430 cm−1 and 3335–3370
cm−1, and the relative intensity of the latter band increased as the
length of the peptides became longer. On the other hand, a band
derived from the intramolecular hydrogen bond of the N–H···–O–
(acetal) type was not observed at approximately 3370–3390 cm−1.
These FT-IR spectra of peptides were similar to those of achiral
Ac4c peptides, forming 310-helical structures.[16]
1H NMR (400 MHz) experiments for the hepta- and octa-
peptides 11 and 12 by the addition of the hydrogen-bonding
acceptor DMSO-d6 or free-radical TEMPO to CDCl3 solution were
performed. Two N–H chemical shifts were sensitive to the
addition of DMSO-d6, and two N–H peak widths significantly
broadened with the addition of the TEMPO radical. On the other
hand, five or six other N–H peaks were independent of the
addition of DMSO-d6 and the TEMPO radical (Figure S2). These
results suggested that two N–H protons were solvent-exposed;
however, other N–H protons were solvent-shielded, suggesting a
310-helical conformation, in which five N–H in 11 and six N–H in
12 were intramolecularly hydrogen-bonded, while two N-terminal
N–H were not.[16b,c] The concentration of 12 in CDCl3 solution did
Figure 2. Variable temperature 1H NMR spectra (NH region) of the octapeptide
12.
Figure 3 shows the circular dichroism (CD) spectra of Cbz-
{(R,R)-Ac4c3BD}n-OiPr (10-12: n = 6–8) in 2,2,2-trifluoroethanol
(TFE) solution. Weak negative maxima at 208 nm and 222 nm
were observed in the CD spectra of 11 and 12, and a positive
maximum at 192 nm was also noted. These maxima are
characteristic of right-handed (P) helical structures; however, the
intensity of ellipticity was very weak.[19] The intensities of these
maxima in the hexapeptide 10 were extremely weak and neither
maxima at 208 nm or 222 nm were presented. The CD spectrum
of 12 measured in MeOH and MeCN did not display the showed
characteristic shape of a one-handed helical structure (Figure S6).
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a)
b)
c)
Figure 3. CD spectra of Cbz-{(R,R)-Ac4c3BD}n-OiPr {10: n = 6 (― red), 11: n = 7
(― green), 12: n = 8 (― blue)} in TFE solution (concentration: 0.05 mM).
Figure 4. An X-ray crystallographic analysis of the (R,R)-Ac4c3BD heptapeptide
11: a) view perpendicular to the 310-helical axes; the (P)-helix (salmon pink) and
(M)-helix (blue) (chloroform omitted for clarity); b) view along the 310-helical axes
with chloroform molecules; c) Superimposition of the (P) 310-helix and a mirror
image of the (M) 310-helix.
The heptapeptide 11 was a suitable crystal for an X-ray
crystallographic analysis by recrystallization from a mixture of
CHCl3 and n-hexane.[20] The structure was solved in a triclinic P1
space group to show one right-handed (P) 310-helical conformer
A and one left-handed (M) 310-helical conformer B, accompanied
by fifteen chloroform molecules surrounding the lateral position of
310-helices in an asymmetric unit (Figure 4) (Table S1). All  and
 torsion angles of amino acid residues in conformer A showed
minus signs, while those in conformer B showed positive signs.
The average  and  torsion angles in conformer A were −62.9°
and −26.3°, while those in conformer B were +62.6° and +26.3°,
which are consistent with the ideal torsion angles of the 310-helix
(±60°, ±30°).[21] Five intramolecular hydrogen bonds of i+3→i type,
which correspond to the 310-helix, were observed between
N(i+3)–H···O=C(i) (i = 0~4) in conformers A and B (Tables S2 and
S3).
Although the average N–C–C’ () bond angle of the achiral
Ac4c tetrapeptide was reported to be widened to 114.7° from the
normal angle 110~111°, the average N–C–C’ () of 11 was a
regular 111.9° (Table S4).[16c] The distances between the C atom
and plane defined by C, C, and C’ of the amino acid residues
in 11 were within the range of 0.001 Å to 0.419 Å, and their
average was 0.191 Å, indicating that the cyclobutane ring is flatter
than the puckered form. The cyclobutane ring of residue (2) in
conformer A, and those of residues (2) and (3) in conformer B
were coplanar (Table S5).[16c]
The density functional theory (DFT) calculation of 11 with
the B3LYP/6-31G(d,p) level in TFE (polarizable continuum model;
PCM) produced optimized conformers starting from the X-ray
crystallographic structures.[22,23] The energy difference between
the optimized (P) 310-helix and (M) 310-helix was 0.47 kcal/mol,
meaning the existence of (P) and (M) 310-helices at a ratio of 69
to 31 (Table S6).
The one-handed helical-screw sense of peptides has been
reported to be controlled by a covalent or non-covalent single
amino acid or only a few chiral molecules. In contrast, X-ray
crystallographic analysis precisely confirmed that the (R,R)-
Ac4c3BD heptapeptide 11 with covalent-bonded fourteen (R)-
configuration
chiral
centers
unprecedentedly
formed
diastereomeric right-handed (P) and left-handed (M) 310-helical
conformers at a ratio of 1 to 1. The conformational analysis in
solution also indicated that diastereomeric (P) and (M) helical
structures existed in almost equal amounts with a very weak
preference for the right-handed (P) helix, and the (P) and (M)
helical conformers quickly interconverted at room temperature.
The DFT calculation of 11 also supported the experimental results.
The side-chain fourteen chiral centers of the (R,R)-Ac4c3BD
peptide did not or only negligibly influenced the helical-screw bias
of the peptide. Thus, in order to control the one-handed helical
screw, the circumstances of chiral centers are important.
A chiral center at the tethered side chain was previously
reported to induce the helical structures of L--amino acid
peptides, and this strategy may be applied to the enhancement of
target binding affinity.[24] The chiral acetal moiety in the (R,R)-
Ac4c3BD was changeable and may also be used for low pH-
triggering structural changes.[25] Therefore, precisely elucidated
helical secondary structures may be invaluable for designing
The peptide backbones of the (P) helix and (M) helix were
almost enantiomeric, as shown in Figure 4(c); however, both
helices had fourteen (R)-configuration chiral centers, and thus,
were diastereomeric. Conformer A (P) connected to conformer B
(M) via four intermolecular hydrogen bonds to form a chain of
···P···M···P···M···· (Table S3).
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organo-catalysts,[26] cell-penetrating peptides,[27] and target-
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[14] P. E. Pigou, C. H. Schiesser, J. Org. Chem. 1988, 53, 3841.
[15] A chiral acetal moiety in cyclic amino acid could be changed. For
example, the acetalization with (2S,4S)-pentane-2,4-diol afforded a
cyclic amino acid 4’ with a (2S,4S)-pentane-2,4-diol acetal moiety. See
SI.
Acknowledgments
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This work was supported in part by JSPS KAKENHI
Grant Numbers JP-17H03998, and JP-16J03592.
Keywords: amino acid • chirality •conformation analysis •
foldamers • helical structures
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AMBER* (H2O); 10,000 calculations} were performed. See SI.
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Diastereomeric
helix:
The
R. Eto, M. Oba, A. Ueda, T. Uku, M. Doi,
Y. Matsuo, T. Tanaka, Y. Demizu, M.
Kurihara, and M. Tanaka*
relationship between the right-handed
(P) and left-handed (M) helices of the
(R,R)-Ac4c3BD heptapeptide appears to
be enantiomeric at peptide backbone;
Page No. – Page No.
however,
these
helices
are
Diastereomeric Right- and Left-Handed
Helical Structures with Fourteen (R)-
Chiral Centers
diastereomeric because both helices
have fourteen (R)-configuration chiral
centers.
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