A cyclochiral conformational motif constructed using a robust hydrogen-bonding network

Article abstract of DOI:10.1021/ja407051k

A novel conformational motif constructed with a robust intramolecular hydrogen-bonding (H-bonding) network was discovered. A pyrrolidine derivative possessing four identical amide substituents at C(2) and C(5) formed a strong intramolecular H-bonding network consisting of all the amide groups. This conformation yielded a cyclochiral structure with a handedness that depended on the directionality of the H-bonding network. The most stable compound was isolated and applied to the acylative kinetic resolution of secondary alcohol. The handedness of the H-bonding network was biased by the presence of chiral substituents, and the preferred direction could be switched under an external stimulus. A structural analysis using NMR, X-ray crystallography, and theoretical calculation techniques indicated that the conformation of the substituents was highly ordered and depended on the directionality of the H-bonding network.

Full text of DOI:10.1021/ja407051k

Communication
pubs.acs.org/JACS
A Cyclochiral Conformational Motif Constructed Using a Robust
Hydrogen-Bonding Network
Kenji Mishiro,* Takumi Furuta,* Takahiro Sasamori, Kazuhiro Hayashi, Norihiro Tokitoh, Shiroh Futaki,
and Takeo Kawabata
Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
S
* Supporting Information
the basicity of a H-bonding acceptor, the bond length, and the
ABSTRACT: A novel conformational motif constructed
with a robust intramolecular hydrogen-bonding (H-
bonding) network was discovered. A pyrrolidine derivative
possessing four identical amide substituents at C(2) and
C(5) formed a strong intramolecular H-bonding network
consisting of all the amide groups. This conformation
yielded a cyclochiral structure with a handedness that
depended on the directionality of the H-bonding network.
The most stable compound was isolated and applied to the
acylative kinetic resolution of secondary alcohol. The
handedness of the H-bonding network was biased by the
presence of chiral substituents, and the preferred direction
could be switched under an external stimulus. A structural
analysis using NMR, X-ray crystallography, and theoretical
calculation techniques indicated that the conformation of
the substituents was highly ordered and depended on the
directionality of the H-bonding network.
geometry (extent of orbital overlap) governing the donor and
acceptor can critically affect the stability of a H-bonding.5
Recently cumulative stabilizing effect of multiple H-bonding is
attracting intense attention. Jorgensen suggested the impor-
tance of secondary electrostatic interactions in the stability of
contiguous H-bonding array.6 Kass explored the synergetic
stabilizing effects of an appropriately arranged continuous H-
bonding array. The synergetic stabilizing effects of the
continuous H-bonding have been applied toward the develop-
ment of strong Brønsted acids and bases.7 These cumulative
stabilizing effects might be also useful for the design of a robust
higher-order structure.
We developed several nucleophilic catalysts based on the 4-
pyrrolidinopyridine (PPY) structure, which features amide
substituents.8 These catalysts were effective for the regiose-
lective monoacylation of polyols8a and the acylative kinetic
resolution and desymmetrization of diols.8b−d During the
course of the catalyst development process based on PPY
derivatives, we synthesized compound 1 having four identical
1
igher-order structures of proteins, such as α-helices and
amide substituents at the pyrrolidine moiety. The H NMR
H
β-sheets, are supported by a continuous hydrogen-
bonding (H-bonding) network constructed from alternating
sequences of N−H and CO moieties in a series of amide
groups on the protein backbone.1 Continuous H-bonding array
is also widely employed to construct artificial helical2 and sheet3
structures. Rebek and other groups have reported cavity and
capsule shaped functional molecules constructed using a
continuous H-bonding network.4
spectra of 1 displayed four identical amide protons as two sets
of nonequivalent signals at a quite low field (12.17 and 11.95
ppm). The chemical shifts of these amide protons did not
depend on the concentration of 1, suggesting that all four
amide groups were involved in a strong intramolecular H-
bonding network. X-ray analysis of 1 revealed a C2 symmetric
cyclic intramolecular H-bonding network constructed entirely
from the amide groups. The distances between the amide
nitrogen and oxygen atoms were 2.695 Å and 2.819 Å,
respectively (Figure 2).
In this conformation, 1 had a chirality depending on the
directionality of the H-bonding network composed of two
identical malonamide moieties having the same conformation.
The interconversion of the enantiomers 1a and 1b
(racemization) should occur by 180° rotation of all the
amide groups (Figure 3a). Take the conformation in which all
of the amide groups are arranged at appropriate positions into
account, we envisioned that the H-bonding arrangement could
be tuned to create a chiral structure that was sufficiently robust
to permit isolation of each enantiomer. Herein, we report the
first example of a stable and isolable cyclochiral structure
derived from a directionality of a continuous H-bonding
network.
Hydrogen bonding can give rise to conformational chirality
in a molecule, the handedness of which will depend on the
directionality of the intramolecular H-bonding as typically
shown by enantiomeric structures of a malonamide derivative
(Figure 1). Racemization barriers of these molecules tend to be
low because the H-bonding stabilization energy is not
sufficiently high to preserve the chiral conformation. The
isolation of directional stereoisomers has been thought to be
impossible without chiral auxiliary groups.4j
Significant efforts have been directed toward characterizing
the strengths of H-bonding. The acidity of a H-bonding donor,
Figure 1. Interconversion of conformational central chirality of a
malonamide derivative.
Received: July 10, 2013
© XXXX American Chemical Society
A
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Communication
Table 1. Effects of Substituents and Solvent on the
Racemization Barriers
Figure 2. X-ray crystallographic analysis of 1. (a) Side and (b) top
views. Distances between the amide carbonyl oxygen and the nitrogen
are given in Å.
a
b
kcal/mol at 0 °C. These activation parameters, ΔH⧧ (kcal/mol) and
ΔS⧧ (cal/mol·K), were determined by VT NMR with line shape
analysis and time-dependent racemization of an isolated enantiomer by
HPLC analysis for entries 1−10 and entry 11, respectively, and
following Eyring plots.
Figure 3. Analysis of the racemization barrier of 1. (a) Interconversion
of the enantiomers of 1 through rotation of the amide moieties. (b)
Coalescence of the amide protons observed in a VT NMR study in o-
dichlorobenzene-d4. (c) CD spectra of both enantiomers in
hexane:CH2Cl2:Et2NH (60:40:0.1). (d) A trace of racemization was
observed based on the CD spectra.
bonding network is generally higher for combinations of more
acidic H-bonding donors and more basic H-bonding acceptors;
however, the strength of the cyclic H-bonding network seemed
not controllable simply through the electronic tuning of the
amide group because an increase in the acidity of one of the
N−H group by electronic tuning weakens the basicity of the
CO group in the corresponding amide. In fact, p-Br and p-
OMe substitution on the phenyl groups of 1 did not show the
clear electronic effect (Table 1, entries 1−3). Although the
steric effect of the amide substituents on the racemization
process was not clearly observed, it might affect on various
factors such as solvation to the amide groups, orbital overlap of
the H-bonding, and steric repulsion of the neighboring amide
groups. Solvent effect on the racemization was clearly explained
by comparison of the activation parameters (Table 1, entries
7−10). Smaller values of ΔH⧧ and larger negative values of ΔS⧧
for 7 and 8 in DMSO-d6 than those in o-dichlorobenzene-d4
strongly suggested that the H-bonding network was disrupted
by the solvation of DMSO-d6.
Introduction of dicyclohexylmethyl group dramatically
increased the racemization barrier to 23.8 kcal/mol at 0 °C
(Table 1, entry 11). The enantiomers of 9 could be completely
separated and isolated by preparative HPLC using chiral
stationary phase. ΔH⧧ and ΔS⧧ for the racemization process of
9 were evaluated by Eyring plot based on temperature
dependency of racemization rate constant obtained by chiral
HPLC analysis (see the SI).
The racemization barrier of 1 was evaluated based on full line
shape analysis of variable temperature (VT) NMR spectra. The
rotation of the amide groups, which was thought to be a key
step in the racemization, was indicated by the coalescence of
the two set of amide signals. The line shape analysis of these
signals in o-dichlorobenzene-d4 using WINDNMR-Pro,9 and
following Eyring plot gave ΔH⧧ = 17.0 kcal/mol, ΔS⧧ = −10.8
cal/mol·K and ΔG⧧ = 19.9 kcal/mol at 0 °C (Figure 3b).
Next, HPLC analysis of 1 using a chiral stationary phase was
examined (see the Supporting Information, SI). Although the
chromatogram indicated partial racemization of 1 during the
analysis, the enantio-enriched isomers could be successfully
separated and collected by preparative HPLC at 0 °C. The
mirror image of the CD spectra obtained from the isomers
indicated that the isomers were enantiomers (Figure 3c). The
racemization barrier at 0 °C was found to be 20.7 kcal/mol,
based on the decay of the CD intensity (Figure 3d). The
racemization barrier was similar to the amide rotational barrier
(19.9 kcal/mol) obtained through VT NMR analysis (Figure
3b). These results suggested that the amide rotation was the
rate-limiting step to the racemization of 1.
The effects of the amide substituents and solvent on the
racemization barrier were investigated in a VT NMR study
(Table 1, entries 1−10). ΔH⧧ and ΔS⧧ of the racemization
process varied depending on the amide substituents. These
parameters were thought to be affected by both electronic and
steric factors of the amide substituents. The strength of the H-
The half-life of racemization of 9 in hexane at 20 °C was
found to be 173 h, corresponding to the racemization barrier of
B
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Journal of the American Chemical Society
Communication
25.5 kcal/mol. Furthermore, 9 was found to be quite stable in
the solid form, and no racemization was observed, even after
storing for one month at 20 °C. The energy-minimized
structure of 9, which was generated by a molecular modeling
conformational search (see the SI), revealed that all of the
amide groups played a role in the cyclic H-bonding network, as
shown in Figure 4. All the dicyclohexylmethyl groups assumed
1
Figure 5. H NMR spectrum of 10 in CDCl3 at 20 °C.
according to the directionality of the H-bonding network. Thus,
all aromatic substituents were thought to be oriented in the
same direction, thereby shielding one side of the molecule. As
shown in Figure 4, all amide substituents were thought to
prefer the same conformation to minimize the allylic strain on
the carbonyl groups. Therefore, the conformations of the major
and minor conformers were thought to resemble those of 10a
and 10b, respectively. The X-ray crystallographic analysis of a
single crystal of 10 supported the hypothesis that the
conformations of the amide substituents depended on the
directionality of the H-bonding network (Figure 6). Although
Figure 4. Energy-minimized conformation of 9. (a) Side and (b) top
views.
the same conformation, in which the hydrogen atoms were
present in an eclipsed conformation with respect to the
carbonyl groups, which minimized the 1,3-allylic strain.10
The stability of 9 might be explained by the following kinetic
and thermodynamic reasons. The optimized structure gen-
erated by molecular modeling study indicated that the
cyclohexyl groups are surrounding the cyclic H-bonding
network. This might contribute to kinetic stabilization11 of
the H-bonding network by preventing from solvation. The
cyclohexyl groups would also contribute to enhance the
strength of the H-bonding network. The steric repulsion
between neighboring these bulky groups might allow all amide
groups in a homogeneous geometry, in which the orbital
overlap of the H-bonding is facilitated. The large ΔH⧧ value
(21.4 kcal/mol) for the racemization of 9 supports this
thermodynamic factor.
Figure 6. X-ray crystallographic analysis of 10. (a) Side and (b) top
views.
The compounds we have described above were chiral, with a
handedness that depends on the directionality of the H-
bonding network; therefore, the introduction of chiral
substituents should lead to the conversion of enantiomeric
conformers to the diastereomeric isomers. Compound 10,
which included four identical (R)-1-(1-naphthyl)ethylamino
moieties, was prepared to investigate the conformations of the
diastereomeric conformers. As expected, two conformational
isomers of 10 (10a and 10b) were observed separately in the
1H NMR analysis in a ratio of 73:27 in CDCl3. The HPLC
chromatogram suggested that the molecules underwent
interconversion among the diastereomeric conformers, even
at 0 °C (see SI). The 1H NMR spectra of the conformers of 10
were quite characteristic. Figure 5 shows that the signals
corresponding to the pyrrolidine hydrogen atoms in the major
conformer were shifted upfield (2.2−1.8 ppm) relative to the
corresponding hydrogen atoms of the minor isomer (2.8−2.6
ppm). On the other hand, the signals corresponding to the
pyridine hydrogen atoms in the minor isomer were shifted
upfield (7.2 and 5.4 ppm) relative to the corresponding
hydrogen atoms of the major isomer (8.4 and 6.3 ppm). In
general, the signals of the pyrrolidine and pyridine protons in
1−9 appeared around 2.5 and 8.0/6.0 ppm, respectively (see
the SI). Therefore, the pyrrolidine proton signals of the major
isomer and the pyridine proton signals of the minor isomer
were substantially shifted upfield. These results indicated that
the conformations of the amide substituents could be tuned
the reason why 10a was a major conformer was not clear, van
der Waals repulsion4i and associative π−π or CH-π interactions
between side chains and pyrrolidine or pyridine moiety might
play key roles to determine the population of 10a and 10b.12
Protonation of 10 by HCl yielded 10b-HCl as the major
isomer in CDCl3 (10a-HCl:10b-HCl = 32:68, Figure 7). The
pyridine signals in 10b-HCl (6.0 and 4.9 ppm) were further
shifted upfield from 10b (7.2 and 5.4 ppm) despite its cationic
form. The result suggests the cationic pyridinium moiety
strongly associated with the naphthyl group by π−π or CH−π
1
Figure 7. H NMR spectrum of 10-HCl in CDCl3 at 20 °C.
C
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Journal of the American Chemical Society
Communication
interactions.13 These stabilization effects might contribute to
the switching of the population of the directional isomers.
Finally the utility of the chiral structure of 9 for asymmetric
reactions was investigated by the acylative kinetic resolution of
rac-1-(1-naphthyl)ethylalcohol using isobutyric anhydride in
the presence of (−)-isomer of 9 isolated by preparative HPLC
with chiral stationary phase. The reaction proceeded to give the
corresponding acylate and the recovered alcohol with a 59% ee
and 36% ee in a 36% conversion (kS/kR = s = 5) without
racemization of (−)-9. Thus, the chiral structure was proved to
be applicable to asymmetric reaction (Scheme 1).
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Scheme 1. Kinetic Resolution of Racemic Secondary Alcohol
in the Presence of (−)-9
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We succeeded in developing a cyclochiral structure
constructed using a robust intramolecular H-bonding network,
which enabled the first isolation and application of a stable
cyclochiral molecule whose chirality derives from intra-
molecular H-bonding directionality. Conformational chemistry
based on such robust H-bonding arrays will pioneer a new field
of organic chemistry and provide useful functional molecules
such as asymmetric catalysts, host molecules, and organic
materials.
ASSOCIATED CONTENT
* Supporting Information
Synthetic and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
(12) Several examples of conformational chirality induction of
multicomponent arrangement: (a) Prince, R. B.; Barnes, S. A.; Moore,
J. S. J. Am. Chem. Soc. 2000, 122, 2758. (b) Nakano, T.; Okamoto, Y.
AUTHOR INFORMATION
Corresponding Authors
mishiro@fos.kuicr.kyoto-u.ac.jp
furuta@fos.kuicr.kyoto-u.ac.jp
■
Chem. Rev. 2001, 101, 4013. (c) Clayden, J.; Lund, A.; Vallverdu, L.;
́
Helliwell, M. Nature 2004, 431, 966. (d) Clayden, J.; Vassiliou, N. Org.
Biomol. Chem. 2006, 4, 2667. (e) Inouye, M.; Waki, M.; Abe, H. J. Am.
Chem. Soc. 2004, 126, 2022. (f) Hembury, G. A.; Borovkov, V. V.;
Inoue, Y. Chem. Rev. 2008, 108, 1 See also refs 2, 4d−f, i, j.
(13) This type of interaction has been reported previously. Yamada,
S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005, 46, 2239.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan,
and by Grant-in-Aid for JSPS Fellows to K.M. The authors
would like to thank Dr. Chihiro Wakai and Prof. Dr. Takeshi
Hasegawa for support for VT NMR experiment.
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