A complete gear system in N-benzoyl-carbazole derivatives

Article abstract of DOI:10.1021/ol500417t

2′,6′-Disubstituted N-benzoylated carbazole derivatives were found to exhibit atropisomerism. The bulky substituents restricted rotation about the N-C7′ and C7′-C1′ bonds to separate four atropisomers, in which rotation about the C7′-C1′ bond was in perfect concert with rotation about the N-C7′ bond. Complete geared rotation without slippage at 37 C for 7 days was observed for the first time. Conformational analysis clarified the preference for the gear system over other internal conversion pathways.

Full text of DOI:10.1021/ol500417t

Letter
pubs.acs.org/OrgLett
A Complete Gear System in N‑Benzoyl-Carbazole Derivatives
Hidetsugu Tabata,† Susumu Kayama,† Yuka Takahashi,† Norihiko Tani,† Shintaro Wakamatsu,†
Tomohiko Tasaka,‡ Tetsuta Oshitari,† Hideaki Natsugari,† and Hideyo Takahashi*,†
†Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
‡Affinity Science Corporation, 4-1-1 Akasaka, Minato-ku, Tokyo 107-0052, Japan
S
* Supporting Information
ABSTRACT: 2′,6′-Disubstituted N-benzoylated carbazole derivatives were
found to exhibit atropisomerism. The bulky substituents restricted rotation
about the N−C7′ and C7′−C1′ bonds to separate four atropisomers, in which
rotation about the C7′−C1′ bond was in perfect concert with rotation about
the N−C7′ bond. Complete geared rotation without slippage at 37 °C for 7
days was observed for the first time. Conformational analysis clarified the
preference for the gear system over other internal conversion pathways.
s part of our research on stereochemical and phys-
icochemical analyses of biologically active molecules,1 we
reported the atropisomeric property of the 2′,6′-disubstituted
indole derivatives (N-benzoylated 2-methylindoles) (Figure
1).2 The isolation of each enantiomer of 1 (aR, aS) with high
system moves was examined in detailed experimental and
computational studies.
A
In order to estimate the steric effect at the ortho-positions of
the benzoyl moiety on the rotation about the N−C7′ and C7′−
C1′ axes, we planned to synthesize the variously 2′-alkyl-6′-
iodo-substituted derivatives. Following the established method,
N-benzoylated carbazole derivatives (2−5) were synthesized as
shown in Scheme 1.4
Scheme 1. Preparation of 2′,6′-Disubstituted N-Benzoyl-
carbazoles
Figure 1. 2′-Iodo-6′-methylsubstituted N-benzoyl-indole derivative 1
and 2′,6′-disubstituted N-benzoyl-carbazole derivatives.
First, N-(2′-iodo-6′-methylbenzoyl)-3-bromocarbazole 2 was
1
characterized using H NMR spectroscopy, which showed two
stereochemical stability confirmed that the rotation about the
C7′−C1′ axis is fully restricted by substituents at C2′ and C6′
to form a twisted conformation.
sets of resonances corresponding to cis and trans conformations
(cis/trans = 1:1.25). Because the rotational barrier of the N−
C7′ axis is less than that required for the isolation of each
conformer at 23 °C, compound 2 was observed as one peak on
nonchiral HPLC. However, 2 was separated into two peaks
when analyzed in a chiral column (CHIRALPAK IB) at 23 °C,
which means that the C7′−C1′ axis was frozen as observed in
indole derivative 1 (Figure 2).2 The enantiomers of compound
2 were successfully isolated using preparative chiral HPLC with
In this context, our attention next focused on carbazole.
Carbazoles have attracted increasing attention from medicinal
chemists owing to their therapeutic value derived from
carbazole alkaloids that act as antibacterial, antifungal, and
antiviral agents.3 However, no reports have considered its N-
benzoylated structure from the viewpoint of axial chirality.
In this paper, we report the atropisomeric properties of 2′,6′-
disubstituted N-benzoylated carbazole derivatives. It was found
that the bulky substituents at the 2′- and 6′-positions of the
benzoyl moiety make the N−C7′ and C7′−C1′ axes move
together like a complete gear. The process by which this gear
20
opposite [α]D values: 2A (with shorter retention time in
Received: February 10, 2014
Published: February 24, 2014
© 2014 American Chemical Society
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Letter
IB). All the isomers were successfully isolated using preparative
chiral HPLC.
For compound 5 containing the tert-butyl and iodo groups at
the ortho-positions of benzoyl, rotation about the N−C7′ and
C7′−C1′ axes are fully restricted, mainly due to the steric effect.
In such systems, four stereoisomers can potentially result since
each axis can assume two orientations (cis/trans for the N−C7′
axis, aR/aS for the C7′−C1′ axis). The chromatogram of chiral
HPLC of the stereoisomers and the [α]D data are shown in
Figure 3. Fortunately, 5I-B and 5II-B could be analyzed by X-
Figure 2. Interconversion path for stereoisomers of 2.
20
HPLC) as 99%ee showed [α]D −10.7 (c 0.12, CHCl3), and
2B (with longer retention time in HPLC) as 99%ee showed
20
[α]D +10.9 (c 0.15, CHCl3). We also examined the
stereochemical stability with a ΔG‡ value of 108 kJ mol−1 for
2A and 2B.5 The similar barrier height in compound 1 in
comparison with that in N-(2′-iodo-6′-methylbenzoyl)-2-
methylindole (ΔG‡ value of 109 kJ mol−1) is likely explained
by the similar steric or electronic effect due to the methyl group
vs the aromatic C−H.
Figure 3. Separation of 5 (5I and 5II) into the enantiomers (A and B)
on a chiral column and [α]D data measured in CH3OH.
We next examined carbazoles with bulkier substituents, ethyl
and isopropyl groups (3 and 4, respectively). For both
compounds, two sets of resonances corresponding to cis and
trans conformations (cis/trans = 1:1.16) were observed in the
1H NMR spectra, although the isolation of each diastereomer
(cis/trans) on a nonchiral column failed. Separation analysis of
3 and 4 on a chiral column (CHIRALPAK IB) provided results
contrary to our expectations. Compound 3 was partially
separated at 23 °C, and we managed to isolate the atropisomers
ray crystallography to determine the absolute stereochemistry
(Figure 4).7 5I-B was assigned to be (trans, aS), and 5II−B was
assigned to be (cis, aS); hence, 5I-A was (trans, aR), and 5II-A
(cis, aR).
20
of 3 with opposite [α]D values: 3A (with shorter retention
20
time in HPLC) as 99%ee showed [α]D −10.2 (c 0.12,
CHCl3), and 3B (with longer retention time in HPLC) as 92%
20
ee showed [α]D +9.5 (c 0.09, CHCl3). The stereochemical
stability with a ΔG‡ value of 110 kJ mol−1 for 3A and 3B may
account for the increased stability of the C7′−C1′ axis in 3,
although less separable peaks were observed on CHIRALPAK
IB. In addition, 4 was observed as one peak on all chiral
columns examined at 23 °C. Thus, we failed to isolate
atropisomers of 4. Considering the van der Waals volumes of
methyl (21.6 Å3), ethyl (38.9 Å3), and isopropyl (56.2 Å3)
groups,6 it appears strange that steric hindrance does not
contribute to separating the atropisomers arising from the
C7′−C1′ axis. Especially in compound 4, the more hindered
isopropyl group may produce an unusual effect that unfreezes
the rotation about the C7′−C1′ axis, causing loss of the
atropisomeric property.
Finally, amazing results were provided by tert-butyl-
substituted compound 5. Similar to the above-mentioned
compounds 1−4, two sets of resonances corresponding to cis
and trans conformations were observed in the 1H NMR
spectrum (cis/trans = 1:1.17). However, 5 was observed as two
separated peaks (5I, 5II) on nonchiral HPLC, and four
stereoisomers were resolved by a chiral column (CHIRALPAK
Figure 4. X-ray crystal structures of 5I-B (left) and 5II-B (right).
Using the enantiomerically pure stereoisomer (5II-B), the
stereochemical stability was examined using chiral HPLC
analysis at 37 °C in toluene after 9 days. We observed that 5II-
B was converted to 5I-A with a ΔG‡ value of 102 kJ mol−1, and
no interconversion between any other pair (i.e., 5II-B/5II-A,
5II-B/5I-B) was seen (Figure 5). Similarly, enantiomerically
pure 5I-B was converted to 5II-A with a ΔG‡ value of 103 kJ
mol−1; no interconversion between any other pair (i.e., 5I-B/
5I-A, 5I-B/5II-B) was observed over 7 days.8 It is clear that the
rotation about the C7′−C1′ axis must be in perfect concert
with the rotation about the N−C7′ axis at 37 °C for at least 7
days (Figure 6). Although such behavior has been observed in
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Figure 5. Conversion between 5II-B (left) and 5I-A (right) at 37 °C.
Figure 7. Energy surface for 5.
tertiary aromatic amide systems,9 complete geared rotation
without slippage was observed here for the first time.
M3 and M4, is easy. Furthermore, we carried out additional
calculations to estimate the activation barrier of geared rotation
at the RB3LYP/LanL2DZ level.13 These results are consistent
with the experimental results obtained from HPLC analysis and
X-ray crystallography.
In conclusion, an atropisomeric property was found in 2′,6′-
disubstituted N-benzoylated carbazole derivatives. The bulky
tert-butyl group and iodo group restricted the rotation about
the N−C7′ and C7′−C1′ bonds to separate the four
atropisomers, in which the rotation about the C7′−C1′ bond
is in perfect concert with the rotation about the N−C7′ bond.
The process by which this molecular gear system starts moving
was investigated by comparison with the stereochemical
properties of variously 2′,6′-disubstituted N-benzoylated
carbazole derivatives. Furthermore, conformational analysis
clarified the preference for the gear system over other internal
conversion pathways. Although we have only limited
information on this molecular gear system, we hope that this
study will contribute to elucidating the stereochemical
properties of the N-acylated pyrrole derivatives including
indoles and carbazoles. We also hope that the perfect gear
system might shed light on the practical use of molecular gears.
Figure 6. Interconversion path for stereoisomers of 5.
In order to estimate the stability of this gear system,
conversion of the enantiomerically pure 5II-B to 5I-A at higher
temperature was followed by analytical HPLC until the gear
slipped. In previous papers on molecular gear systems, gear
slippage was observed at ambient temperature.9 However, the
slippage in this system was finally observed only after 27 h of
heating at 100 °C.10
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
We next carried out in silico conformational analysis11 of 5 to
confirm the advantage of this geared rotation over other
conversion pathways.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hide-tak@pharm.teikyo-u.ac.jp
Notes
To obtain the initial 3D molecular coordinates of 5, the X-ray
crystal structures of 5II-B shown in Figure 4 were used. Ab
initio calculations were performed using the RHF/CEP-4G
basis set with a Gaussian program.12 To cover all conforma-
tional spaces, rotational steps of the single bonds in 5 were 15
degrees. As mentioned above, 5 can rotate around the N−C7′
and C7′−C1′ axes, which results in the energy surface shown in
Figure 7.
There were four stable conformers (M1, M2, M3, and M4),
corresponding to 5I-A, 5II-B, 5II-A, and 5I-B, respectively, as
shown in Figure 6. Based on the energy barriers of the
pathways on the energy surface, it is clear that the
interconversion between conformers M1 and M2, and between
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (24590020) from the Japan Society for the
Promotion of Sciences and by a research grant from the Astellas
Foundation for Research on Metabolic Disorders.
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