A helically twisted imine macrocycle that allows for determining the absolute configuration of α-amino carboxylates

Article abstract of DOI:10.1039/c3cc46754f

Binding of α-amino carboxylates to a helically twisted imine macrocycle based on the indolocarbazole scaffold gives rise to characteristic circular dichroism spectra, and the patterns of the Cotton effects are consistent with the absolute configuration of

Full text of DOI:10.1039/c3cc46754f

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A helically twisted imine macrocycle that allows for
determining the absolute configuration of a-amino
carboxylates†
Cite this: Chem. Commun., 2013,
49, 11412
Received 4th September 2013,
Accepted 15th October 2013
Min Jun Kim, Ye Rin Choi, Hae-Geun Jeon, Philjae Kang, Moon-Gun Choi and
Kyu-Sung Jeong*
DOI: 10.1039/c3cc46754f
www.rsc.org/chemcomm
Binding of a-amino carboxylates to a helically twisted imine macro-
Compound 1 consists of two indolocarbazole chromophores
cycle based on the indolocarbazole scaffold gives rise to characteristic connected through a butadiynyl spacer and two benzaldehyde units
circular dichroism spectra, and the patterns of the Cotton effects are at the ends (Scheme 1). In particular, ortho-ethynylbenzaldehyde
consistent with the absolute configuration of a-amino carboxylates.
was chosen to form imine macrocycles with 1,2-diamines.9 The
methoxy substituents help increase the solubility in organic
Circular dichroism (CD) spectroscopy is a convenient and powerful solvents. Synthesis of 1 is straightforward and details are
technique to investigate the chirality of chemical species, includ- summarized in the ESI.†
ing the absolute configuration of stereocenters, the screw sense of
The formation of imine macrocycle 3a between 1 (1 mM) and
helically twisted species, enantiomeric excesses (ee’s), and stereo- cyclohexane-(1S,2S)-diamines(2a) (B2 equiv.) was first examined
dynamic conformational changes. For this purpose, exciton in CD2Cl2 at room temperature by 1H NMR spectroscopy
coupled circular dichroism (ECCD) has been widely implemented (Fig. 1a). As a template, acetate was used because the hydrogen
for synthetic molecules that possess two or more interacting bonding between 1 and the acetate ion leads to the helical
chromophores oriented in a twisted array.1 Several molecular folding of 1. Consequently, the two aldehyde groups are brought
probes for chirality sensing have been described such as bis- in close proximity facilitating formation of imine macrocycle 3a.
porphyrins,2 triaryl propellers,3 arylethynyl foldamers,4 etc.5
Indolocarbazoles are a class of fully conjugated aromatic
heterocycles that show strong absorption in the UV-visible
region. They have two indole-type NH protons which are able
to form strong hydrogen bonds and have been utilized as useful
building blocks for synthetic anion receptors.6 Previously, we
demonstrated that indolocarbazole foldamers could bind
anions with high affinity and selectivity and fold to form helical
conformations in solution and in the solid state.7 It was also
shown that the helical orientation of an indolocarbazole dimer
with chiral residues could be reversibly and completely inverted
by anion stimulation, thus functioning as a chiroptical mole-
cular switch.8 Herein, we extend our work to develop a stereo-
dynamic probe that allows for determining the absolute
stereochemistries and ee’s of a-aminocarboxylates based on
the CD signals. The chirality sensing is ascribed to the helically
twisted nature of imine macrocycles 3, and the helical bias is
induced by hydrogen bonding of chiral carboxylates to the
internal cavity of 3b.
Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
E-mail: ksjeong@yonsei.ac.kr; Fax: +82-2-364-7050; Tel: +82-2-2123-2643
† Electronic supplementary information (ESI) available: Characterization data of
the new compound, NMR studies, circular dichroism studies, computer model-
ing, and X-ray crystallographic data. CCDC 951760. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc46754f
Scheme 1 Molecular structures of compound 1, 1,2-diamines 2a and 2b, and
imine macrocycles 3a and 3b.
c
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Fig. 2 Two views of the crystal structure of (R,R)-3a complexed with tetrabutyl-
ammonium acetate. In the crystal, 3a has P-helix, and the hydrogen bond
distances of N3Á Á ÁO97, N23Á Á ÁO98, N6Á Á ÁO97 and N26Á Á ÁO98 are 3.19, 3.03, 2.85
and 2.85 Å, respectively. Countercations and hydrogen atoms except NH protons
have been omitted for clarity.
Fig. 1 (a) Partial 1H NMR spectra (400 MHz, CD2Cl2, 25 1C) for the formation of
3a between 1 and (1S,2S)-2a in the presence of tetrabutylammonium acetate.
(b) CD spectra (5.0 Â 10À5 M in CH2Cl2, 25 1C) of 3a derived from cyclohexane-
(1R,2R)-diamine (blue) and its enantiomer (red).
The reaction was completed within 30 min in the presence of
tetrabutylammonium acetate (2 equiv.), affording only one set
of 1H NMR signals corresponding to the molecular structure of 3a.
However, the reaction was complicated in the absence of the
acetate ion possibly due to the formation of the 1 : 2 (1/diamine)
condensation product and higher oligomers (Fig. S1, ESI†).
Moreover, the reaction was significantly slower, having not
completed after several hours, which implies that the acetate
ion acts as a template as well as facilitates the formation of
imine macrocycle 3a.
The formation of 3a was also investigated by CD spectroscopy
(Fig. 1b). When diamine 2a (1.5–2 equiv.) was added to a CH2Cl2
solution of 1 and tetrabutylammonium acetate (B2 equiv.) at room
temperature, induced CD signals at wavelengths ranging from
300 nm to 460 nm appeared as a result of the formation of 3a.
More specifically, addition of (1R,2R)-2a gave strong exciton-
coupled CD signals with positive Cotton effects at 328, 390, and
Fig. 3 (a) CD spectra (5.0 Â 10À5 M in CH2Cl2, 25 1C) of imine macrocycle 3b
upon hydrogen bonding with various anionic N-Boc amino acids. (b) CD spectra
obtained from different ratios of anionic D-Ala and L-Ala, and (c) plots of CD
spectral intensities in (b) against ee’s of Ala at four different wavelengths.
421 nm and a negative Cotton effect at 363 nm. The CD spectrum was conducted in the presence of chiral N-protected a-amino-
was completely inverted when the enantiomer (1S,2S)-2a was used. carboxylates. As representative example, when anionic
a
The structure of imine macrocycle (R,R)-3a, derived from N-Boc-alanine (Ala) was used, the imine macrocycle 3b exhibited
(1R,2R)-2a, was confirmed by single crystal X-ray analysis (Fig. 2). strong CD signals with first positive Cotton effects from D-Ala but
(R,R)-3a is helically twisted with the right-handed (P) orientation, inverted negative effects from L-Ala. When a mixture of D- and L-Ala
as anticipated by the exciton chirality rule1 based on the CD was used for the reaction, the intensity of CD spectra was linearly
spectrum showing positive Cotton effects at longer wavelengths. proportional to the enantiomeric excess (ee) of the mixture at any
The dihedral angle between two indolocarbazole planes is approxi- wavelength (R2 > 0.99) (Fig. 3b and c). It should be emphasized that
mately 221. The acetate ion is coordinated to the internal cavity by the amino acids examined here all exhibit the same trend of CD
four hydrogen bonds; both NÁÁÁO distances are 2.85 Å with two spectra, that is, first positive Cotton effects from D-amino acids and
NHs (one of each indolocarbazole) on the butadiynyl side, while negative effects from L-amino acids (Fig. 3a; Fig. S6 and Table S1,
they are 3.03 and 3.19 Å with two NHs on the methoxyphenyl side. ESI†). It is also worth mentioning that identical patterns of CD
The condensation reaction between 1 and ethane-1,2-diamine spectra are observed regardless of the kind of protective groups,
(2b) in the presence of acetate yielded a CD-inactive, racemic N-acetyl (Ac) and N-carboxybenzyl (Cbz) protected amino acids
mixture of imine macrocycle 3b (Fig. 3a). If a chiral carboxylate (Table S1, Fig. S7 and S8, ESI†). These results demonstrate that imine
is instead used for the reaction, two helical isomers may be formed macrocycle 3b can be used as a stereodynamic probe to determine
in an unequal ratio. To test this hypothesis, the same reaction the absolute configuration and ee’s of a-aminocarboxylates.
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carbazole NH protons, and it is therefore directed toward the lower
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M-helices in the complexes with D-amino acids, which agrees
well with the observed Cotton effects in the CD spectra.
In conclusion, simple mixing of a precursor with a dialdehyde,
a diamine and a carboxylate leads to the in situ formation of a
helically twisted imine macrocycle exhibiting strong CD signals.
The helical orientation of the imine macrocycle faithfully depends
on the chirality of carboxylates coordinated to the internal cavity
by hydrogen bonds, which allows us to conveniently determine
the absolute stereochemistries and ee’s of carboxylates.
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This study was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korean government (MEST)
(2013R1A2A2A05005796). We thank Dr J.-m. Suk and M. J. Kim for
participating in this project at an early stage. M.J.K. and Y.R.C.
acknowledge the fellowship of the BK 21-plus program from the
Ministry of Education and Human Resources Development.
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c
11414 Chem. Commun., 2013, 49, 11412--11414
This journal is The Royal Society of Chemistry 2013