Cyclomaltooligosaccharide (cyclodextrin)-assisted enantiomeric recognition of benzo[lmn][3,8]phenanthroline-derived amino acids

Article abstract of DOI:10.1016/j.carres.2005.03.002

Formation of self-assembly molecular aggregates and cyclomaltooligosaccharide (cyclodextrin) molecular aggregates with benzo[lmn][3,8]phenanthroline-derived amino acids is presented. The nature of the molecular aggregates was studied by negative-ion elect

Full text of DOI:10.1016/j.carres.2005.03.002

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Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 1413–1418
Note
Cyclomaltooligosaccharide (cyclodextrin)-assisted enantiomeric
recognition of benzo[lmn][3,8]phenanthroline-derived amino acids
Branko S. Jursic* and Paresh K. Patel
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, United States
Received 7 December 2004; accepted 2 March 2005
Available online 9 April 2005
Abstract—Formation of self-assembly molecular aggregates and cyclomaltooligosaccharide (cyclodextrin) molecular aggregates
with benzo[lmn][3,8]phenanthroline-derived amino acids is presented. The nature of the molecular aggregates was studied by nega-
tive-ion electrospray-ionization mass spectrometry (ESIMS). The enantiomeric recognition was demonstrated by NMR enantio-
meric discrimination of the amino acid derivatives in aqueous solutions of cyclodextrins.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Cyclomaltooligosaccharide; Cyclodextrin; Enantiomeric recognition; Molecular aggregation; Electrospray-ionization mass spectrometry;
ESIMS
There are many drugs that are marketed as racemic mix-
tures. Preparing enantiomerically pure compounds is
r
COO
no
do
crucial for the pharmaceutical industry.1 It is known
acceptor
r
o
n
that cyclomaltooligosaccharides (hereafter, Ôcyclodex-
o
OOC
d
M
trinsÕ) are capable of forming stable complexes with aro-
matic compounds.2 Therefore, it is reasonable to
Figure 1. Chiral molecule with two donors and one acceptor.
propose that cyclodextrins can form diasteriomeric
inclusion complexes with racemic aromatic compounds.
Based on the knowledge that diastereomers have differ-
ent physical properties, it is reasonable to expect that
preparation of optically active molecules are natural
one of the diasteriomeric inclusion complexes will crys-
Some of the most utilized starting materials for the
amino acids. We chose three amino acids from which
tallize out from a solution of the racemic compound
to prepare our compounds for the study of formation
complexed with a cyclodextrin in solution more readily
than the other.
Here we would like to explore the possibility of form-
ing diasteromeric cyclodextrin inclusion complexes with
recognition through formation of diasteromeric molecu-
racemates that have two chiral centers, one relatively
large aromatic acceptor, and two smaller electron-rich
cules contain a naphthalene ring with four carbonyl
aromatic moieties. A graphical representation of our
target molecule is presented in Figure 1. Considering
tion of the molecule electron deficient. The electron-rich
structural properties, one can postulate the formation
of chiral molecular self-assembly.3
of molecular aggregates (Scheme 1). Each of the molec-
ular aggregates synthesized were designed to explore
structural parameters necessary to obtain enantiomeric
lar aggregates. The central portions of the target mole-
groups, structural moieties that make this aromatic por-
part of the molecule was supplied by either the indole
moiety of tryptophan (compound 1c) or the phenyl moi-
ety of phenylalanine (compound 1b). Alanine was
selected for preparation of derivative 1a, which does
not contain an additional aromatic moiety, but was
*
Corresponding author. Tel.: +1 504 280 6311; fax: +1 504 280 6860;
e-mail addresses: bsjcm@uno.edu; bjursic1@uno.edu
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.03.002

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B. S. Jursic, P. K. Patel / Carbohydrate Research 340 (2005) 1413–1418
O
O
N
OH
Me
O
O
O
alanine
pyridine
O
O
O
O
O
O
Me
HO
N
O
O
O
1a
tryptophan pyridine
O
N
OH
Mol. Wt.: 410.33
O
N
OH
H
N
O
N
O
O
O
N
O
O
1b
1H-Indole
1c
N
HO
O
HO
O
H
Scheme 1. Synthetic transformation of three amino acids into 1a, 1b, and 1c.
synthesized to demonstrate the necessity of second
aromatic moiety (Scheme 1).
of each of the three cyclodextrins, a, b, and c (cyclomal-
tohexaose, -heptaose, and -octaose), and the six enantio-
mers (RR and SS of 1a, 1b, and 1c) were the subject
of electrospray mass spectrometric studies. Even with-
out the presence of cyclodextrins, these molecules form
dimers (2M) as was demonstrated with negative-ion
ESIMS of 1a in methanol–water solution (Fig. 2). This
finding supports our postulation that molecular aggre-
gation of 1 in solution can occur spontaneously.
The questions remaining are (a) what is the influence
of cyclodextrin on the molecular aggregation of 1 and
(b) can a cyclodextrin form molecular aggregates with
these compounds? Regardless of which combination of
molecule 1 and cyclodextrin (a-, b-, or c-cyclodextrin)
Considering that compound 1c has electron-deficient
and electron-rich aromatic moieties, it should form
molecular associates through dimerization, trimeriza-
tion, etc. Due to the statistical factor, it is reasonable
to believe that formation of high-order molecular asso-
ciates in solutions is unlikely. We have postulated that
the stability of these molecular associates can be in-
creased through their cyclodextrin inclusion complexes
(Scheme 2).
One excellent method for use in the study of molecu-
lar associates is electrospray-ionization mass spectro-
metry (ESIMS).4 Combinations of an aqueous solution
CO2
CO2
CO2
CD
M + CD
....
acceptor
3M-3CD
O2C
O2C
O2C
M
2M-2CD
Scheme 2. Possible molecular associates in aqueous cyclodextrin solutions.
Figure 2. Negative-ion ESIMS of 1aSS in methanol–water.

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B. S. Jursic, P. K. Patel / Carbohydrate Research 340 (2005) 1413–1418
1415
was used, both self-assembly molecular aggregates and
aggregates with cyclodextrins in aqueous media were
observed. This is demonstrated with the negative-ion
electrospray mass spectra of 1a in an aqueous solution
of a-cyclodextrin (Fig. 3). The signal intensity of the
molecular dimer of 1a increased with reference to the
molecular signal (Fig. 2). Formation of the molecular
trimer (3MÀH+ = m/z1229) was also observed. We were
unable to observe higher order of molecular aggregates.
Molecule 1a cannot form self-assembly molecular aggre-
gates through aromatic stacking interactions, as these
can only form through hydrogen-bonding interactions
present in two carboxylic acid groups.
However, molecule 1c is capable of forming molecular
associates through aromatic stacking interactions, and
c-cyclodextrin (largest cavity size) might stabilize these
molecular associates by forming inclusion complexes be-
tween the aggregates and cyclodextrin. Our negative-ion
electrospray mass spectra fully support our expectations
(Fig. 4). Besides normal molecular dimers formed (proof
of self-assembly), there are signals that demonstrate the
formation of molecular complexes with cyclodextrin
that are of higher order than 1:1, such as a 2:1
(2M + 1cCD) and a 1:2 (1M + 2cCD) complex (Fig.
4). This suggests that due to the formation of high-order
diasteriomeric molecular complexes, spectroscopic
Figure 3. Negative-ion ESIMS of 1aSS in aqueous a-cyclodextrin solution.
Figure 4. Negative-ion ESIMS of 1cS (0.001 M) in Me2SO (1 drop) and c-cyclodextrin (c-CD, 10À2 M).

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B. S. Jursic, P. K. Patel / Carbohydrate Research 340 (2005) 1413–1418
enantiomeric discrimination of 1c should occur. As use-
ful as ESIMS is in proving the formation of molecular
complexes, this method cannot demonstrate the exist-
ence of enantiomer recognition or discrimination. For
this purpose an NMR spectroscopic study of the cyclo-
dextrin aqueous solution of racemic 1a, 1b, and 1c was
performed.
We were not able to observe evidence of NMR dis-
crimination of alkaline aqueous solutions of racemic
1a and 1b with or without the presence of a-, b-, and
c-cyclodextrin. This is a very interesting finding, consid-
ering that molecular complexes of these compounds are
formed, as demonstrated in the example of the ESIMS
spectra of 1a and a-cyclodextrin (Fig. 3). If we assume
that inclusion complexes with cyclodextrin (inclusion
complex is formed when part of the molecule enters
the cyclodextrin cavity) are necessary for NMR spectro-
scopic enantiomer discrimination, then one can argue
that these molecular aggregates are not formed by inclu-
sion cyclodextrin complexation, but rather by hydrogen-
bonding interactions on the outside of the cyclodextrin
cavity. The NMR spectrum represents the average asso-
ciation of a molecule that is in fast equilibrium with
many different aggregates. It is therefore important that
molecule 1 form a strong diastereomeric complex, pref-
erably with cyclodextrin as the molecular dimer. For in-
stance, formation of a ternary complex between 1a in a-
cyclodextrin is not evident in the ESIMSs. On the other
hand there is a strong signal for the ternary b-cyclodex-
trin complex with the 2cS dimer (Fig. 5).
This finding is in agreement with our NMR spectro-
scopic study of the enantiomeric discrimination of 1c
in aqueous cyclodextrin solution (Fig. 6). The racemic
mixture of 1cRR and 1cSS in water shows only one
set of signals, belonging to both 1cRR and 1cSS. The
molecule is too big to enter the a-cyclodextrin cavity;
therefore, a diastereomeric inclusion complex cannot
be formed, and the enantiomer cannot be observed by
NMR spectroscopy as was demonstrated in Figure 6.
The cavity of b-cyclodextrin can accommodate the
molecular size; therefore, strong diastereomeric inclu-
sion complexes are formed and NMR recognition is ob-
served (Fig. 6). The c-cyclodextrin has the largest cavity
of the three studied cyclodextrins; therefore, it can form
a ternary inclusion complex (two molecules and one
cyclodextrin). Formation of a strong ternary complex
also results in its lower water solubility and difficulty
in NMR characterization (Fig. 6).
Figure 5. Negative-ion ESIMSs of 1cSS in aqueous b-cyclodextrin solution.