Enantioselective CD analysis of amino acids based on chiral amplification with a stereodynamic probe

Article abstract of DOI:10.1016/j.tet.2010.04.030

The condensation between stereolabile 1,8-bis(3′-formyl-4′-hydroxyphenyl)naphthalene, 1, and two amino acid molecules results in the formation of chiral diimines exhibiting strong CD signals. This reaction has been used to develop a chiroptical sensing me

Full text of DOI:10.1016/j.tet.2010.04.030

Tetrahedron 66 (2010) 3989e3994
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective CD analysis of amino acids based on chiral amplification
with a stereodynamic probe
*
Marwan W. Ghosn, Christian Wolf
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
a r t i c l e i n f o
a b s t r a c t
The condensation between stereolabile 1,8-bis(30-formyl-40-hydroxyphenyl)naphthalene, 1, and two
amino acid molecules results in the formation of chiral diimines exhibiting strong CD signals. This re-
action has been used to develop a chiroptical sensing method for the determination of the absolute
configuration and enantiomeric composition of unprotected amino acids. This sensing approach is based
on distinctive chiral amplification due to central-to-axial chirality induction within the diimine scaffold
formed and does not require the use of an enantiopure ligand or metal complex.
Article history:
Received 17 February 2010
Received in revised form 5 April 2010
Accepted 6 April 2010
Available online 10 April 2010
Keywords:
Amino acids
Ó 2010 Elsevier Ltd. All rights reserved.
Sensing
Chiral amplification
Circular dichroism
Dynamic stereochemistry
1. Introduction
between the enantiomers of tryptophan in the presence of alco-
hols or alkyl sulfates.7 Corradini et al. have shown that in-
The development of molecular sensors with a potential use in
high-throughput stereoselective analysis of chiral compounds has
received increasing attention in recent years.1 Due to their bi-
ological relevance and prevalence, amino acids are inarguably
among the most important sensing targets. Although many ex-
amples of amino acid probes have been reported, few cases have
been exploited for time-efficient determination of the absolute
configuration and quantification of the enantiomeric composition.
In particular, chiral receptors carrying a fluorophore that changes
its signal output upon enantioselective binding to a chiral sub-
strate have proven quite versatile. Pu et al. have introduced fluo-
rescent BINOL-derived macrocycles that undergo enantioselective
hosteguest complexation with N-protected amino acids.2 The
success with these sensors prompted the synthesis of equally
useful BINOL analogues bearing imidazolium,3 benzoyl,4 and chiral
amino units.5 Our group has demonstrated that 1,8-diheteroar-
ylnaphthalenes and their N,N0-dioxide derivatives embed amino
acids into a highly stereoselective cleft via hydrogen bonding in-
teractions. The resulting fluorescence quenching allows analysis of
the absolute configuration and accurate determination of the ee of
corporation of a carefully designed copper binding site and
a dansyl fluorophore into -cyclodextrin produces an intriguing
class of sensors that utilizes enantioselective ligand exchange for
‘switch on’ detection of amino acids.8 Noteworthy, a wide range of
macrocyclic enantioselective fluorosensors,9 including a chiral
b
terpyridine crown ether specific for a-phenylglycine methyl ester
hydrochloride,10 a tryptophan-derived calix[4]arene for N-Boc
protected alanine,11 and a (þ)-tubocurarine receptor suitable for
the analysis of phenylalanine, have also been reported.12 Some-
what less attractive fluorescence sensing approaches rely on co-
valent attachment of a dansyl or pyrene group to the amino acid
substrate and enantioselective recognition using either a chiral
copper(II) complex13 or excess of
serum albumine.14
a-acid glycoprotein and bovine
Compared to the diversity of fluorescent sensors, few UV15 and
CD16 probes for amino acids have appeared in the literature. Ans-
lyn’s group developed a practical UVevis indicator displacement
assay utilizing a chiral copper complex for the quantitative analysis
of the enantiomeric composition of free amino acids in aqueous
media.17 Alternatively, this can be accomplished with several un-
protected amino acids by using an axially chiral diacridylnaph-
thalene N,N0-dioxide-derived scandium complex.18 Canary’s group
has demonstrated that induced circular dichroism measurements
of a copper(II) complex carrying an amino acid derivative allows
determination of both the absolute configuration and the ee based
on distinct exciton coupled CD signals at 240 nm.19 By contrast,
a
wide range of substrates.6 Bohne realized that
a pyr-
eneecyclodextrin inclusion complex can be used to differentiate
* Corresponding author. Tel.: þ1 202 687 3468; fax: þ1 202 687 6209; e-mail
address: cw27@georgetown.edu (C. Wolf).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.030

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M.W. Ghosn, C. Wolf / Tetrahedron 66 (2010) 3989e3994
coordination of amino acids to a Cu(II) complex tethered to
b
-cy-
2. Results and discussion
clodextrin or to chiral porphyrins has been reported to result in
very small Cotton effects and appears less suitable for quantitative
analysis.20 In addition to fluorescence, UV and CD methods, ex-
amples of enantioselective amino acid sensing with electro-
chemical probes,21 and inhibition and immunomechanical assays
with tailored antibodies have been reported.22 Chiral nanotubes
fitted with a peptide have been found to be sensitive to the ad-
sorption of the enantiomers of alanine, resulting in different reso-
nance frequencies.23
Recognizing the importance and remaining shortcomings of
stereochemical CD analysis of amino acids, we decided to develop
a metal-free sensing method for the determination of the absolute
configuration and %ee of amino acids without the need for elabo-
rate purification. We recently introduced the stereodynamic triaryl
probe 1, which exhibits two salicylaldehyde units attached to the
peri-positions of naphthalene.24 Sensor 1 can easily be prepared in
two steps from boronic acid 2, Scheme 1. Since both arene rings
readily rotate about the two chiral axes, the sensor exists as
Slow evaporation of a solution of 1 in chloroform gave single
crystals suitable for X-ray analysis. Although the anti-conformation
is generally expected to be thermodynamically favored in solution,
1 crystallizes in its syn-conformation, Figure 1. The splaying angle
between the two cofacial salicylaldehyde rings was determined as
13.5ꢀ, which results in a centroidal areneearene distance of 3.33 Å.
The projection along the naphthalene unit shows that the two
salicylaldehyde rings are almost perfectly aligned, having a torsion
angle of only 4.3ꢀ.27
a
mixture of enantiomeric anti-conformers that rapidly in-
terconvert via a meso syn-isomer at room temperature.25 This
fluxional and CD silent probe, however, can favor population of
a single chiral conformation upon binding to a chiral substrate. This
has been shown in the case of amino alcohols.24 Crystallographic
analysis of the diimines obtained from opposite enantiomers of
a chiral amino alcohol proved that the central chirality of the
substrate controls the arrangement of the two pivotal arylearyl
bonds in the probe, Scheme 2. The corresponding axially chiral
structure is locked by intramolecular hydrogen bonding, which
favors strong Cotton effects.
Figure 1. Single crystal structure of syn-1. The side and top views show the p-stacking
of the two salicylaldehyde rings (left and middle). The view along the naphthalene ring
reveals that both salicylaldehyde rings are almost perfectly aligned (right).
After screening various reaction conditions, we found that the
tetrabutylammonium hydroxide (TBAOH) salts of free amino acids
react with 1 in DMSO toward a diimine, which resembles results
obtained with amino alcohols.24 The condensation can easily be
monitored by MS analysis and by the disappearance of the formyl
peaks in the NMR spectra. Amino acids 4e11 were selected for this
study to cover a wide range of steric bulk and to determine effects
of additional functionalites such as alcohol groups. We were
pleased to observe that the corresponding diimines display strong
CD signals at high wavelengths, Figures 2 and 3.
Scheme 1. Synthesis of sensor 1.
Since both free 1 and the amino acids tested do not show any CD
signals above 300 nm under the same conditions, the observed
chiroptical activity can be attributed to the relative orientation and
Amino acid sensing assays are generally based on competitive
formation of diastereomeric adducts with profoundly different
thermodynamic stability or generation of diastereomers with in-
dividual UV, fluorescence or CD properties. However, the induction
of axial and helical chirality in stereodynamic biphenyls and 2,20-
dihydroxybenzophenone, respectively, upon covalent binding of
amino acids provides alternative entries to chirality imprinting and
stereoselective analysis.26 Based on these reports and our finding
that 1 shows remarkable chiral amplification upon condensation
reaction with amino alcohols, we envisioned that diimine forma-
tion between this stereodynamic sensor and 2 equiv of an amino
acid would generate a rigid, axially chiral scaffold exhibiting
a strong CD signal.
pep interactions of the cofacial salicylidenimine rings formed upon
O
O
O
O
S
OH
OH
OH
OH
NH2
NH2
NH2
NH2
4
5
6
7
O
O
O
O
OH
OH
HO
OH
OH
NH2
NH2
NH2
NH
HO
9
8
10
11
Figure 2. Structures of the amino acids used in this study.
Scheme 2. Amino alcohol-controlled central-to-axial chirality induction using sensor 1.

M.W. Ghosn, C. Wolf / Tetrahedron 66 (2010) 3989e3994
3991
Figure 3. CD spectra of the diimines obtained from 1 and (R)-alanine (4), (R)-leucine (5), (R)-valine (6), (R)-methionine (7), and (R)-phenylalanine (8) at 2.5ꢁ10ꢂ4 M in CHCl3.
condensation. As expected, enantiomeric substrates yielded prod-
ucts with opposite Cotton effects, see Figure 5 and Supplementary
data. Based on the rapid enantioconversion of the sensor at room
temperature and in analogy to our observations with chiral amino
alcohol substrates, it is assumed that the conformational isomerism
of the diimines derived from 1 is controlled by the central chirality of
the amino acid. Accordingly, diimine formation perturbs the equi-
librium of the stereoisomers of 1 and favors a single rotamer, which
is stabilized by intramolecular hydrogen bonding, Scheme 2 and
Figure 4. Upon diimine formation between the sensor and 2 equiv of
an amino acid, previously treated with TBAOH to improve solubility,
each carboxylate group is expected to participate in hydrogen
bonding with the salicylidenimine unit to lock the stereodynamic
sensor into a conformation that minimizes steric repulsion between
the two substrate moieties. Importantly, employing free salicy-
laldehyde and various amino acids in the same experiment gave
imines that proved CD-silent in the same region. The strong Cotton
effects observed with the diimines obtained with 1 are therefore due
to the cofacial arrangement of the two salicylidenimine units.28
Acidification of the solutions containing the diimines derived from
4e8 gave blue shifted CD signals with significantly higher ampli-
tude, Figure 5 and Supplementary data. Protonation of the imine and
the carboxylate groups should facilitate hydrogen bonding between
the phenol and the carboxylic acid groups in the opposite salicyli-
amino alcohol was found to cause a similar blue shift but gave
a decreased CD amplitude while diimines obtained with amino es-
ters remained CD silent. This implies that the presence of both the
carboxylate and the free carboxylic acid functions generated under
acidic conditions plays a crucial role in determining the stereo-
chemical arrangement and the chiroptical properties of the amino
acid-derived diimine scaffold. The significance of hydrogen bonding
for the generation of a rigid structure and intense Cotton effects is in
agreement with solvent effects. The CD amplitudes of the diimines
deniminium ring, resulting in a rigid array with increased p-stack-
ing, Figure 4.29 The blue UV shift and the enhanced CD amplitudes
may thus be attributed to a redirection of the hydrogen bonding
motif between the proximate functionalities and an increase in the
polarization of the salicylideniminium moieties. Acidification of
a solution containing a diimine derived from 1 and 2 equivof a chiral
O
O
O
O
O
O
H
OH
HO
R
R
R
R
H
H
N
O O
N
H
H
NH HO OH HN
H
Figure 5. UV and CD spectra showing diimine products obtained with (R)-valine in the
presence of TBAOH and upon acidification with HCl in ether (solid and dashed blue
lines, respectively) and with (S)-valine (solid and dashed red lines). All spectra were
recorded using samples having a concentration of 2.5ꢁ10ꢂ4 M in CHCl3.
Figure 4. Hydrogen bonding motif in 1-derived diimines obtained in the presence of
TBAOH (left) and under acidic conditions (right).

3992
M.W. Ghosn, C. Wolf / Tetrahedron 66 (2010) 3989e3994
Figure 6. CD spectra of the diimines obtained with (R)-serine (10), (R)-tyrosine (11) (both 2.5ꢁ10ꢂ4 M), and (R)-2-amino-1-propanol (12) (5.0ꢁ10ꢂ4 M) in CHCl3.
formed from 1 were strongly diminished when chloroform was
replaced with ethanol as solvent.
Comparison of the CD spectra obtained with the diimines derived
from amino acids 4e8 show a consistent relationship between ab-
solute configuration of the substrate and the sign of the Cotton effect;
all (R,R)-diimines give positive Cotton effects, Figure 3. Accordingly,
the induced axial chirality of the diimine product and the corre-
sponding CD signal can be correlated to the central chirality of the
amino acid used. In contrast, negative Cotton effects were obtained
with the (R)-enantiomers of tyrosine and serine, the latter being
similar to that of (R)-2-aminopropanol, Figure 6. The appearance of
strong Cotton effects at high wavelengths is quite promising for both
qualitative and quantitative CD analysis of amino acids. It is worth
noting here that enantioselective sensing of proline and alanine often
suffers from low selectivity.17,21 We were pleased to find that upon
acidificationofthediimineobtainedwithalanine, oursensorprovides
remarkable Cotton effects with this challenging analyte, Figure 7.
To evaluate the practical use of sensor 1 for CD analysis of free
amino acids, a calibration curve was obtained using leucine in
varying %ee, Figure 8. To a solution of the amino acid mixture in
Figure 7. CD spectra of the diimines obtained from (R)- and (S)-alanine (green and
orange, respectively) and (R)- and (S)-proline (blue and red, respectively) after acidi-
fication, collected at 2.5ꢁ10ꢂ4 M in chloroform.
Figure 8. CD spectra obtained using leucine with varying enantiomeric composition. The amplitudes (m deg) at 460 nm are plotted vs %ee. The calibration curve shows a linear
relationship between the CD amplitude of the diimine and the enantiomeric composition of leucine.

M.W. Ghosn, C. Wolf / Tetrahedron 66 (2010) 3989e3994
3993
600
mL of anhydrous DMSO, a stoichiometric amount of tetrabu-
4.2. Diimine formation and MS and CD analysis
tylammonium hydroxide (1.0 M in MeOH) was added and allowed
to stir for 1 min. To 1 (4.0 mg, 0.01 mmol) in DMSO, 2 equiv of the
prepared amino acid solution were added and the mixture was
allowed to stir for 2 h at 70 ꢀC. All reactions were conducted at
0.02 M and then diluted with chloroform to 2.50ꢁ10ꢂ4 M to collect
the CD spectra in triplicate. We then tested four scalemic samples
exhibiting 79.1, 53.7, ꢂ67.2, and ꢂ88.7%ee. Formation of the sensor-
derived diimines and subsequent CD analysis gave 78.0, 50.1, ꢂ63.0
and ꢂ92.0%ee, respectively. These results are in good agreement
with the actual values and thus show that our sensor can be used
for the assignment of the absolute configuration of unprotected
amino acids and for the determination of the %ee of small sample
amounts.
The following conditions have been optimized in terms of re-
action time, solvent, concentration and equivalents. To a solution of
the selected amino acid in 400 mL of anhydrous DMSO, a stoichio-
metric amount of tetrabutylammonium hydroxide (1.0 M in MeOH)
was added and allowed to stir for 1 min. To a mixture of 1 (4.0 mg,
0.01 mmol) in DMSO, 2 equiv of the prepared amino acid solution
were added and the mixture was allowed to stir for 2 h at 70 ꢀC.
Prior to each use, the CD instrument was purged with nitrogen for
20 min and the temperature was set to 25.0 ꢀC. Spectra were col-
lected between 335 and 545 nm with a standard sensitivity of
100 m deg, a data pitch of 0.5 nm, a band width of 1 nm, a scanning
speed of 500 nm sꢂ1 and a response of 0.5 s using a quartz cuvette
(1 cm path length). The data were adjusted by baseline correction
and binomial smoothing. Samples were diluted to 2.50ꢁ10ꢂ4 M
with chloroform. To collect CDs under acidic conditions, a stoi-
chiometric amount of HCl (2 M in ether, accounting for the 2 equiv
of TBAOH and the two carboxylate groups in the diimine formed)
was added and allowed to stir for 2 min. Samples were then diluted
to 2.50ꢁ10ꢂ4 M with chloroform. Control experiments with sali-
cylaldehyde were conducted to compare the CD signal of salicyli-
denimine with that of the sensor-derived diimine. At
a concentration of 0.4 M, 2 equiv of enantiopure valine were added
under the same conditions as described above for sensor 1. The
reaction was complete after 2 h, and the CD spectrum was collected
at 5.0ꢁ10ꢂ4 M. No CD signal was detected in the region of interest
for both salicylidenimine enantiomers in chloroform or ethanol,
even at 10 times the concentration of the diimines obtained with 1.
Electrospray mass spectrometry (1 mg/mL in methanol, negative
detection mode) of several dimines proved the formation of the
desired condensation product, see Supplementary data.
3. Conclusion
We have introduced a metal-free chiroptical sensing method for
the determination of the absolute configuration and enantiomeric
composition of unprotected aliphatic and aromatic amino acids. In
contrast to previously reported enantioselective sensing of amino
acids, this approach does not require the use of an enantiopure li-
gand or metal complex. The CD analysis with readily available 1 is
based on the condensation of a stereodynamic racemic sensor
exhibiting two salicylaldehyde rings with free amino acids to afford
a diimine scaffold that undergoes substrate-controlled stereo-
divergent amplification of chirality. The cofacial arrangement of the
two salicylaldehyde rings in the sensor favor intramolecular
pep
interactions. The diimine formation and concomitant chiral in-
duction is reported in the form of a sensitive CD signal. The Cotton
effects of these amino acid-derived diimines occur at relatively high
wavelengths, which eliminates interference with CD active analytes
and impurities. After completion of the condensation reaction, the
CD spectra can be obtained without further purification and the
sensor can be reused after hydrolysis.
4.3. Crystallization and X-ray diffraction
Single crystal X-ray analysis was performed at 100 K using a Sie-
mens platform diffractometer with graphite monochromated Mo K
a
4. Experimental section
4.1. Synthetic procedures
radiation (
l
¼0.71073 Å). Data were integrated and corrected using the
Apex 2 program. The structures were solved by direct methods and
refined with full-matrix least-square analysis using SHELX-97-2 soft-
ware. Non-hydrogen atoms were refined with anisotropic displace-
ment parameters. A crystal of 1 was obtained by slow evaporation of
a solution of 5.0 mg of 1 in 3 mL CHCl3. Crystal structure data for 1:
Formula C24H16O4, M¼368.38, crystal dimensions 0.6ꢁ0.4ꢁ0.3 mm,
monoclinic, space group C2/c, a¼20.4576(27) Å, b¼6.8831(9) Å,
All reagents and solvents were used without further purifica-
tion. Reactions were carried out under nitrogen atmosphere and
under anhydrous conditions. 1,8-Diiodonaphthalene was prepared
from 1,8-diaminonaphthalene and converted to 3 as described in
the literature.24,30 Products were purified by flash chromatography
on SiO2 (particle size 0.032e0.063 mm). NMR spectra were
obtained at 400 MHz (1H NMR) and 100 MHz (13C NMR) using
CDCl3 as solvent. Chemical shifts are reported in parts per million
relative to TMS.
c¼25.3924(34) Å,
a
,
.
g
¼90ꢀ,
b
¼98.623(2)ꢀ, V¼3535.13 Å3, Z¼70,
rcalcd¼1.3841 g cmꢂ3
4.1.1. 1,8-Bis(30-formyl-40-hydroxyphenyl)naphthalene (1). To a so-
lution of 1,8-bis(30-formyl-40-methoxyphenyl)naphthalene, 3,
(0.38 g, 1.0 mmol) in 15 mL of anhydrous dichloromethane at 0 ꢀC,
BBr3 (5.8 mL, 5.8 mmol) was added dropwise and the mixture was
stirred for one hour. It was then quenched with isopropyl alcohol
and then with water, and extracted with dichloromethane. The
combined organic layers were dried over MgSO4 and concentrated
in vacuum. Purification by flash chromatography on silica gel
(dichloromethane/hexanes 20:1) afforded 1 in 70% yield as a white
solid. Anal. Calcd for C24H16O4: C, 78.25; H, 4.38; O, 17.37. Found: C,
78.40; H, 4.31; O, 17.27.
1H NMR:
2H), 7.58 (dd, J¼7.0, 8.0 Hz, 2H), 8.00 (d, J¼8.0 Hz, 2H), 9.62 (s, 2H),
10.75 (s, 2H). 13C NMR:
¼116.6, 116.9, 119.2, 125.4, 129.3, 131.0,
134.8, 135.2, 135.5, 137.6, 137.8, 159.9, 195.9.
d
¼6.64 (m, 2H), 7.00e7.25 (m, 4H), 7.42 (d, J¼7.0 Hz,
Acknowledgements
d
This material is based upon work supported by the NSF under
CHE-0910604.

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M.W. Ghosn, C. Wolf / Tetrahedron 66 (2010) 3989e3994
15. Karakaplan, M.; Aral, T. Tetrahedron: Asymmetry 2005, 16, 2119.
Supplementary data
16. Araki, K.; Inada, K.; Shinkai, S. Angew. Chem., Int. Ed. 1996, 35, 72.
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2008, 130, 12318; (b) Leung, D.; Anslyn, E. V. J. Am. Chem. Soc. 2008, 130, 12328.
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19. (a) Zahn, S.; Canary, J. W. Org. Lett. 1999, 1, 86; (b) Holmes, A. E.; Zahn, S.;
Canary, J. W. Chirality 2002, 14, 471.
20. (a) Corradini, R.; Dossena, A.; Impellizzeri, G.; Maccarrone, G.; Marchelli, R.;
Rizzarelli, E.; Sartor, G.; Vecchio, G. J. Am. Chem. Soc. 1994, 116, 10267; (b)
Ogoshi, H.; Mizutani, T. Acc. Chem. Res. 1998, 31, 81.
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Evtyugin, G. A.; Budnikova, Y. G.; Al’fonsov, V. A. J. Anal. Chem. 2008, 63, 2.
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Synthetic procedures including NMR spectra, MS analysis of the
condensation products, and CD spectra. Supplementary data asso-
ciated with this article can be found in online version at
doi:10.1016/j.tet.2010.04.030.
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Kingdom (fax: 44 1223 336033 or email: deposit@ccdc.cam.ac.uk).
28. All attempts to obtain a crystal structure of the amino acid-derived diimines
have been unsuccessful.
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29. Based on the basicity of salicylidenimines, we expect that the imine groups
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