Self-assembly of folic acid derivatives: Induction of supramolecular chirality by hierarchical chiral structures

Article abstract of DOI:10.1002/chem.200400424

Hierarchical chiral structures made up of dendritic oligo(L- or D-glutamic acid) moieties of folic acid derivatives induce supramolecular chirality in the self-assembled columnar structures of the folic acids. These folic acids self-assemble through the i

Full text of DOI:10.1002/chem.200400424

FULL PAPER
Self-Assembly of Folic Acid Derivatives: Induction of Supramolecular
Chirality by Hierarchical Chiral Structures
Yuko Kamikawa, Masayuki Nishii, and Takashi Kato*[a]
Abstract: Hierarchical chiral structures
made up of dendritic oligo(l- or d-glu-
tamic acid) moieties of folic acid deriv-
atives induce supramolecular chirality
in the self-assembled columnar struc-
tures of the folic acids. These folic
acids self-assemble through the inter-
molecular hydrogen bonds of the
pterin rings to form disklike tetramers.
In the neat states, the stacked tetram-
ers form thermotropic hexagonal col-
umnar phases over wide temperature
ranges, including room temperature.
Addition of alkali metal salts induces
chirality in the columnar phases. In
dilute solution states in a relatively
polar solvent (chloroform), the folic
acid derivatives form non-chiral, self-
assembled structures. In the presence
of sodium triflate, the folic acid forms
chiral columnar assemblies through the
oligo(l-glutamic acid) moiety, similar
to those formed in the liquid-crystalline
(LC) states. The enantiomer of the
folic acid induces columnar assemblies
with reversed helicity. In the case of
the diastereomer, no induced helicity is
observed. Application of an apolar sol-
vent (dodecane) drives the folic acid
derivatives to form chiral assemblies in
the absence of ions. In this case, lipo-
philic interactions promote nanophase
segregation, which enhances the forma-
tion of chiral columns. Interestingly,
the chiral supramolecular structure of
the diastereomer induces the most in-
tense circular dichroism. In both cases,
the molecular chirality in the oligo(glu-
tamate) moieties yields supramolecular
chirality of the folic acids that self-as-
semble through cooperative molecular
interactions.
Keywords: chirality
·
hydrogen
crystals
supramolecular
bonds
·
liquid
·
self-assembly
chemistry
·
Introduction
acid moiety, and self-assembly of folic acids and related mol-
ecules through intermolecular hydrogen bonds can result in
the formation of self-organized materials.[6] We have previ-
ously developed thermotropic liquid-crystalline folic acids.[7]
The addition of alkali metal salts to folic acid derivatives
changes their self-assembled structures. Recently, we have
found that folic acid derivatives form supramolecular liquid-
crystalline cubic structures.[7a]
Another interesting feature of biomolecules is chirality.
Folic acid is a useful candidate for such a chiral building
block, because of its self-assembling nature and the molecu-
lar chirality in its amino acid component. Gottarelli, Spada,
and co-workers reported that folic acids self-assembled in
the presence of alkali metal salts to form chiral lyotropic
liquid crystals.[6a–c] We have observed supramolecular chirali-
ty of folic acid derivatives in the thermotropic cubic phase.
In these materials, p-stacked columnar assemblies play key
roles in the induction of chirality.[7a,8] To date, a variety of
supramolecular assemblies of chiral molecules have been re-
ported.[9]
Intensive studies have been focused on the development of
molecular self-assembled materials obtained through nonco-
valent interactions.[1] Hydrogen bonding has been shown to
be useful in molecular self-assembly, because this noncova-
lent interaction has moderate bonding energy, reversibility,
and selectivity. Synthetic approaches to the construction of
dynamically functional materials that use hydrogen bonds
have been achieved for self-assembly in systems such as
supramolecular liquid crystals,[2] ionophores,[3] nano-ob-
jects,[4] and supramolecular polymers.[5]
Our intention here is to develop functional materials
based on biomolecules, because of their capability for mo-
lecular recognition and supramolecular association. Here we
focus on folic acid, a vitamin, because of its self-assembling
nature. The molecule consists of a pterin ring and a glutamic
[a] Y. Kamikawa, M. Nishii, Prof. T. Kato
Department of Chemistry and Biotechnology
School of Engineering, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113–8656 (Japan)
Fax : (+81)3-5841-8661
Columnar assemblies made up of stacked aromatic mole-
cules have been explored widely in liquid-crystalline and
dilute solution states. These p-stacked materials are basic
structural motifs of discotic liquid crystals,[10] which are
useful as electronic and photoconductive materials.[11] In
E-mail: kato@chiral.t.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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5942– 5951
contrast, association of molecules in dilute solution is
strongly influenced by solvent and temperature, since the at-
tractive strengths of simple aromatic surfaces are generally
weak. Several investigations into the creation of stable col-
umnar assemblies through the use of cooperation between
two or more secondary interactions, such as hydrogen bonds
and lipophilic interactions, have been carried out.[12] Intro-
duction of chirality into the side-chains of disk-shaped com-
ponents induces helical stacked arrays that can be detected
by CD spectroscopy. Molecular chirality is transferred to the
central aromatic core, and is subsequently often amplified
through the formation of supramolecular helical columns.[13]
The potential for tuning of the supramolecular chirality of
the columnar assemblies by external stimuli makes the de-
velopment of new chiral architectures with dynamic proper-
ties particularly interesting.
Here we describe the induction and tuning of supramolec-
ular chirality in the self-assembled folic acids 1a–c in polar
and apolar solution states and in bulk states (Scheme 1).
Molecules 1a–c are new chiral molecules with three-compo-
nent structures consisting of pterin rings, chiral glutamate
parts, and lipophilic alkyl parts, with the chiral glutamate
part located between the pterin ring and the lipophilic part.
We report on how such chiral molecular structures induce
supramolecular chiral structures. We have synthesized the
enantiomer of 1a (1b) from d-glutamic acid, and also the di-
astereomer (1c). Their self-assembly properties have been
examined. An analogous molecule of 1a with undecyl
chains forms a chiral cubic phase in the neat state.[7a] To the
best of our knowledge, tuning of supramolecular chirality
through these hierarchical chiral groups in one molecule has
not yet been reported. We have found that molecular chiral-
ity greatly affects the supramolecular self-assembled struc-
tures in such hierarchical chirality.
Results and Discussion
Synthesis of the folic acid derivative 1: Folic acid derivative
1 was prepared as shown in Scheme 2. 2-[3,4-Bis(hexyloxy)-
phenyl]ethanol (4), N-Fmoc-glutamic acid, and N10-(trifluoro-
acetyl)pteroic acid were synthesized according to the litera-
ture.[7d] Esterification of 4 with N-Fmoc-l-glutamic acid, fol-
lowed by deprotection with piperidine as a base, gave 5a in
a yield of 67%. Similarly, esterification of 4 with N-Fmoc-d-
glutamic acid and subsequent deprotection afforded 5b in
75% yield. Oligo(glutamate) derivatives 2a–c were obtained
in moderate yields after repetition of the same procedure
with 5a and 5b as starting materials. Finally, 1a–c were pre-
pared after coupling of compounds 2 with N10-(trifluoro-
acetyl)pteroic acid.
Self-assembly of 1 in neat states and structural analysis:
Compounds 1a–c exhibit hexagonal columnar phases over
wide temperature ranges (Table 1). Compounds 1a and 1b
show identical thermal properties, while the diastereomer 1c
has a clearing point of 1738C, 118C higher than that of 1a.
Interestingly, the chiral structural change between 1a and
1c induces thermal stabilization.
Scheme 1. Design and structures of folic acid derivatives 1a–c.
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The isotropization temperature of 1a and 1b is 1628C,
while for folic acid derivatives 3 (n=18) with one glutamic
acid moiety, more thermally stable columnar phases are ob-
served over 2008C.[7d] Steric repulsion of the bulky alkyl
part of 1a may suppress effective stacking, resulting in de-
creasing isotropization temperatures.
Variable-temperature infrared (IR) spectra show the for-
mation of hydrogen bonds involving the pterin rings. The
À
pterin ring N H stretching bands show three broad peaks
(3334, 3160, and 3054 cmÀ1), indicating the disklike aggrega-
tion of the folic acid derivatives[7d] (see Supporting Informa-
tion). Small-angle X-ray scattering (SAXS) measurements
show that the diameters of the self-assembled columns of 1a
and 1c are 48 and 49 Š, respectively (see Supporting Infor-
mation). These values agree well with that estimated by the
MM2method for the tetramer (50 Š). Folic acid is known
to form disklike tetramers through these intermolecular hy-
drogen bonds.[6a–c,7] The current observations suggest that
compounds 1a–c self-assemble into disklike tetramers
through intermolecular pterin ring hydrogen bonds, and that
these tetramers stack to form hexagonal columnar struc-
tures.
For 1a and 1b, the addition of sodium triflate (NaO-
SO2CF3, 25 mol%) increases their clearing points from 162
to 1698C, and also induces the cubic phases above 1438C
(Table 1). No thermal stabilization of the mesophases is ob-
served for the complex of diastereomer 1c and sodium tri-
flate (25 mol%). We have recently reported that a com-
pound analogous to 1a but possessing undecyl chains shows
a chiral cubic phase.[7a] We focus here on the columnar
phase relevant to self-assembled structures in the solution
state. The SAXS profiles of 1a–c forming columnar phases
in the presence of NaOSO2CF3 show the same trends as
those of 1a–c alone (see Supporting Information); these re-
sults suggests that diastereomer 1c and its complex with
sodium salts forms stacked
Scheme 2. a) N-Fmoc-glutamic acid, DMAP, EDC, CH2Cl2, r.t., 1 d;
b) piperidine, CHCl3, RT, 1 h; c) N10-(trifluoroacetyl)pteroic acid, iBuO-
COCl, Et3N, THF/DMF, 408C, 3 d, dark.
structures similar to compounds
1a and 1b (Scheme 3).
Table 1. Liquid-crystalline behavior of 1 and complexes of 1/NaOSO2CF3 on the second heating.
Compounds[a]
Phase transition behavior[c]
Lattice
Circular dichroism (CD) and
UV/Vis spectra of thin films of
1a and 1a/NaOSO2CF3 were
measured in the hexagonal col-
umnar states (Figure 1). The
samples were prepared on
quartz plates by casting solu-
tions of the compounds pre-
pared in chloroform. The CD
spectrum of pure 1a is inactive
(Figure 1a), indicating that the
columnar structures formed do
parameter [Š][e]
1a
1b
G
G
G
G
Colh
Colh
Colh
Colh
À28
Colh
Colh
Colh
Colh
Cub
Cub
Cub
Cub
162(4.4)
162(6.4)
173 (5.3)
162(6.7)
169 (6.9)
169 (6.4)
171 (11)
169 (2.8)
Iso
Iso
Iso
Iso
Iso
Iso
Iso
Iso
48.3
47.7
48.8
48.5
51.0
51.3
51.2
50.2
À28
1c
À19
1a+1b[b]
À28
1a/NaOSO2CF3
1b/NaOSO2CF3
1c/NaOSO2CF3
(1a+1b)/NaOSO2CF3
G
G
G
G
À22
À22
À16
À22
143 (–[d]
143 (–[d]
143 (–[d]
143 (–[d]
)
)
)
)
[b]
[a] Molar ratio of 1/NaOSO2CF3 =0.25. [b] Racemic mixture of 1a and 1b. [c] Transition temperatures [8C]
and enthalpy changes [kJmolÀ1] in parentheses. G: glassy; Colh: hexagonal columnar; Cub: cubic; Iso: isotrop-
ic. [d] Transitions from columnar to cubic phases were not detected on DSC thermograms. [e] Colh phase at
608C.
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Folic Acid Derivatives
5942– 5951
effects of polar and apolar envi-
ronments on supramolecular
chirality induction of 1.
The CD and UV/Vis spectra
of 1a in chloroform are shown
in Figure 2. The absorption of
the pterin rings of 1a appears
at 280 and 352 nm (Figure 2b),
and an inactive CD spectrum is
observed (Figure 2a). The 1a/
NaOSO2CF3 complex (molar
ratio
of
1a/NaOSO2CF3 =
Scheme 3. Schematic representation of self-assembled 1a/NaOSO2CF3 in hexagonal columnar phases.
1:0.25) induces a coupled CD
curve centered at 280 nm with a
positive extreme at 293 nm, a
negative extreme at 272 nm,
and a broad negative CD band
around 360 nm (Figure 2a).
It is considered that disklike
tetramers of 1 stack to form
columnar assemblies in the
presence of NaOSO2CF3 for
the following reasons:
1) In our previous work on
folic acid derivatives in neat
states,[7a] we reported that
an analogous folic acid com-
pound possessing undecyl
chains formed the disklike
tetramer in the presence of
alkali metal ions.
2) The
infrared
spectrum
in
(3000–3500 cmÀ1) of
1
Figure 1. a) CD spectra of 1a (broken line) and 1a/NaOSO2CF3 (solid line; molar ratio=0.25); b) CD spectra
of 1b (broken line) and 1b/NaOSO2CF3 (solid line; molar ratio=0.25); c) UV spectra of 1a (broken line) and
1a/NaOSO2CF3 (solid line; molar ratio=0.25); d) CD spectra of 1c (broken line) and 1c/NaOSO2CF3 (solid
line). All spectra were measured in the hexagonal columnar phase at 608C.
concentrated chloroform is
almost identical to those of
not have chiral order. In contrast, the addition of sodium tri-
flate to 1a gives rise to a positive CD spectrum in the ab-
sorption wavelength ranges of pterin rings (Figure 1a,c).
These results show that the introduction of sodium ions into
the columnar assemblies leads to the formation of supra-
molecular chiral structures along the columnar axis. Sodium
salts play important roles not only in the stabilization of the
self-assembled structures, but also in the induction of the
supramolecular chiral assemblies, in which helical stacking
may be induced. For 1c, less active CD spectra are seen
both in the presence and in the absence of sodium ions (Fig-
ure 1d), suggesting that the molecular structure of 1c is not
suitable for the formation of chiral columnar structures.
Self-assembly of 1 in solution: We have examined the self-
assembly behavior of 1 in dilute solution states and have
found that supramolecular chirality in solution is induced by
Figure 2. a) CD and b) UV/Vis spectra of 1a (broken line) and 1a/NaO-
SO2CF3 (solid line; molar ratio=0.25) in chloroform (5.0”10À3 m) at
208C.
the salt for self-assembled 1. Particularly interesting are the
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T. Kato et al.
FULL PAPER
1 in the LC states and of the tetramer form of 3 (n=
11)[7d] (see Supporting Information).
3) Moreover, an aqueous solution of a simple sodium folate
exhibits an induced CD spectrum generated through hel-
ical stacking of self-assembled tetramers of folic
acids.[6b,c]
4) For guanosine derivatives with the same hydrogen-
bonded pattern as 1, a single-crystal X-ray structure de-
termination shows the formation of the same hydrogen-
bonded pattern as seen in the stacked tetramer structure
of 1 in the presence of alkali metal ions.[3a] When dis-
solved in tetrachloroethane, these G-quadruplex crystals
produced a strong CD spectrum in the absorption ranges
of the guanine chromophores, originating from helical
stacking of tetramers.
form columnar assemblies through ion–dipolar interactions
between sodium salts and the carbonyl groups of the pterin
rings (Scheme 4).
Compound 1a has three chiral groups, and we are inter-
ested in how the molecular chirality of these three amino
acids in 1a affects its self-assembled structures in solution.
The CD spectra of 1b and 1c and their complexes are com-
pared with those of 1a and its complex in Figure 3. Each of
the single components of 1a–c has only a weak CD spec-
trum (Figure 3a), while the complex of the enantiomer 1b
and NaOSO2CF3 shows a negative Cotton effect (Figure 3b),
which is a mirror image of the induced CD spectrum of 1a/
NaOSO2CF3. These results indicate the formation of the
same chiral columnar assemblies of 1b as in 1a, but with re-
versed helicity. In contrast, no supramolecular chirality is
observed for 1c either in the presence or in the absence of
sodium salts, and the diastereomer 1c/NaOSO2CF3 shows
only an inactive CD spectrum. Thus, compound 1c may
form columnar structures con-
These results suggest that compounds 1 self-assemble in
chloroform to form disklike tetramers, which should stack to
sisting of randomly stacked tet-
ramers.
A racemic mixture of equi-
molar 1a and 1b was also pre-
pared; Figure 3b shows that no
CD effect is observed for the
racemic mixture in the presence
of sodium salts.
When 1a/NaOSO2CF3 was
mixed with 1b/NaOSO2CF3 in a
different molar ratio, the CD
intensity decreased in propor-
tion to the added amount of 1b
(within experimental error), in-
dicating that no specific cooper-
ative interactions were occur-
1
ring. The H NMR spectrum of
an equimolar mixture of (1a+
1b)/NaOSO2CF3 is identical to
those of 1a or 1b alone in the
presence of the salts (see Sup-
porting Information). These re-
sults suggest that homochiral
tetramers are formed and that
no cooperative interactions
exist between the columns.[9f,14]
It is difficult to distinguish by
spectroscopic methods whether
a column consists of pure enan-
tiomers or stacks of segmented
homochiral columns. For neat
columnar materials, a racemic
mixture of 1a and 1b shows the
same thermal properties as 1a
alone, both in the presence and
in the absence of sodium salts
(Table 1). Moreover, XRD pro-
files are identical for the colum-
nar liquid crystals of the race-
Scheme 4. Schematic representation of self-assembled 1a/NaOSO2CF3 in chloroform solution state.
mic mixture and the enantio-
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Folic Acid Derivatives
5942– 5951
Figure 4. a) 1H NMR spectrum of 1a; b) 1H NMR spectrum of 1a/NaO-
SO2CF3; c) 1H NMR spectrum of 1b/NaOSO2CF3; d) 1H NMR spectrum
of 1c/NaOSO2CF3; e) 1H NMR spectrum of 1c. Asterisks denote amide
protons of oligo(glutamate) parts. All spectra were measured in chloro-
form-d (5.0”10À3 m).
Figure 3. CD spectra of 1a–c a) in the absence and b) in the presence of
NaOSO2CF3 (molar ratio=0.25) in chloroform (5.0”10À3 m, 2 08C).
merically pure components. These results are consistent with
our proposed formation of homochiral columns.
1
The H NMR spectrum of 1 in CDCl3 at the same concen-
tration as used in the CD measurements is shown in
Figure 4. No difference in the spectrum of 1 is observed in
the absence or in the presence of NaOSO2CF3 (Figure 4a,b).
The two complexes of 1a and 1b with NaOSO2CF3 have
identical spectra, as would be expected (Figure 4b,c), while
for 1c/NaOSO2CF3, the amide proton peaks appear at
7.8 ppm (Figure 4d), due to weak hydrogen bonding. The
hydrogen-bonded structures of self-assembled 1c/NaO-
SO2CF3 are different from those of 1a and 1b, although
these hydrogen-bonding properties are the same for the
complex of 1c/NaOSO2CF3 and compound 1c alone (Fig-
ure 4d,e).
Scheme 5. Schematic representation of the formation of chiral columnar
assemblies in chloroform solution.
These results suggest that supramolecular chirality in-
duced in the aggregates of 1a–c is dependent on the chirali-
ty of the oligo(glutamate) parts (Scheme 5). Moreover, co-
operative interactions such as ion–dipolar interactions and
hydrogen bonds play key roles in transferring the molecular
chirality of the oligo(glutamate) parts to the supramolecular
chirality of the assemblies.
crophase segregation at the nanometer scale and the lipo-
philic units surround the column. Self-assembly behavior in
dodecane was examined for 1a–c. The UV/Vis and CD spec-
tra of 1a alone in dodecane are compared with those in
chloroform in Figure 5. A strong negative CD spectrum is
induced for 1a in dodecane, whereas no appreciable CD is
observed in chloroform (Figure 5a). The red shift from
357 nm to 367 nm in the UV/Vis spectra indicates that the
tetramers of 1a stack in dodecane, resulting in p–p interac-
tions between the pterin rings (Figure 5b). These results sug-
gest that use of dodecane as solvent results in self-organiza-
Self-assembly of 1 in a lipophilic environment: In apolar sol-
vents we expected that molecular assembly of the columnar
structures for 1a–c should proceed due to lipophilic interac-
tions between the alkyl chains of 1 and the solvent (dodec-
ane). The three components of the molecules undergo mi-
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T. Kato et al.
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the internal chirality (the Chiral I part of 1a–c in Scheme 1)
of the oligo(glutamic acid) parts; that is, the chirality closest
to the pterin rings. The effects of the apolar environment on
the self-assembly of 1a–c are summarized in Scheme 6.
Figure 5. a) CD and b) UV/Vis spectra of 1a in chloroform (broken line)
and in dodecane (solid line) solution (5.0”10À4 m at 208C).
Scheme 6. Schematic representation of the formation of chiral columnar
assemblies in dodecane solution.
tion of compound 1a in the absence of salts, the chiral as-
semblies being formed solely through cooperative hydrogen
bonds and lipophilic interactions. In this case, the lipophilic
fraction of the material increases and the microphase-segre-
gated structures are enhanced, resulting in the induction of
supramolecular chirality without the need for the ion. The
IR spectrum (3000–3500 cmÀ1) of a concentrated solution of
1a in dodecane (1.0”10À2 m) is similar to those in chloro-
form in the presence of salts and in the LC state; these re-
sults indicate that compound 1a undergoes disklike aggrega-
tion in hydrocarbon solvents.
It should be noted that 1c adopts the same supramolec-
ular chiral structures as 1b in dodecane. However, 1c forms
a different structure both in chloroform and in columnar
liquid crystal states, as shown in the CD spectra of 1 (Fig-
ures 1 and 3). These observations suggest that this series of
molecules is capable of changing its supramolecular chiral
structures depending on external environments.
The effects of hierarchical molecular chirality on the self-
assembled structures were also studied for 1a–c in dodecane
(Figure 6). The induced CD spectra of 1a and 1b are mirror
images, as in the solutions prepared in chloroform. Com-
pound 1b induces a positive CD spectrum, in contrast to 1a.
It is of interest that the positive CD spectrum of 1c is simi-
lar to that of 1b, while its intensity is greater than that of
1b. The stronger Cotton effect should be due to more stable
chiral aggregates formed by 1c. These results indicate that
the supramolecular chirality of the assemblies depends on
Meijer reported that disk-shaped molecules helically as-
semble in an apolar hydrocarbon solvent, while they molec-
ularly dissociate in chloroform.[13b] Unlike Meijerꢁs com-
pounds, the materials in this study—the disk-shaped folic
acid tetramers in chloroform—helically assemble to exhibit
Cotton effects in the presence of salts. In dodecane they as-
semble in a different manner, to induce circular dichroism
in the absence of salts. It should be noted that the folic acid
derivatives form chiral columnar structures both in polar
and in apolar solvents.
The helical stacked disklike tetramers should be formed
in dodecane solution. In the case of lyotropic liquid crystal-
line properties of compound 3 (n=11), which forms a ther-
motropic smectic phase in the bulk state, the compound
shows hexagonal and nematic columnar phases without
added ions.[7c] The formation of nematic columnar phases
supports the involvement of the stacked tetramer. Without
templating sodium salts, self-assembly of compounds 1a–c
should be strongly affected by hydrogen bonds of peripheral
glutamic acid parts. The diastereomer 1c forms the same
chiral structure as 1b, as shown in Figure 6. The inner chiral
parts of the oligo(glutamate) moieties in 1b and 1c have the
same stereoregularity. Thus, from this model we suggest that
the chirality of the self-assembled columns is determined by
the chiral part closest to the pterin ring (Scheme 6). Anoth-
Figure 6. CD spectra of 1a–c in dodecane solution (5.0”10À4 m at 208C).
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Folic Acid Derivatives
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Synthesis
Bis{2-[3,4-bis(hexyloxy)phenyl]ethyl} l-glutamate (5a): 1-Ethyl-3-(3-di-
methylaminopropyl)carbodiimide hydrochloride (EDC, 6.65 g,
er possible structure would be supramolecular pterin helices
similar to guanosine helices, as recently suggested by Gottar-
elli and co-workers.[6d] These helices are formed through the
same disklike hydrogen bonding of pterin rings in the ab-
sence of templating ions. Furthermore, the CD patterns of
solutions of 1a–c in chloroform and dodecane are similar to
those of guanosine derivatives in dichloroethane and dodec-
ane. According to modeling simulations,[6d] the energies of
the two assembled structures are almost the same for guano-
sine materials.
34.7 mmol), dissolved in dry CH2Cl2 (30 mL), was added to a mixture of
4 (8.69 g, 26.9 mmol), N-Fmoc-l-glutamic acid (4.81 g, 13.0 mmol), and 4-
dimethylaminopyridine (DMAP, 0.244 g, 2.00 mmol) dissolved in dry
CH2Cl2 (100 mL). The solution was stirred under an Ar atmosphere at
room temperature for 12h. The reaction mixture was extracted three
times with ethyl acetate, the collected organic fractions were washed with
saturated aquesous NaCl and dried over MgSO4, and the solvent was re-
moved in vacuo. The residue was dissolved in CHCl3 (100 mL), piperi-
dine (5.0 mL) was added, and the mixture was left stirring at room tem-
perature for 1 h. The reaction mixture was poured into saturated aqueous
NH4Cl (150 mL) and was extracted with CHCl3 (3”100 mL). The collect-
ed organic fractions were washed with saturated aqueous NaHCO3 and
dried over MgSO4, and the solvent was removed under reduced pressure.
The crude product was purified by silica gel column chromatography
(hexane/ethyl acetate 1:1) to afford 5a (6.86 g, 9.08 mmol, 67%) as a pale
yellow oil.Spectroscopic data for 5a are given in our previous paper.[7d]
Conclusion
This paper reports supramolecular chirality arising from hi-
erarchical chiral structures in oligo(glutamate) moieties in
folic acid derivatives 1a–c. The self-assembled columns of
the folic acid derivatives are formed through cooperative
secondary interactions, such as hydrogen bonds, stacking in-
teractions, ion–dipolar interactions, and nanophase segrega-
tion of molecular block structures. The addition of salts trig-
gers chiral self-assembly of 1a–c in the liquid-crystalline
state and in polar environments, whereas chiral self-assem-
bly in 1a–c proceeds spontaneously in apolar environments,
induced by lipophilic interactions. The chiral behavior of the
compounds depends on their environments. This is the first
example of tuning of supramolecular chirality through hier-
archical chiral block structures. The results presented here
may provide a new design strategy for developing chiral
functional materials.
Bis{2-[3,4-bis(hexyloxy)phenyl]ethyl} d-glutamate (5b): N-Fmoc-d-gluta-
mic acid (2.51 g, 6.80 mmol) and DMAP (0.163 g, 1.33 mmol) were added
to a solution of 4 (4.31 g, 13.4 mmol) and dry CH2Cl2 (100 mL). EDC
(6.65 g, 34.7 mmol) dissolved in dry CH2Cl2 (30 mL) was added to the
mixture, followed by constant stirring under an Ar atmosphere at room
temperature for 12h. The procedure was the same as that used for 5a.
Yield: 3.79 g, 5.02mmol, 75%. The spectroscopic data for 5b were identi-
cal to those for 5a.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(l-glutamoyl)-l-
glutamic acid (2a): N-Fmoc-l-glutamic acid (0.545 g, 1.48 mmol) and
DMAP (35.4 mg, 0.290 mmol) were added to a solution of 5a (2.18 g,
2.88 mmol) and dry CH2Cl2 (100 mL). EDC (0.693 g, 3.62mmol), dis-
solved in dry CH2Cl2, (30 mL) was added to the solution, which was
heated at reflux under an Ar atmosphere at 508C for 3 h. The reaction
mixture was extracted with ethyl acetate (3”50 mL), the collected organ-
ic fractions were washed with saturated aqueous NaCl and dried over
MgSO4, and the solvent was removed under reduced pressure. The resi-
due was dissolved in CHCl3 (100 mL), piperidine (5 mL) was added, and
the reaction mixture was stirred at room temperature for 1 h. The reac-
tion mixture was poured into saturated aqueous NH4Cl (150 mL) and ex-
tracted with CHCl3 (3”50 mL). The collected organic fractions were
washed with saturated aqueous NaHCO3 and dried over MgSO4, and the
solvent was removed in vacuo. The crude product was purified by flash
column chromatography (silica gel, gradient hexane/ethyl acetate/chloro-
form 2:5:3 followed by CHCl3/MeOH 10:1) to give 2a (1.30 g,
0.804 mmol, 56%) as a colorless solid. Rf =0.20 (hexane/ethyl acetate
2:5); 1H NMR (400 MHz, CDCl3): d=8.02(d, J=9 Hz, 1H), 7.60 (d, J=
8 Hz, 1H), 6.68–6.83 (m, 12H), 4.70–4.71 (m, 1H), 4.59–4.64 (m, 1H),
4.20–4.32 (m, 8H), 3.92–3.98 (m, 16H), 3.23–3.32 (m, 1H), 2.80–2.89 (m,
8H), 2.30–2.41 (m, 6H), 2.13–2.19 (m, 4H), 1.77–1.84 (m, 18H), 1.22–
1.47 (m, 48H), 0.90 ppm (t, J=6 Hz, 24H); IR: n˜ =3444, 3312, 3217,
3048, 2956, 2931, 2859, 1732, 1686, 1652, 1590, 1519, 1468, 1428, 1392,
1264, 1236, 1171, 1140, 1071, 1017, 799 cmÀ1; MS (MALDI): m/z: 1623.06
[M+H]+; calcd 1623.11; elemental analysis calcd (%) for C95H151N3O18: C
70.29, H 9.38, N 2.59; found: C 70.67, H 9.47, N 2.93.
Experimental Section
General methods and materials: All starting materials were obtained
from commercial suppliers and were used without further purification.
Analytical thin-layer chromatography (TLC) was performed on 0.25 mm
silica gel plates (E. Merck, Silica Gel F254), and silica gel column chroma-
tography was carried out with silica gel 60 (Kanto Chemicals, Silica
Gel 60, spherical, 40–50 mm). Recycling preparative GPC was carried out
with a Japan Analytical Industry LC-908 chromatograph. IR measure-
ments were conducted on a JASCO FT/IR-660 Plus instrument in KBr.
1H and 13C NMR spectra were recorded on a JEOL JNM-LA400 instru-
ment, while 19F NMR spectra were recorded on a Varian Mercury 300
1
machine at 282 MHz. Chemical shifts of H, 13C, and 19F NMR signals are
expressed in parts per million (d) with use of the internal standards
Me4Si (d=0.00 ppm), CDCl3 (d=77.00 ppm), and CFCl3 (d=0.00 ppm),
respectively. Coupling constants (J) are reported in Hertz (Hz). Mass
spectra were recorded on a PerSeptive Biosystems Voyager-DE STR
spectrometer. Elemental analyses were carried out on a Perkin–Elmer
CHNS/O 2400 apparatus. DSC measurements were conducted on a Met-
tler DSC 30 to determine the thermal transitions (scanning rate:
108CminÀ1). An Olympus BH-2polarizing optical microscope fitted with
a Mettler FP82HT hot stage was used for visual observation. X-ray dif-
fraction measurements were carried out on a Rigaku RINT 2100 diffrac-
tometer with a heating stage and with use of Ni-filtered CuKa radiation.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(d-glutamoyl)-d-
glutamic acid (2b): N-Fmoc-d-glutamic acid (0.781 g, 2.12 mmol) and
DMAP (52.4 mg, 0.429 mmol) were added to a solution of 5b (3.14 g,
4.15 mmol) and dry CH2Cl2 (100 mL). EDC (0.944 g, 4.92mmol) dis-
solved in dry CH2Cl2 (30 mL) was added to the solution, which was
heated at reflux under an Ar atmosphere at 508C for 3 h. The procedure
was the same as that used for 2a. Yield: 2.27 g, 1.40 mmol, 67%. The
spectroscopic data for 2b were identical to those for 2a.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(l-glutamoyl)-d-
glutamic acid (2c): N-Fmoc-d-glutamic acid (0.622 g, 1.68 mmol) and
DMAP (68.2mg, 0.558 mmol) were added to a solution of 5a (2.48 g,
3.28 mmol) and dry CH2Cl2 (100 mL). EDC (1.10 g, 5.74 mmol), dissolved
in dry CH2Cl2, (100 mL) was added to the solution, which was heated at
reflux under an Ar atmosphere at 508C for 3 h. The procedure was the
same as that used for 2a. Yield: 1.26 g, 0.780 mmol, 48%; Rf =0.20
(hexane/ethyl acetate 2:5); 1H NMR (400 MHz, CDCl3): d=8.17 (d, J=
Absorbance and circular dichroism measurements: The UV/Vis absorp-
tion spectra were recorded on an Agilent 8453 spectrophotometer in
1 mm and 100 mm rectangular quartz cells. Circular dichroism spectra
were recorded on a Jasco J-700 spectropolarimeter fitted with a Jasco
PTC-423 L temperature controller in 1 mm and 100 mm rectangular
quartz cells. UV/Vis and CD measurements in LC states were conducted
on the same spectrometer fitted with a Mettler FP82HT hot stage in
200 mm quartz plates.
Chem. Eur. J. 2004, 10, 5942– 5951
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5949

T. Kato et al.
FULL PAPER
8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.69–6.81 (m, 12H), 4.62–4.67 (m, 2H),
4.21–4.33 (m, 8H), 3.92–3.99 (m, 16H), 3.61 (t, J=5 Hz, 1H), 2.81–2.90
(m, 8H), 2.22–2.40 (m, 6H), 2.03–2.15 (m, 4H), 1.74–1.83 (m, 18H),
1.24–1.47 (m, 48H), 0.90 ppm (t, J=7 Hz, 24H); MS (MALDI): m/z:
1622.68 [M+H]+; calcd 1623.11; elemental analysis calcd (%) for
C95H151N3O18: C 70.29, H 9.38, N 2.59; found: C 70.26, H 9.38, N 2.70.
cially supported by a Grant-in-Aid for Scientific Research on Priority
Areas of “Dynamic Control of Strongly Correlated Soft Materials”
(No. 413/13031009) and a Grant-in-Aid for the 21 st Century COE Pro-
gram for Frontiers in Fundamental Chemistry from the Ministry of Edu-
cation, Culture, Sports, Science and Technology.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(l-glutamoyl)-N-
[N10-(trifluoroacetyl)pteroyl]-l-glutamic acid (1a): N10-(Trifluoroacetyl)p-
teroic acid (0.556 g, 1.36 mmol) was dried over P2O5 for 24 h in vacuo,
dry DMF (10 mL) was added, and the mixture was stirred under an Ar
atmosphere. Triethylamine (230 mL, 1.66 mmol) and isobutyl chlorofor-
mate (198 mL, 1.51 mmol) were added dropwise to the resulting dark red
solution, which was stirred for 1 h at room temperature. Compound 2a
(1.18 g, 0.730 mmol), dissolved in dry THF (20 mL), was then added, and
the mixture was left stirring for 3 days in the dark at 408C under an Ar
atmosphere. The reaction mixture was filtered through a Celite pad and
was washed with CHCl3 (50 mL) and EtOH (10 ml), and the solvent was
removed in vacuo. The residue was purified by flash column chromatog-
raphy (silica gel, CHCl3/EtOH/benzene 13:1:1), followed by GPC to
yield 1a (0.572g, 0.284 mmol, 39%) as a yellow wax. Rf =0.56 (CH2Cl2/
MeOH 10:1); 1H NMR (400 MHz, CDCl3): d=8.78 (brs, 1H), 8.09–8.29
(m, 1H), 7.88 (d, J=8 Hz, 2H), 7.55–7.76 (m, 1H), 7.42 (d, J=8 Hz),
6.69–6.79 (m, 12H), 5.14 (brs, 2H), 4.64–4.81 (m, 1H), 4.43–4.60 (m,
1H), 4.10–4.43 (m, 8H), 3.78–4.03 (m, 16H), 3.64–3.69 (m, 1H), 2.67–
3.00 (m, 8H), 2.28–2.57 (m, 6H), 1.90–2.26 (m, 6H), 1.64–1.90 (m, 16H),
1.17–1.55 (m, 48H), 0.74–1.06 ppm (m, 24H); 19F NMR (300 MHz,
CDCl3): d=À67.7 ppm; IR: n˜ =3366, 2956, 2932, 2860, 1734, 1699, 1653,
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1540, 1517, 1473, 1429, 1395, 1263, 1212, 1163, 1141, 1018, 802, 668 cmÀ1
;
MS (MALDI): m/z: 2013.28 [M+H]+; calcd 2013.17; elemental analysis
calcd (%) for C111H160F3N9O21: C 66.21, H 8.01, F 2.83, N 6.26, found: C
66.25, H 8.17, N 6.70.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(d-glutamoyl)-N-
[N10-(trifluoroacetyl)pteroyl]-d-glutamic acid (1b): N10-(Trifluoroace-
tyl)pteroic acid (0.608 g, 1.49 mmol) was dried over P2O5 for 24 h in
vacuo, dry DMF (10 mL) was added, and the mixture was stirred under
an Ar atmosphere. Triethylamine (238 mL, 1.72mmol) and isobutyl chloro-
formate (215 mL, 1.64 mmol) were added dropwise to the solution, and
the mixture was left to stir for 1 h at room temperature. Compound 2b
(1.87 g, 1.15 mmol), dissolved in dry THF (20 mL), was then added to the
mixture, which was left to stir for 3 days in the dark at 408C under an Ar
atmosphere. The workup procedure was the same as that used for 1a.
Yield: 0.965 g, 0.479 mmol, 42%. The spectroscopic data for 1b were
identical to those for 1a.
Tetra{2-[3,4-di(hexyloxy)phenyl]ethyl} ester of a,g-bis(l-glutamoyl)-N-
[N10-(trifluoroacetyl)pteroyl]-d-glutamic acid (1c): N10-(Trifluoroacetyl)p-
teroic acid (0.386 g, 0.945 mmol) was dried over P2O5 for 24 h in vacuo,
dry DMF (10 mL) was added, and the mixture was stirred under an Ar
atmosphere. Triethylamine (151 mL, 1.09 mmol) and isobutyl chlorofor-
mate (137 mL, 1.04 mmol) were added dropwise to the solution, which
was stirred for 1 h at room temperature. Compound 2c (1.16 g,
0.72mmol), dissolved in dry THF (20 mL), was then added to the reac-
tion mixture, which was stirred for 3 days in the dark at 408C under an
Ar atmosphere. The workup procedure was the same as that used for 1a.
Yield: 0.685 g, 0.340 mmol, 47%; Rf =0.56 (CH2Cl2/MeOH, 10:1); 1H
NMR (400 MHz, CDCl3): d=8.78 (s, 1H), 7.90 (d, J=7 Hz, 2H), 7.75–
7.83 (m, 1H), 7.60–7.69 (m, 1H), 7.45 (d, J=7 Hz, 2H), 6.59–6.87 (m,
12H), 4.94–5.11 (m, 2H), 4.75–4.86 (m, 1H), 4.48–4.66 (m, 1H), 4.07–
4.34 (m, 8H), 3.87–3.97 (m, 16H), 2.77–2.85 (m, 8H), 2.28–2.54 (m, 6H),
2.07–2.27 (m, 6H), 1.63–1.90 (m, 16H), 1.17–1.54 (m, 48H), 0.72–
0.97 ppm (m, 24H); MS (MALDI): m/z 2013.44 [M+Na]+; calcd=
2013.17; elemental analysis calcd (%) for C111H160F3N9O21: C 66.21, H
8.01, F 2.83, N 6.26; found: C 66.42, H 8.08, N 6.53.
Acknowledgements
We gratefully acknowledge Prof. E. Yashima and Dr. T. Nishimura for
MM2modeling calculations. We would also like to thank Prof. E. Yashi-
ma and Prof. E. W. Meijer for helpful discussions. This work was finan-
5950
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Folic Acid Derivatives
5942– 5951
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Received: May 1, 2004
Published online: November 5, 2004
Chem. Eur. J. 2004, 10, 5942– 5951
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5951