Homochiral supramolecular polymerization of an "S"-shaped chiral monomer: Translation of optical purity into molecular weight distribution

Article abstract of DOI:10.1021/ja028403h

An "S"-shaped chiral motif of a p-xylylene-bridged bis(cyclic dipeptide) (1), having four hydrogen-bonding amide functionalities, formed a homochiral supramolecular polymer in solution. X-ray crystallography of a slightly modified version of 1 for an enha

Full text of DOI:10.1021/ja028403h

Published on Web 10/31/2002
Homochiral Supramolecular Polymerization of an “S”-Shaped Chiral
Monomer: Translation of Optical Purity into Molecular Weight Distribution
Yasuhiro Ishida* and Takuzo Aida*
Department of Chemistry and Biotechnology, Graduate School of Engineering,The UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
Received September 4, 2002
Scheme 1. Schematic Representation of Homochiral
Supramolecular Polymerization of 1
Supramolecular polymers, formed via noncovalent interactions,
have attracted increasing attention as a new class of environment-
responsive polymeric materials because of their reversible polym-
erization/depolymerization characteristics.1 For example, those via
quadruple hydrogen-bonding interactions2 have been demonstrated
to cope with both a sufficient thermodynamic stability (comparable
to that of covalent polymers) and stimuli-responsive depolymeri-
zation characteristics.3 We report here the first example of “ho-
mochiral supramolecular polymerization”, where a racemic cyclic
and D-1 composed of L- and D-valine units, respectively, are
expected to possess “S” and “anti-S”-shaped (NH w CO) w
(CO w NH) sequences. Such a conformational preference results
in an antiparallel arrangement of the two hydrogen-bonding amide
functionalities on each side of the “S” (or “anti-S”) shape, thereby
enhancing the steric requisites for the complementary hydrogen-
bonding interactions (Scheme 1).
L-1 and D-1 were synthesized by diastereoselective alkylation
of
1,4-bis(4-methoxybenzyl)-3-(1-methylethyl)piperazine-2,5-
dione,8 followed by oxidative removal of the N-protecting groups.9
We succeeded in obtaining a crystal structure of L-3 (Figure 1), a
slightly modified version of 1 for an enhanced crystallinity, which
clearly displayed an “S”-shaped conformation, as expected for 1,4-
xylylene-bridged bis(diketopiperadine) derivatives. Furthermore, L-3
in the crystalline state forms a columnar assembly via complemen-
tary hydrogen bonds at every amide functionality, suggesting that
1 could form a one-dimensional supramolecular polymer in
solution.10,11
dipeptide derivative (1) in solution forms two enantiomeric su-
pramolecular polymers of individual optical antipodes, poly(L-1)
and poly(D-1), via enantioselective hydrogen-bonding interactions
(Scheme 1). As the result of this unique chiral association event,
“optical purity of monomer 1” is translated into “molecular weight
distribution of the resulting polymer”. Homochiral supramolecular
polymers can be regarded as discrete one-dimensional conglomer-
ates. Over the past 150 years since the discovery of Pasteur,4
successful examples of spontaneous optical segregation have been
limited to crystalline states5 and more recently extended to liquid
crystalline states.6 However, no examples have been reported for
the formation of large homochiral assemblies in solution.
Size-exclusion chromatography (SEC) indicated that 1 in aprotic
solvents forms a supramolecular polymer,12 whose average molec-
ular weight is dependent on the concentration of 1. For example,
A xylylene-bridged bis(cyclic dipeptide) (1), which was chosen
as the monomer for supramolecular polymerization, exhibited an
extremely high enantioselectivity in hydrogen-bonding interactions.
Conformational studies on cyclic dipeptides with benzylic side
chains have indicated that the aromatic groups most likely “hover
over” the diketopiperadine ring, due to a dipole-dipole interaction.7
Hence, 1 having a p-xylylene bridge should adopt an “S”-shaped
conformation with the aromatic ring stacked by the two diketo-
piperadine units. According to molecular models, monomers L-1
Figure 1. Crystal structure of L-3 viewed along (a) the c-axis and (b) the
a-axis. The dotted lines represent hydrogen bonds. Solvent molecules are
omitted for clarity.
* To whom correspondence should be addressed. E-mail: aida@
macro.t.u-tokyo.ac.jp and ishida@chiral.t.u-tokyo.ac.jp.
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J. AM. CHEM. SOC. 2002, 124, 14017-14019
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Figure 3. 1H NMR spectral changes of an amide-NH signal of L-6 (1.0
mM) upon mixing with (a) L-5 (1.0 mM) and (b) D-5 (1.0 mM) in freshly
distilled CDCl3 at 20 °C.
Scheme 2. Schematic Representations of Size-Exclusion
Chromatographic (SEC) Profiles of an Enantiomerically
Unbalanced (D-enriched) Monomer, as Expected for (a)
Non-stereoselective, (b) Homochiral, and (c) Heterochiral
Polymerizations
Figure 2. Size-exclusion chromatography (SEC) traces of L-1 and L-2
with freshly distilled CHCl3 as eluent on a JAIGEL-2.5H-A column,
monitored by a UV detector at 250 and 290 nm, respectively. Loading
concentrations: (a) [L-1]loaded ) 25 mM, (b) [L-1]loaded ) 0.5 mM, and (c)
[L-2]loaded ) 25 mM. (d) Concentration dependence of retention time (L-1;
filled circles, L-2; open circles).
SEC trace of L-1 (loading concentration: [L-1]loaded ) 25 mM)
with CHCl3 as eluent displayed a monodisperse chromatogram with
a broad tail (Figure 2a), typical of noncovalent polymeric ag-
gregates, whereas that of N-protected L-2 without hydrogen-bonding
capability showed a less broad elution peak with a longer retention
time (Figure 2c).13 Since supramolecular polymerization has a
dynamic character, loading of a lower concentration of L-1 to SEC
obviously resulted in a longer elution time (lower molecular weight)
of the resulting polymer (Figure 2b).
1H NMR spectroscopy at 20 °C of a CDCl3 solution of L-1 at
2.0 mM showed one set of very broad signals due to hydrogen-
bonded amide-NH with significant downfield shifts at δ 9.4 and
9.8 ppm, which turned to ordinary, sharp signals upon addition of
trifluoroacetic acid (2.5%) to break the hydrogen bonds among
L-1.11 Since L-4 with only a single diketopiperadine ring (4.0 mM),
under similar conditions, did not show any sign of hydrogen-
bonding interactions (amide-NH: δ 5.9 ppm),11 a high association
tendency of L-1 is most likely due to the simultaneous participation
of the two diketopiperadine units, to allow the formation of four
In supramolecular polymerization of the chiral monomer, the
molecular weight of polymer and its distribution (MWD) are
generally affected by the stereoselectivity of the association event
as well as the optical purity of the monomer. Scheme 2 shows three
extreme cases of supramolecular polymerization of an enantio-
merically unbalanced monomer (e.g., [D] > [L]). For nonstereo-
selective supramolecular polymerization, SEC profiles (monitored
by absorption [UV] and circular dichroism [CD] detectors) shown
in Scheme 2a are expected, where MWD is unimodal as in the
case of the polymerization of optically pure monomers and should
not change with [L]/[D], whereas the CD intensity response should
just reflect enantiomeric purity of the monomer. Scheme 2b shows
SEC profiles, as expected for perfect homochiral supramolecular
polymerization, where a bimodal MWD should result due to the
formation of poly(L) and poly(D) with different molecular weights,
depending on chiral monomer concentrations [L] and [D], respec-
tively. According to a theoretical prediction,14 the CD response
should initially be positive (or negative) but display a sudden drop
to the baseline level at the beginning of the second peak, due to
partial cancellation in ellipticity of poly(D) by lower-molecular-
1
double-hydrogen bonds (Scheme 1). The H NMR spectrum also
showed that L-1 adopts an “S”-shaped conformation in solution,
where a notable ring current effect from the xylylene unit was
observed for the C*-H resonance (δ 2.85 ppm; for reference, C*-H
in L-4: δ 3.80 ppm).11 As described in the introductory part, the
homochiral association is strongly favored by the “S”-shaped
conformation of 1, since the two diketopiperadine units can
simultaneously participate in hydrogen-bonding interactions. On the
other hand, the heterochiral association of 1 must be unlikely to
occur, since a possible mismatch of the hydrogen-donor/acceptor
arrays would allow only one of the two diketopiperadine units to
participate in hydrogen-bonding interactions (Scheme 1). In fact,
5 and 6, half-protected analogues of 1, formed a stable dimeric
complex only when they were homochiral; the amide-NH signal
of L-6, upon mixing with L-5, showed a 1-ppm downfield shift
due to the hydrogen-bonding interactions (Figure 3a), but the signal
remained totally intact with the addition of D-5 (Figure 3b).
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C O M M U N I C A T I O N S
beginning of the second peak and remained almost unchanged
thereafter (Figure 4f). By virtue of this homochiral supramolecular
polymerization, enantiomerically pure L-1 and D-1 could be isolated
from the fractions corresponding to the shaded parts of the
chromatograms, b, c, e, and f, in Figure 4.11
In conclusion, we demonstrated the first example of spontaneous
optical segregation of a chiral compound in solution, through studies
on supramolecular polymerization of “S”-shaped bis(cyclic dipep-
tide) 1. Here, the optical purity of 1 is translated into molecular
weight distribution, thereby enabling isolation of enantiomers by
means of size-exclusion chromatography. Chiral motifs with “S”-
shaped hydrogen-bonding arrays such as 1, 5, and 6 would also
allow exploration of nonlinear phenomena in asymmetric transfor-
mations.
Acknowledgment. Y.I. thanks the JSPS Young Scientist
Fellowship. We acknowledge K. Sugimoto of Rigaku Corporation
for X-ray crystallography of L-3.
Supporting Information Available: Experimental details for
synthesis of 1-6, details of crystal structure determination of L-3 and
its diastereoisomer, 1H NMR spectra of L-1 and L-4, and experimental
details for the measurements of SEC and VPO of L-1, theoretical
calculation of molecular weight distribution expected for supramolecular
polymerization (PDF). X-ray crystallographic data for L-3 and its
diastereoisomer (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 4. UV (left) and CD (right) responses at 250 nm in size-exclusion
chromatography (SEC) traces of mixtures of L-1 and D-1 (loading
concentration; [L-1 + D-1] ) 25 mM] with freshly distilled CHCl3 as eluent
on a JAIGEL-2.5H-A column at L:D molar ratios of (a) 100:0, (b) 90:10,
(c) 75:25, (d) 50:50, (e) 25:75, (f) 10:90, and (g) 0:100. The shaded parts
were fractionated for the evaluation of optical purity of 1.
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concentration of 1 ([L-1 + D-1]loaded ) 25 mM) (Figure 4, a-g),
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JA028403H
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