One-pot optical resolution of oligopeptide helices through artificial peptide bundling

Article abstract of DOI:10.1002/anie.200460703

The helical sense of the peptidic parts of a cyclodimeric zinc porphyrin host with helical oligopeptide units (1) determines whether a right- or left-handed oligopeptide guest (2) is selectively bound (see picture). In contrast, enantiomers of nonhelical

Full text of DOI:10.1002/anie.200460703

Angewandte
Chemie
Inclusion Compounds
One-Pot Optical Resolution of Oligopeptide
Helices through Artificial Peptide Bundling
Yan-Ming Guo, Hideaki Oike,* Naoko Saeki, and
Takuzo Aida*
Molecular recognition through helix–helix interactions is an
interesting subject in relation to biologically important
peptide bundling.[1] Although the design of peptide bundling
[*] Dr. Y.-M. Guo, Dr. H. Oike, N. Saeki, Prof. T. Aida
Aida Nanospace Project
Exploratory Research for Advanced Technology (ERATO)
Japan Science and Technology Agency (JST)
2-41 Aomi, Koto-ku, Tokyo 135-0064 (Japan)
Fax : (+81)3-3570-9183
E-mail: oike@nanospace.miraikan.jst.go.jp
Prof. T. Aida
Department of Chemistry and Biotechnology
School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax : (+81)3-5841-7310
E-mail: aida@macro.t.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 4915 –4918
DOI: 10.1002/anie.200460703
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4915

Communications
(coiled-coil) based on natural peptide motifs has been studied
The oligopeptide parts in compounds 1–3 contain a-
aminoisobutyric acid (Aib) units (Scheme 1).[7] Poly(Aib) is
known to adopt a dynamic helical structure, which switches
back and forth between right- and left-handed conforma-
tions.[8] Recently, we have found that a cyclodimeric zinc
porphyrin with dynamic oligo(Aib) units can detect the
helical sense of oligopeptides.[9] Although this chiroptical
sensor lacks a stereogenic center, it becomes optically active
through stereochemical interactions with helical guests upon
inclusion in its cavity. In contrast, host 1 and guests 2 and 3
(Scheme 1) possess leucine residues (Leu) as a chiral source,
which can induce, depending on their configurations, either a
right- or left-handed helicity in the oligopeptide chains.
Therefore, the stabilities of the host–guest complexes may be
affected by the conformational matching among the three
single-handed oligopeptide helices. Compounds 1 and 2 also
contain two dehydrophenylalanine (DPhe)[10] units adjacent
to the Leu residue whose benzylidene groups would have a
steric influence on the host–guest interaction.
extensively,[2–4] secondary structure recognition between heli-
cal macromolecules has never been utilized in artificial host–
guest chemistry for the one-pot separation of right- and left-
handed helices in solution.[5,6] Herein, we report the first
example of one-pot optical resolution of helical oligopeptides
(rac-2 and rac-3) through stereoselective helix bundling by
using a cyclodimeric zinc porphyrin host 1 bearing a guest-
binding chiral cavity with two helical peptidic units (Figure 1).
Figure 1. Schematic representation of helix-sense-selective host–guest
complexation.
Scheme 1. Structures of helical oligopeptide host 1 and guests 2–5, as well as molecular models of l-1, l-2, and d-2.
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Cyclic host 1 was obtained by metalation with Zn(OAc)2
of a precursor free-base porphyrin cyclic dimer, synthesized
by coupling of 5,15-bis(3-aminophenyl)-10,20-dimesitylpor-
phyrin with a nonapeptide containing Leu and DPhe residues,
followed by macrocyclization with 5,15-bis(3-carboxyphenyl)-
10,20-dimesitylporphyrin.[7] The CD spectrum (Figure 2a,
right-handed l-2 is favored over left-handed d-2 in the
complexation with l-1. Accordingly, host d-1 (which has left-
handed helical units) shows a much larger affinity toward left-
handed d-2 than right-handed l-2 (Table 1, entry 5), and the
observed Kassoc(dꢀd)/Kassoc(dꢀl) ratio of 4.9:1 is identical to
that observed for l-1ꢀ2 (Table 1, entry 1).
Inclusion complexes l-1ꢀl-2 and l-1ꢀd-2 also display
different CD spectral profiles (Figure 2a). Mixing l-1 with
the favorable guest l-2 (10 equiv) results in the exciton-
couplet at the Soret absorption band of the zinc porphyrin
moieties being red-shifted from 424 to 431 nm (because of the
coodination with the pyridyl terminus of l-2[9]) and signifi-
cantly enhanced (Figure 2a, black!blue curves), whereas
mixing of l-1 with the unfavorable left-handed d-2 (10 equiv)
results in a red-shifted but much less enhanced CD band
(Figure 2a, black!green curves). When d-1 is used as the
host, an analogous CD enhancement is observed upon
complexation with d-2 (Figure 2b, blue curve) rather than
with l-2 (green curve). These observations indicate that the
twisted geometry of the zinc porphyrin units in the host is
likely stabilized by the inclusion of a favorable guest in its
cavity to form a peptide bundle. Interestingly, mixing of l-1 or
d-1 with racemic guest rac-2 (10 equiv) also results in a large
enhancement of the CD signal (Figure 2, black!red curves),
the extent of which is 87% of those observed for the favorable
host–guest combinations (Figure 2, blue curves). This result
suggests the occurrence of optical resolution of rac-2 in
solution by selective binding with 1 under competitive
conditions (Figure 1). To prove this[7] inclusion complex l-
1ꢀ2, formed upon mixing l-1 with rac-2 (10 equiv) in CHCl3,
was isolated by size-exclusion chromatography (SEC) with
Figure 2. Complexation of 1 with 2 at[ 2]/[1]=10:1 in CHCl3 at25 8C.
a) CD spectra of l-1 in the absence (black curve) and presence of l-2
(blue curve), d-2 (green curve), and rac-2 (red curve). b) CD spectra of
d-1 in the absence (black curve) and presence of d-2 (blue curve), l-2
(green curve), and rac-2 (red curve).
Table 1: Association constants (Kassoc) for the complexation of helical host 1 with guests 2–5 in CHCl3 at
258C, upon spectroscopic titration, and enantiomer ratios of 2 extracted from 1ꢀ2, upon
decomplexation.
black curve) of the l-leucine-con-
taining host (l-1) in CHCl3 displays
an exciton-coupled CD band cen-
tered at 280 nm, as a result of the
DPhe units. The oligopeptide units
in l-1 adopt a right-handed helical
conformation, as evident by the sign
Entry Host Guest Kassoc(lꢀl) [mꢁ1
]
Kassoc(lꢀd) [mꢁ1
]
Klarge
Ksmall
/
l-2/d-2 extracted
from 1ꢀ2[a]
1
2
3
4
5
l-1
l-1
l-1
d-1
d-1
2
3
4
5
2
14.2”106
4.0”106
2.1”105
3.2”105
2.9”106
1.2”106
2.7”105
3.6”105
4.9
3.3
1.3
1.1
86:14
–
–
–
of the split Cotton effect.[10]
A
characteristic exciton-couplet is
also observed at the Soret absorp-
2.7”106 [=Kassoc(dꢀl)] 13.3”106 [=Kassoc(dꢀd)] 4.9
10:90
[a] Determined by HPLC on a Daicel Chiralpak AD-H column.
tion band of the zinc porphyrin
moieties (400–440 nm), which indi-
cates a clockwise-twisted geometry
of the two facing zinc porphyrin units.[9,11] As expected, the
CD spectrum of d-1 bearing left-handed helical units
(Figure 2b, black curve) is a perfect mirror-image of that of
l-1.
CHCl3 as eluent. Decomplexation of l-1ꢀ2 in THF[12]
followed by SEC with THF as eluent allowed isolation of
guest 2 in 78% yield based on l-1. HPLC analysis on a chiral
stationary phase (Daicel ChiralPak AD-H, Figure 3b) with
rac-2 as reference (Figure 3a) demonstrated that the 2 thus
isolated was considerably enriched in the l isomer, with a l-2/
d-2 ratio of 86:14 (72% ee; Table 1, entry 1). However, the
use of d-1 in place of l-1 for the competitive complexation
with rac-2, followed by an analogous chromatographic
analysis (Figure 3c), resulted in a l-2/d-2 ratio of 10:90
(80% ee; Table 1, entry 5).
Spectroscopic titration in CHCl3 and Job plots[7] suggest
that l-1 forms a stable 1:1 inclusion complex with l-2, a
pyridine-anchored right-handed helical pentapeptide con-
taining l-Leu, with an association constant Kassoc(lꢀl) of
14.2 ” 106 mꢁ1 (Table 1, entry 1). In contrast, the association
constant for the complexation of left-handed helical guest d-2
with l-1, is much smaller (Kassoc(lꢀd) = 2.9 ” 106 mꢁ1, Table 1,
entry 1). The large difference between these association
constants (Kassoc(lꢀl)/Kassoc(lꢀd) = 4.9:1) demonstrates that
To explore the origin of stereochemical guest selection we
investigated the complexation of l-1 with leucine-containing
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Keywords: amino acids · helical structures · optical resolution ·
.
peptides · porphyrinoids
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[7] See Supporting Information.
Figure 3. HPLC traces obtained on a chiral stationary phase of a) rac-2
(reference) and b), c) 2 extracted from inclusion complexes with l-1
and d-1, respectively (column: Daicel Chiralpak AD-H, eluent: hexane/
2-propanol/Et2NH=75:25:0.1).
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[12] Host 1 did not show any changes in its absorption and CD
spectra in the visible region upon mixing with guest 2 in THF.
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guests 4 and shorter-chain 5 as nonhelical reference com-
pounds (Scheme 1). Although the number of atoms along the
main chain of 4 is identical to that of 2, the molecular length of
5 is more likely to be similar to that of 2 adopting a helical
conformation. Spectroscopic titration experiments showed
that the association constants of these nonhelical guests with
l-1 are one order of magnitude smaller than those observed
for helical 2, and more importantly, their enantiomers were
not discriminated stereochemically (Table 1, entries 3 and
4).[7] From these observations we can conclude that a helix–
helix (host–guest) interaction is responsible for the stereo-
chemical guest selection in the complexation between 1 and 2.
Moreover, substituents on the helical chains play a role in the
helix–helix interaction upon bundling.[2–4,13] For example,
smaller association constants are found for the complexation
of l-1 with the enantiomers of helical guest 3, which does not
contain benzylidene units, than those with 2 (Table 1, entry 2).
In particular, the l enantiomer of 3 is preferentially selected
by l-1, but the observed Kassoc(lꢀl)/Kassoc(lꢀd) ratio of 3.3:1
is clearly smaller than that of l-1ꢀ2.
In conclusion, we have demonstrated one-pot optical
resolution of helical peptidic guests in solution by using a
cyclodimeric zinc porphyrin host bearing single-handed
oligopeptide units. In conjunction with control experiments
on nonhelical chiral guests, the results clearly show that the
host and guest molecules stereochemically recognize their
helical structures, rather than the point chiralities (Leu) in
their chains, upon bundling of the host molecule in the
confined cavity. We believe that exploration of asymmetric
transformations through artificial peptide bundling is worthy
of further investigation.
Received: May 18, 2004
4918
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