Diphenic acid as a general conformational lock in the design of bihelical structures

Article abstract of DOI:10.1002/chem.200601393

The bihelical (figure of "∞") topology was examined from vantages of design, crystal structures, chirality, circular dichroism (CD) studies and molecular-orbital calculations. The minimalistic design envisaged the sequential linking of cystine to the anch

Full text of DOI:10.1002/chem.200601393

FULL PAPER
DOI: 10.1002/chem.200601393
Diphenic Acid as a General Conformational Lockin the Design of Bihelical
Structures
Isabella L. Karle,*[a] Punna Venkateshwarlu,[b] Ramakrishnan Nagaraj,[c]
Akella V. S. Sarma,[d] Dolly Vijay,[e] Narahari G. Sastry,[e] and
Subramania Ranganathan*[b]
Abstract: The bihelical (figure of “1”)
topology was examined from vantages
of design, crystal structures, chirality,
circular dichroism (CD) studies and
molecular-orbital calculations. The
minimalistic design envisaged the se-
quential linking of cystine to the
anchor diphenic acid, which proved to
be a general conformational lock. The
bihelical compound 4 was obtained in
two steps from diphenic anhydride 1
and cystine di-OMe. The chirality of 4
arises largely from the l-cystine. The
bihelical compound 5 obtained from d-
cystine di-OMe was found, by X-ray
crystallography, CD studies, and optical
rotation, to be the perfect mirror
image of 4 prepared from l-cystine.
The crystal structure of prototype 8,
prepared by protocols used for 4 from
the achiral cystine analogue cystamine,
had a “U”-shaped conformation held
together by intramolecular hydrogen
bonds. Analysis of 4 and 5 show that
the pairs of nine-membered b-turn-like
constructs made compact through hy-
drogen bonding with DMSO hold the
key for the bihelical conformation. An-
other factor is the need for the pres-
ence of a ligand at the Ca position.
The absence of this, as in 8, allows
major flexibility in the torsional angles
around this critical region, promoting
flexible alternatives. The CD analysis
of 4, confirmed to be bihelical by X-
ray crystallography, showed a typical
negative band at about 210 Š attribut-
ed to the b-turn-like motif, and in the
positive-band region a peak at about
227 Š, generally related to the twist of
the biphenyl unit. The cystamine ana-
logue 8, which showed a “U”-type
structure, presented a CD spectrum
with no typical features. The total
energy, derived from theoretical calcu-
lations by using the X-ray structure
data, support the bihelical structure for
4 and a “U”-shaped one for 8. The lim-
ited utility of such calculations was
tested with composite 9. Composite 9,
in which the anchor diphenic acid is
linked to cystamine on the one hand
and to cystine on the other, showed a
CD spectrum similar to that of 4, and
this coupled with molecular-orbital cal-
culations, using data from 4 and 8, pre-
dict a bihelical structure for this com-
pound.
Keywords: chirality
·
diphenic
acid · helical structures · hydrogen
bonds · topochemistry
Introduction
crafting therapeutic systems, molecular recognition, DNA
mechanisms and ion sensors.
Closed bihelical modules (figures of “1”) have emerged as
structural motifs across a variety of carbon substrates of nat-
ural and synthetic origin. Their uses include complexation,
The present work should be viewed from a general con-
text as it, inter alia, projects diphenic acid as a “conforma-
tional lock” for crafting a range of bihelical structures and
[a] Dr. I. L. Karle
[d] Dr. A. V. S. Sarma
Laboratory for the Structure of Matter
Naval Research Laboratory, Washington DC, 20375-5341 (USA)
Fax : (+1)202-767-6874
Centre for NMR, Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
[e] D. Vijay, Dr. N. G. Sastry
E-mail: isabella.karle@nrl.navy.mil
Molecular Modeling Group, Organic Chemical Sciences
Indian Institute of Chemical Technology, Hyderabad 500 007 (India)
[b] P. Venkateshwarlu, Dr. S. Ranganathan
Discovery Laboratory, Organic III
Supporting information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author: H, 13C NMR and
Indian Institute of Chemical Technology, Hyderabad 500 007 (India)
E-mail: ranga@iict.res.in
HSQC spectra (Figures S1–S9) for 4, 5 and 8.
[c] Dr. R. Nagaraj
Centre for Cellular and Molecular Biology, Hyderabad 500 007 (India)
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elucidates analyses factors obtained from X-ray crystallogra-
phy, circular dichroism and molecular-orbital calculations
that govern the formation of these structures. Although a
large number of bihelical systems have been reported, the
basic elements related to the formation of such compounds
over alternate conformations have been hardly explored.
The principles that lead to the bihelical system reported
here are general and hold promise of applications across
chemical and biological domains.
such species by metal-stabilized polyiodide. The metal sup-
port and that of the counter ion offer several possible varia-
tions in the construction of the species.[15]
Bihelical structures with extraordinary biological proper-
ties have been encountered in naturally occurring systems.
An in-depth analysis of diverse topological forms present in
proteins has been made.[16] In the domain of nucleic acids,
bihelical motifs have been recognized for some time. Several
have been associated with specific functions and some have
been made synthetically. An interesting case is the bihelical
sequence preceding the initiation system of transcription in
E. coli.[17]
The increasing role of bihelical structures is reflected in
the following brief overview.
A number of bihelical systems have as their basis the for-
mation of a closed system from an open one, which can be
achieved only by severe folding. Such constraints have been
imposed in several ways. Polyacetylenic systems built on a
range of scaffolds have lead to a number of bihelical systems
with potential for a variety of applications. For example,
“bow-tie” shaped bihelical structures built on an acetylenic
and 2,2’-bipyridyl scaffold have been used to detect several
metal ions. The acetylene constructs have been replaced by
several others to achieve bihelical systems on the same prin-
ciple.[1] A variation is the open figure of “1” structure; an
elegant example of which is that created from chiral 1,1’-bi-
napthalene units and phenanthroline whose cavity strongly
binds metal ions.[2] An interesting strategy that leads to bi-
helical structures open at both ends takes advantage of
strong ionic interactions.[3]
The highly cytotoxic cyclic hexapeptides from marine tu-
nicates Lissoclinum patella are members of a closely related
family harboring oxazoline and thiazole amino acids. Open
structures are seen in symmetric and less-substituted mem-
bers, whereas asymmetric-substituted members fold to bihel-
ical forms. All members are biologically active. An examina-
tion of open and bihelical conformation of patellamides has
shown that, topologically, an open frame folded by two b
turns with compatible dihedral angles generates a bihelical
structure. This is exemplified by patellamide D, which has a
bihelical structure whose genesis is attributed to the pairs of
b turns with isoleucine and cyclized threonine residues at
the corners of the turns. On the other hand, lissoclinamide 7,
which possess only a b turn and a b loop, is planar.[18] Di-
demnin, a highly active depsipeptide isolated from Carib-
bean tunicates, exhibits high activity against viruses and a
range of cancers. The X-ray structure of didemnin shows a
figure of “1” topology.[19]
A noteworthy illustration of the generation of multitopo-
logical systems is the tethering of the circular frame of a ro-
taxane to the axle by a ligand pair.[4]
The recent synthesis of giant porphyrin systems has lead
to the preparation of a variety of bihelical structures.[5] The
mixing of porphyrin with other heterocycles has given rise
to bihelical structures with specific metal-uptake properties.
Results of NMR experiments have shown that the bihelical
systems in these cases are dynamic and move in a “ convey-
er belt” fashion without undergoing racemization.[6] Figure
of “1” macropyrroles can be separated on a chiral column.
The metal complexes resulting from the pure antipodes
have potential as catalysts in asymmetric synthesis.[7] Inter-
estingly, the large porphyrin Turcasarin forms crystals in
both l and d configurations.[8] Metal complexes of oxidative
degradation products of haem have been shown to have bi-
helical structures.[9]
Regardless of their conformation, all of the members
show activity. Ironically, ulithiacyclamide, which has
a
planar structure but possesses an unusual cystine band, is
the most active in this category.
A unique example is the cyclic tryptophane-containing
peptide arising from a rearrangement. This compound ex-
hibits a bihelical structure both in solid and in solution. That
an analogue that lacks the chiral group was found to have
an open structure has implications regarding the choice be-
tween two conformers.[20]
The relationship between bihelical topology and its bio-
logical activity requires an extensive study of a variety of an-
alogues. The present work attempts to achieve this purpose.
Open compounds having proper substituents can be col-
lapsed to bihelical structures by metal complexes.[10] An un-
usual process is the transformation of a figure of “1” motif
from palladium complexation to catenanes and other topo-
logical systems.[11] Palladium complexes of pyrroles flanked
by oxazoles form bihelical structures in which one halogen
is retained.[12]
Extended bihelical motifs mostly stabilized by hydrogen
bonding have been either carefully crafted[13] or unexpected-
ly encountered, as in the case of fumaropumaric acid, a
member of the rosin family that act as acceptors for a varie-
ty of small organic molecules.[14] In the extended helical
domain, a recent interesting discovery is the formation of
Results and Discussion
Design of compounds: The increasing interest in the forma-
tion of bihelical structures made it attractive to design a
minimalistic bihelical motif whose parameters can serve to
discriminate other possible models obtained from theoreti-
cal predictions. The specific knowledge of parameters for
one bihelical structure would narrow the choice among sev-
eral possibilities. A general scaffold in the form of a “con-
formational lock” was identified in diphenic acid, as this
molecule not only possesses the necessary functional groups,
but also the nearly orthogonally aligned phenyl rings[21] that
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Bihelical Structures
FULL PAPER
were anticipated to generate the necessary b-turn-like ele-
ment. Cystine was chosen as the key linker element because
of its chiral nature and ability to take part in several topo-
logical forms.[22] The design envisaged the sequential linking
of cystine to the anchor diphenic acid.
Synthesis and X-ray analysis: Diphenic anhydride 1 was con-
sidered a suitable substrate to join the initial linker to a
second unit. The reaction of cystine di-OMe (freshly gener-
ated from hydrochloride with aqueous NaHCO3) afforded
the dicarboxylic acid 2, which was characterized further as
the methyl ester 3. Reaction of 2 with another cystine di-
OMe linker by using EDCI/HOBt (1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide/1-hydroxy-1,2,3-benzotriazole)
in CH2Cl2 afforded, as expected, 4 as the major compound
(Scheme 1).[23,24]
Figure 1. “Edge-on” crystallographic view of 4. The molecule lies on a
true crystallographic two-fold rotation axis. Hydrogen bonds are formed
between DMSO molecules and N1a and N1aa, in which N1a···O1sa
2.82 Š and H···O1s 2.00 Š.
Figure 2. Perpendicular view of 4. Nine-membered b turns are formed
with N2a···O1a 2.86 Š and H···O1a 1.99 Š.
The core structure is further promoted by the hydrogen
bonding of the remaining NH to DMSO. The importance of
this hydrogen bonding was also revealed by molecular-orbi-
tal calculations.
Scheme 1. Preparation of compound 4. a) cystine di-OMe; b) EDCl-
HOBt.
In principle, the bihelical motif could have a left or right
disposition of the intercrossing helices. The fact that only
one arrangement of 4 (Scheme 1, Figures 1 and 2) with
[a]3D1:6 =ꢀ36.0494 (c=0.27, CHCl3) was obtained, suggests
the existence of a control element. Analogous to the forma-
tion of right- or left-handed helices, which is controlled by
the chirality of the amino acids involved, it is likely that the
chirality observed in 4 (Scheme 1, Figures 1 and 2) arises
from that of the l-cystine used in the construction of the bi-
helical motif 4. This has been demonstrated experimentally
by using d-cystine in place of the l-analogue. The reactions
carried out as shown in Scheme 1 afforded compound 5 in
56% yield. This compound exhibited spectral data identical
The structural assignments for 2, 3, and 4 are fully sup-
ported by spectral and analytical data. Compound 4 deposit-
ed beautiful colorless rods from hot DMSO. An X-ray crys-
tallographic analysis showed clearly its bihelical (figure of
“1”) topology, edge-on and perpendicular views of which
are presented in Figures 1 and 2, respectively.
A scrutiny of the X-ray structure of 4 (Figure 1) highlights
the presence of two nine-membered b-turn-like features,
made compact by the hydrogen bonding across the ring, and
made possible by the twist of the biphenyl core. These ob-
servations are supported by circular dichroism (CD) spectra
(see below).
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I. L. Karle, S. Ranganathan et al.
to that of 4, but precisely opposite rotation [a]3D1:6 =+38.00
(c=0.275, CHCl3).
Crystallization of 5 from DMSO afforded beautiful color-
less rods, whose structure was established by X-ray crystal-
lography to be precisely the mirror image of 4. A structural
representation of 5 given in Figure 3 shows the mirror-image
relationship between 4 and 5.
Figure 3. Structural representation of 5.
Crystallographic edge-on and perpendicular views of 5 are
presented in Figures 4 and 5. A comparison with Figures 1
and 2 clearly reveals the mirror-image relationship. The
composite edge-on view of the antipodes presented in
Figure 6 is striking.
Figure 6. Composite picture of the mirror images of 4 and 5 obtained by
X-ray crystallography (edge-on view).
The preparation and characterization of the bihelical
structures 4 and 5 have shown that diphenic acid can be
used as a general “conformational lock” for the possible
synthesis of a variety of bihelical structures with the proper
choice of linker element. The synthesis of a possible biheli-
cal structure without a chiral centre seemed desirable, be-
cause in at least one case, a bihelical system having chiral
centres was transformed to an open system in its absence.[20]
The obvious option was the readily available cystamine;
structurally similar to cystine, but without side groups and,
therefore, without the chiral centre.
Figure 4. Crystallographic edge-on view of 5 (the mirror image of 4).
The reaction of diphenic anhydride with freshly prepared
cystamine free base afforded dicarboxylic acid 6, which was
further characterized as the methyl ester 7. The reaction of
6 with another unit of cystamine followed by chromatogra-
phy afforded compound
8
(22%, m.p. 232–2358C;
Scheme 2). Compound 8 formed colorless thick crystals
from CHCl3/MeOH 1:1. A crystallographic analysis showed
that 8 had a rather “U”-shaped backbone structure, held to-
gether by three intramolecular hydrogen bonds.
The crystallographic representations of edge-on and per-
pendicular views of 8 are presented in Figures 7 and 8. Inter-
estingly, the crystals of 8 obtained from MeOH and DMSO
Figure 5. Perpendicular view of 5.
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Bihelical Structures
FULL PAPER
Figure 8. Perpendicular view of 8.
Scheme 2. Preparation of compound 8. a) cystamine; b) DCC-SuOH.
Table 1. Comparison of torsional angles [8] in macrocycles 4 and 8.
Angle
4
8
lgD[a]
S2b-S1a-C1a-C2a
S1a-C1a-C2a-N1a
ꢀ68
ꢀ66
142
ꢀ174
ꢀ137
6
+81
+67
ꢀ113
ꢀ171
ꢀ143
12
*
*
*
C1a-C2a-N1a-C3a
C2a-N1a-C3a-C4a
N1a-C3a-C4a-C9a
C3a-C4a-C9a-C10a
C4a-C9a-C10a-C15a
C9a-C10a-C15a-C16a
C10a-C15a-C16a-N2a
C15a-C16a-N2a-C17a
C16a-N2a-C17a-C18a
N2a-C17a-C18a-S2a
C17a-C18a-S2a-S1b
C18a-S2a-S1b-C1b
S2a-S1b-C1b-C2b
S1b-C1b-C2b-N1b
C1b-C2b-N1b-C3b
C2b-N1b-C3b-C4b
N1b-C3b-C4b-C9b
C3b-C4b-C9b-C10b
C4b-C9b-C10b-C15b
C9b-C10b-C15b-C16b
C10b-C15b-C16b-N2b
C15b-C16b-N2b-C17b
C16b-N2b-C17b-C18b
N2b-C17b-C18b-S2b
C17b-C18b-S2b-S1a
C18b-S2b-S1a-C1a
ꢀ103
ꢀ130
10
11
43
63
ꢀ177
138
70
ꢀ175
91
67
81
177
ꢀ77
ꢀ68
ꢀ66
142
ꢀ174
ꢀ137
6
*
ꢀ88
ꢀ58
175
ꢀ86
ꢀ175
ꢀ153
11
*
*
Figure 7. Crystallographic “edge-on” view of 8. Intramolecular hydrogen
bonds have the lengths: N2a···O1b 3.197, H···O1b 2.43, N2b···O1b 2.973,
H···O1b 2.10; N2b···O1a 3.298, H···O1a 2.76 Š.
ꢀ103
ꢀ111
10
9
43
55
were identical.[25] No solvent was cocrystallized with 8. A
comparison of the torsional angles in 4 and 8 in Table 1
shows that the regions of the nine-membered b turns are
quite similar, although the O1a···N2a distance has increased
to 3.67 Š in 8. Consequently, this is no longer considered as
an NH···O=C hydrogen bond (Figure 7). However, large dif-
ferences (greater than 1008) in torsional angles occur at or
near C2a, C2b, C17a, and C17b, the atoms from which the
side chains in 4 were removed. This accounts for the dispa-
rate shapes of the macromolecular rings in 4 and 8.
ꢀ177
138
70
177
ꢀ77
ꢀ173
128
179
*
*
ꢀ60
ꢀ94
[a] Large differences (>1008) in values of torsional angles in the back-
bone.
The cystine–cystamine composite 9 was achieved by two
complementary routes (Scheme 3).
Having shown that the absence of chiral groups in the
linker favours a non-bihelical structure, it was logical to
assess the preference with a single chiral linker. Such a
system was prepared by linking the “conformational lock”
with cystine on the one side and cystamine on the other.
Compound 9, obtained by either of the two routes, exhib-
ited identical H NMR, MALDI-TOF MS, and CD features.
Several attempts to secure crystals from 9 did not succeed.
However, CD studies and molecular-orbital calculations sup-
port a bihelical profile for 9 (see below).
1
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I. L. Karle, S. Ranganathan et al.
mained unchanged. The band
at ꢁ230 nm in the CD spec-
trum reflects the twist of the
biphenyl core.[29]
The CD spectrum of
5
(Figure 10) bears an almost
exact mirror-image relationship
to its antipode 4, a fact that is
illustrated effectively in the
composite CD spectrum of 4
and 5 (Figure 11).
Scheme 3. Preparation of compound 9. a) cystine di-OMe; b) cystamine; c) EDCl-HOBt.
Compounds 4, 8, and 9, heavily endowed with amide and
sulfur centres, are attractive for the formation of silver com-
plexes.[26a] Such complexes have potential in 111Ag-based ra-
dioimmuno therapy. Compounds 4, 8, and 9 readily formed
1:1 complexes with AgBF4. Although crystals of these could
not be secured, their structure is supported by results of
ESI-MS analysis. Based on similar studies,[26b] a minimal tet-
rahedral coordination of the Ag+ with the four sulfur atoms
appears possible.
Circular dichroism studies: Results of CD studies in solution
conducted in the present work not only corroborated the
crystallographic findings, but also provided a mechanistic in-
sight into possible conformational requirements for the for-
mation of the bihelical topology.
Figure 10. CD spectrum of 5 in TFE.
The spectra of 4 in trifluoroethanol (TFE) (Figure 9),
MeOH and CH3CNwere recorded. All of them showed a
Figure 11. Composite picture of CD spectra of 4 and its mirror image 5
taken in TFE.
Figure 9. CD spectrum of 4 in TFE.
The suggested nine-membered b-turn motif finds support
in the CD spectra of compound 3 in TFE (Figure 12), which
shows a very similar profile to that of 4 with reduced molar
ellipticity.
The crystal structure of 8, which shows a “U”-type confor-
mation (Figures 7 and 8), exhibited a random CD profile,
similar to that of 7.[30]
The stepwise synthesis of the macrocycles anchored on
the motif of diphenic acid also enables the study of aspects
related to the conformation of such compounds, as seen by
CD analysis. It was stated above that the b-turn-like motifs
present in 3 are responsible for the bihelical structure, which
was absent in the achiral analogue 7.
similar profile, characterized by a negative CD band at
211 nm (TFE), 214 nm (MeOH) and 214 nm (CH3CN), and
a positive CD band at aboout 230 nm. Although the nega-
tive CD band in TFE is reminiscent of a b-hairpin confor-
mation,[27] the positions of negative CD bands in MeOH/
CH3CNare similar to spectra of a distorted b sheet.[28]
A
change in conformation from TFE to MeOH/CH3CNis also
reflected in the diminution of intensity of the positive band
at 228–230 nm in these solvents. However, in all solvents,
the molar-ellipticity values in the negative-band region re-
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Bihelical Structures
FULL PAPER
Table 2. Total energies [Hartrees] for the six conformations in vacuum
and in DMSO at the AM1 level of theory.
Molecule
In vacuum
(E)
With two molecules
of DMSO[a] (E)
8 (U shaped)
8 (bihelical)
9 (U shaped)
9 (bihelical)
4 (U shaped)
4 (bihelical)
ꢀ0.038521
ꢀ0.031771
ꢀ0.283986
ꢀ0.289090
ꢀ0.524169
ꢀ0.539652
ꢀ0.183388
ꢀ0.177930
ꢀ0.417100
ꢀ0.431758
ꢀ0.665396
ꢀ0.684022
[a] Explicitly placed in the orientation obtained from the X-ray structure
of 4.
Figure 12. CD spectrum of 3 in TFE.
are explicitly placed in orientation obtained from the experi-
mental coordinates for 4 showed a preference for bihelical
structures (Table 2) for 4 and 9.
The data for 9 indicate a preference for a bihelical over a
“U”-shaped conformation, particularly in the presence of
DMSO. Work on the basic problems related to the topology
of open cyclic systems is in progress.
The CD spectrum of the composite 9 exhibited in TFE a
negative band at 212 nm and a positive one at 228 nm
(Figure 13) remarkably similar to that of 4. The CD profile
seen here predicts a bihelical conformation.
Conclusion
We have shown that “diphenic acid” can be used as a “con-
formational lock” in a general strategy for the crafting of bi-
helical structures with appropriate linker elements. In a typi-
cal example, the linking of two diphenic acid anchors with
cystine-diOMe generates a pair of compact nine-membered
b-turn-like elements. It is suggested that any linker element
that could satisfy this basic or equivalent criterion can lead
to bihelical structures. In the present case the compact pro-
file of the b-turn-like elements arises from hydrogen bond-
ing of one of the NH bonds to the carbonyl oxygen across
the ring, as seen in 4 (Figures 1 and 2). A second linker then
completes the synthesis. In this strategy the basic criterion,
namely the need for a pair of compact b-turn-like structures,
seems to provide an explanation for open frames. The de-
tailed analysis in the present work of the bihelical conforma-
tion secured by 4 and that of a “U”-shaped conformation
with cystamine lacking the chiral groups is possibly related
to this factor. X-ray crystallography results for 4 and 8 show
a number of common features (Table 3). Besides, as could
be seen, torsional angles that lead to the synthesis of these
compounds (Table 1) are quite similar, except, notably, if
the chiral ester is present. In the preference for bihelical
structures, substituents at the Ca position appear to play a
major role. The presence of such bulky substituents gives ri-
gidity to the b turns involved and, in the case of 4, leads to
the bihelical structure. In the case of 8, in which such sub-
stituents are absent, much more torsional freedom is avail-
able for the Ca atom, which now resembles that in glycine.
This notion is supported by the fact that if a b turn nearly
identical to 4 is inscribed in 8 (Figure 14, left), the rest of
the molecule exhibits greater conformational flexibility, par-
ticularly around erstwhile ligand locations (COOMe), as
seen by the wide divergence in dihedral angles.
Figure 13. CD spectrum of 9 in TFE.
At this point, it would be interesting to compare the
nature of the b-turn-like element possible in 3, 4 and 9.
Compound 4, which has two well-defined b turns, exhibits
the invariance of the negative band, attributed to the b turn
in different solvents, which perhaps arises from the inherent
stabilization of the bonding by the chiral elements here. The
open ester 3 with possible b-turn-like motifs, with increased
torsional freedom, shows a considerably lower molar-ellip-
ticity value. As this unit becomes part of 9, the CD spectrum
shows considerable enhancement of this value, possibly aris-
ing from placement in a restrained position.
Molecular-modelling studies: Quantum-mechanical calcula-
tions were carried out on 4, 8, and 9 in bihelical as well as in
“U”-shaped conformations. The structures were modeled
from the experimentally determined coordinates for 4 and 8.
The Gaussian 03 program package[31] was used. Quantum
chemical calculations at the semiempirical AM1[32] level
were carried out to evaluate the energies of the conforma-
tions. This was then followed by a single-point DFT calcula-
tion on AM1-optimized geometries. The results are summar-
ized in Table 2. The total energies indicate preference for a
bihelical conformation for 4 and “U”-shaped conformation
for 8. Similar calculations in which two molecules of DMSO
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I. L. Karle, S. Ranganathan et al.
Table 3. Crystal data and structure refinement.[35]
to compute total energies in the presence of solvent mole-
cules.
Compound
4
8
formula[a]
Mr
C44H44N4O12S4·3C2H6OS C36H36N4O4S4
Our results suggest that, although the parent bihelical
motif can be chiral, by far the major contribution to the
chirality arises from the linker element, as clearly seen in
the opposite optical rotations of 4 and its mirror image 5.
The presence of bihelical compounds generated from the
use of diphenic acid as a “conformational lock” can be as-
sessed by their CD profile, as in the case of 9.
We have shown that cystine/cystamine is not only a linker
element, but the presence of this unit can lead to complexes
with silver and possibly other metal ions.
1183.46
0.50”0.25”0.10
C2
716.93
crystal size [mm3]
space group
a [Š]
ꢁ0.30”0.30”0.30
P21/n
21.803(9)
9.046(4)
15.571(7)
90.00
10.537(3)
21.317(6)
15.857(4)
90.00
b [Š]
c [Š]
a [8]
b [8]
g [8]
T [8C]
114.948(6)
90.00
97.98(2)
90.00
203
293
l [Š]
Mo, 0.71073
2784.6(20), 2
1.411
Cu, 1.54178
3527.3(17), 4
1.350
V [Š3], Z
1calcd [Mgmꢀ3
]
m [mmꢀ1
(000)
]
0.352
F
A
1244
1504
Experimental Section
limiting indices
ꢀ28ꢂhꢂ28
ꢀ10ꢂkꢂ11
ꢀ20ꢂlꢂ20
13931
ꢀ12ꢂhꢂ1
ꢀ25ꢂkꢂ1
ꢀ18ꢂlꢂ18
7829
General: Melting points were recorded by using Fisher–Johns apparatus
and are uncorrected. Optical rotations were measured by using an auto-
matic JASCO P-1020 polarimeter. Concentrations are given in g per
reflns collected
independent reflns
5665
6186
100 mL. Infrared spectra were recorded as KBr pellets by using
a
data/restraints/parameters 4884/0/361
4214/0/434
1.020
Thermo Nicolet Nexus 670 spectrometer and prominent peaks are ex-
goodness of fit on F2
final R indices [I>2s(I)]
R indices (all data)
extinction coeff.
1.239
1
pressed in cmꢀ1. H and 13C NMR spectra were recorded by using Varian
0.0579, 0.1413
0.0741, 0.1666
–
0.0657, 0.2002
Gemini 200, Bruker Avance 300 and Inova 400 and 500 MHz spectrome-
ters. The chemical shifts are expressed in ppm, with TMS at 0.0000 as in-
ternal reference. Fast atom bombardment mass spectrometry (FABMS)
was performed by using a VG AUTOSPEC mass spectrometer, ESI-MS
0.00117
largest diff. peak/hole
1.25, ꢀ0.75
0.58, ꢀ0.45
ꢀ3
A
]
was conducted by using
a micromass QUATTRO-LC instrument,
MALDI-TOF spectra were recorded by using a KRATOS ANALYTI-
CAL instrument and HRMS was obtained by using a QSTAR XL instru-
ment. Elemental data were obtained by using automatic analysers. The
CD spectra were recorded by using a JASCO J-810 spectrometer, mostly
in TFE at a uniform concentration of 200 mmolLꢀ1. TLC was prepared
on silica gel-coated plates made in the laboratory. ACD nomenclature
for all compounds is listed.[34]
[a] Formula given for asymmetric unit, except for 4 in which the asym-
metric unit is doubled because the molecule lies on a crystallographic ro-
tation axis.
I. Reaction of diphenic anhydride with cystine di-OMe: preparation of 2:
To an ice-cooled and well-stirred suspension of diphenic anhydride 1
(1.67 g, 7.46 mmol) in dry CH2Cl2 (20 mL) was added dropwise cystine
di-OMe free base in dry CH2Cl2 (50 mL) (freshly prepared from cystine
di-OMe·2HCl (1.5 g; 4.4 mmol) and saturated NaHCO3 (8 mL) under
ice-cooling, extraction with CH2Cl2 (3”25 mL), drying (Na2SO4) and
evaporation. The reaction yielded 1.0 g, 3.73 mmol). The reaction mixture
was left to stir at room temperature for 12 h, filtered, the filtrate was
washed sequentially with ice-cold 2n H2SO4 (2”5 mL), brine (10 mL),
dried (Na2SO4) and evaporated to yield 2.18 g (82%) of crude 2 as a
foamy solid that was triturated with saturated NaHCO3 (25 mL), filtered,
made acidic to pHꢁ4 with aqueous citric acid and filtered to give 1.5 g
(56%) of 2. M.p. 128–1328C; [a]3D1:6 =ꢀ86.50 (c=0.28 in DMSO);
1H NMR (400 MHz, CDCl3): d=2.62 (m, 2H; bCH2), 3.02 (m, 2H;
bCH2), 3.45, 3.58, 3.65 (s, s, s, 6H; COOMe), 4.75 (m, 2H; aCH), 6.25
(vbr, 2H; COOH), 7.37 (m, 16H; aromatic), 7.95 ppm (m, 2H; amide);
IR (KBr): n˜ =3260 (br), 3021 (br), 1727 (m), 1549 (m), 1244 cmꢀ1 (m);
MS (FAB): m/z (%): 739 (18) [M+Na+]; HRMS calcd for
C36H32N2O10S2: 716.1576; found: 716.1588.
Figure 14. Illustration of the influence of the Ca ligand on torsional
angles.
II. Reaction of 2 with diazomethane: preparation of diester 3: Ethereal
diazomethane (ꢁ0.113 g, 2.7 mmol, 11 mL), generated from N-methyl-N-
nitroso-toluene-p-sulfonamide, was added to
a solution of diacid 2
This also provides an explanation for a similar observa-
tion reported earlier.[33] This rationale finds particular sup-
port in the conformation of biologically active marine struc-
tures (see above), in which highly substituted members also
invariably lead to bihelical structures.[18]
Here, we have attempted to link structural profiles ob-
tained by X-ray crystallography and circular dichroism, and
to use molecular-orbital data derived from X-ray structures
(0.650 g, 0.9 mmol) in methanol (5 mL). Evaporation of solvents afforded
0.680 g (ꢁ100%) of the crude diester as a thick liquid. The crude prod-
uct was subjected to chromatography on silica gel. Elution with CHCl3/
EtOAc (85:15) afforded 0.580 g (86%) of pure 3 as thick oil. Rf =0.66
(CHCl3/EtOAc 6:4); [a]D31:6 =+35.1698 (c=0.265 in CHCl3); 1H N MR
(300 MHz, CDCl3): d=2.50 (m, 2H; bCH2), 2.95 (m, 2H; bCH2), 3.64 (m,
12H; COOMe), 4.60 (br, 2H; aCH), 7.35 (m, 16H; Ar-H), 7.85 ppm (m,
2H; CONH); 13C NMR (75.47 MHz, CDCl3): d=40.14, 51.54, 52.33,
127.62, 129.15, 129.68, 130.76, 131.52, 134.81, 139.36, 140.15, 168.60,
4260
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4253 – 4263

Bihelical Structures
FULL PAPER
170.04, 170.40 ppm; IR (KBr): n˜ =3418, 2922, 1720, 1662, 1516, 1288,
760 cmꢀ1; MS (FAB): m/z (%): 745 (18) [M+H+], 767 (6) [M+Na+];
HRMS calcd for C38H36N2O10S2: 744.1889; found: 744.1872.
m/z (%): 601 (6) [M+H+], 623 (5) [M+Na+]; HRMS calcd for
C32H28N2O6S2: 600.1467; found: 600.1486.
VII. Reaction of 6 with diazomethane: preparation of diester 7: Com-
pound 6 (0.300 g, 0.5 mmol) was transformed to the dimethyl ester 7, as
described in procedure II, to afford 0.320 g (ꢁ100%) of the crude die-
ster as a thick liquid. Chromatography on silica gel and elution with
CHCl3/EtOAc (70:30) gave 0.270 g (85%) of pure 7 as a thick liquid.
Rf =0.66 (CHCl3/EtOAc 6:4); 1H NMR (300 MHz, CDCl3): d=1.92, 2.32
(m, m, 4H; S-CH2), 3.12, 3.44 (m, m, 4H; N-CH2), 3.70 (m, 6H;
COOMe), 7.15 (m, 16H; aromatic), 7.78 ppm (m, 2H; amide); 13C N MR
(75.47 MHz, CDCl3): d=37.32, 37.92, 52.36, 127.80, 128.96, 129.48,
130.47, 130.73, 131.49, 135.83, 138.85, 168.87, 169.22 ppm; IR (KBr): n˜ =
3325, 1717, 1650, 1524, 1294 cmꢀ1; MS (FAB): m/z (%): 629 (58) [M+H+],
651 (12) [M+Na+]; HRMS calcd for C34H32N2O6S2: 628.1780; found:
628.1756.
III. Reaction of 2 with cystine di-OMe: preparation of 4: HOBt (0.414 g,
3.07 mmol), EDCI (0.589 g, 3.07 mmol) and N,N-diisopropylethylamine
(DIPEA) (0.534 mL, 3.07 mmol) were added sequentially to an ice-
cooled and well-stirred suspension of 2 (1.0 g, 1.396 mmol) and cystine
di-OMe dihydrochloride (0.523 g, 1.536 mmol) in dry CH2Cl2 (60 mL).
The reaction mixture was left stirred overnight and under ice-cooling was
quenched with saturated NH4Cl (20 mL), admixed with additional
CH2Cl2 (40 mL). The organic layer was washed with 1n HCl (20 mL),
water (20 mL), saturated NaHCO3 (20 mL), water (20 mL), brine (2”
20 mL), dried (Na2SO4) and evaporated to give 1.355 g (ꢁ100%) of
solid; m.p. 134–1368C. The crude product was subjected to chromatogra-
phy on silica gel. Elution with benzene/EtOAc (1:1) afforded 0.450 g
(34%) of pure 4. Rf =0.29 (PhH/EtOAc 1:1); m.p. 150–1538C; [a]D31:6
=
VIII. Reaction of 6 with cystamine: preparation of 8: SuOH (0.287 g,
2.5 mmol) and N,M’-dicyclohexylcarbodiimide (DCC) (0.516 g, 2.5 mmol)
ꢀ36.0494 (c=0.27 in CHCl3); 1H NMR (400 MHz, [D]6DMSO): d=2.70
(m, 8H; bCH2), 3.60 (s, 12H; COOMe), 4.50 (m, 4H; aCH), 7.00, 7.45
(m, m, 16H; Ar-H), 9.00 ppm (d, J=8.0 Hz, 4H; CONH); 13C N MR
(100 MHz, [D]6DMSO): d=37.13 (4”bCH2), 50.62 (4”aCH), 52.06 (4”
OCH3), 127.23, 127.64, 129.03, 129.44 (16”Ar-C), 135.04, 139.18 (8”Ar-
quaternary carbons), 168.96 (CONH), 170.36 ppm (COOMe) (the 13C-
NMR peak assignments were confirmed by HSQC and HMBC); IR
(KBr): n˜ =3233, 3027, 2952, 1744, 1642, 1537, 1214 cmꢀ1; MS (MALDI-
TOF): m/z (%): 949 (40) [M+H+], 972 (100) [M+Na+], 988 (42) [M+K+];
HRMS calcd for C44H44N4O12S4: 948.1916; found: 948.1968; elemental
analysis calcd (%) for C44H44N4O12S4 (948.1916): C 55.68, H 4.67, N5.90,
S 13.51; found: C 55.47, H 4.60, N5.91, S 13.42. From a variable tempera-
ture study of 4 in the range of 20–708C in [D]6DMSO, the dd/dT value of
the NH proton is <4.0 ppboCꢀ1, suggesting a significant population of in-
tramolecular hydrogen-bonded structures in solution.
were added sequentially to an ice-cooled and stirred solution of
6
(0.750 g, 1.25 mmol) in dry CH2Cl2 (30 mL). The reaction mixture was
admixed with a dry CH2Cl2 solution of cystamine free base (freshly pre-
pared from cystamine 2HCl (0.42 g; 1.86 mmol) and saturated Na2CO3
(4 mL) under ice-cooling, extraction with CH2Cl2 (3”25 mL), drying
(MgSO4) and evaporation. The reaction yielded 0.228 g (80%) 1.5 mmol)
and was left to stir at room temperature for two days. The precipitated
dicyclohexylurea (DCU) was filtered, the residue was washed with
CH2Cl2 (2”15 mL) and the combined filtrates were washed sequentially
with ice-cooled 2n H2SO4 (20 mL), water (15 mL), saturated NaHCO3
(15 mL), dried (Na2SO4) and evaporated to yield 1.123 g (ꢁ100%) of
crude product; m.p. 215–2258C, which was subjected to chromatography
on silica gel. Elution with CHCl3/EtOAc (60:40) afforded 0.200 g (22%)
of 8, a substantial portion of which was crystallized from CHCl3/MeOH
(1:1) to provide rectangular crystals; m.p. 251–2548C. Most of the data
were determined by using these crystals: Rf =0.55 (EtOAc); 1H N MR
(400 MHz, [D]6DMSO): d=2.15, 2.35, 2.55 (m, m, m, 8H; CH2S), 3.00,
3.10, 3.40 (m, m, m, 8H; CH2N), 7.00, 7.40, 7.50 (m, m, m, 16H; Ar-H),
8.65, 8.70 ppm (m, m, 4H; CONH); 13C NMR (100 MHz, [D]6DMSO):
d=36.52, 36.86 (4”SCH2), 37.69, 37.80 (4”NCH2), 127.18, 127.30,
128.99, 129.14 (16”Ar-C), 135.95, 138.94 (8”quaternary Ar-C),
168.83 ppm (4”CONH) (the 13C-NMR peak assignments were confirmed
by HSQC and HMBC); IR (KBr): n˜ =3266, 1642, 1532, 1299 cmꢀ1; MS
(MALDI-TOF): m/z (%): 740 (100) [M+Na+], 756 (32) [M+K+];
HRMS calcd for C36H36N4O4S4: 716.1697; found: 716.1676; elemental
analysis calcd (%) for C36H36N4O4S4 (716.1697): C 60.31, H 5.06, N7.81,
S 17.89; found: C 60.13, H 4.93, N7.51, S 17.78.
IV. Reaction of 4 with AgBF4: preparation of a monosilver complex: A
homogeneous solution of silver (I) tetrafluoro borate (8.4 mg,
0.043 mmol) and
4 (27 mg, 0.0286 mmol) in nitromethane/toluene
(1.9 mL) was prepared. 0.63 mL of this solution was closed in a tube and
kept in the dark for one week. The tube was opened, covered with perfo-
rated filter paper and solvents were allowed to evaporate in the dark.
The residue was washed with chloroform to give a dark solid. M.p. 150–
1558C; MS (ESI): m/z (%): 1055, 1057 (25) [M+Ag+], 949 (17) [M+H+].
V. Preparation of 5, the mirror image of 4: Diphenic anhydride 1
(0.448 g, 2.0 mmol) was reacted with d-cystine di-OMe free base (0.268 g,
1.0 mmol), as described in procedure I, to afford 0.716 g of the crude di-
carboxylic acid, which was used directly in the next experiment. HOBt
(0.297 g, 2.2 mmol), EDCI (0.421 g, 2.2 mmol) and DIPEA (0.69 mL,
4.0 mmol) were added sequentially to an ice-cooled and well-stirred sus-
pension of the dicarboxylic acid described above (0.716 g, 1.0 mmol) and
d-cystine di-OMe dihydrochloride (0.341 g, 1.0 mmol) in dry CH2Cl2
(60 mL). The reaction mixture was worked up as described in procedure
III to give 0.935 g (ꢁ98%) of solid; m.p. 134–1368C. The crude product
was subjected to chromatography on silica gel. Elution with benzene/
EtOAc (1:1) afforded 0.540 g (56%) of pure 5. Rf =0.29 (PhH/EtOAc
1:1); m.p. 148–1508C; [a]3D1:6 =+38.00 (c=0.275 in CHCl3); 1H N MR
(400 MHz, [D]6DMSO): d=2.70 (m, 8H; bCH2), 3.60 (s, 12H; COOMe),
4.50 (m, 4H; aCH), 7.00, 7.45 (m, m, 16H; Ar-H), 9.00 ppm (d, J=
8.0 Hz, 4H; CONH); 13C NMR (100 MHz, [D]6DMSO): d=37.12 (4”
bCH2), 50.62 (4”aCH), 52.06 (4”OCH3), 127.23, 127.64, 129.03, 129.44
(16”Ar-C), 135.04, 139.18 (8”Ar-quaternary carbons), 168.96 (CONH),
170.36 ppm (COOMe) (the 13C-NMR peak assignments were confirmed
by HSQC and HMBC); IR (KBr): n˜ =3250, 3057, 2953, 1743, 1643, 1536,
1215 cmꢀ1; MS (MALDI-TOF): m/z (%): 949 (40) [M+H+], 972 (100)
[M+Na+], 988 (42) [M+K+]; HRMS calcd for C44H44N4O12S4: 948.1916;
found: 948.1937.
IX. Reaction of 8 with AgBF4: preparation of a monosilver complex:
The reaction of silver (I) tetrafluoro borate (10.5 mg, 0.053 mmol) and 8
(25 mg, 0.035 mmol), as described in procedure IV, afforded the complex
as a white powder. M.p. 145–1508C; MS (FAB): m/z (%): 823, 825 (20)
[M+Ag+].
X(A). Reaction of 6 with cystine di-OMe: preparation of 9: The reaction
of 6 (0.300 g, 0.5 mmol) and cystine di-OMe dihydrochloride (0.170 g,
0.5 mmol), as described in procedure III, gave 0.500 g (ꢁ100%) of
foamy solid. The crude product was subjected to chromatography on
silica gel. Elution with benzene/ethyl acetate (1:1) afforded 0.176 g
(42%) of 9. Rf =0.32 (PhH/EtOAc 1:1); m.p. 130–1358C; [a]D31:6
=
ꢀ7.3580 (c=0.27 in CHCl3); 1H NMR (200 MHz, [D]6DMSO): d=2.49
(m, 12H; CH2S (8H), CH2N(4H)), 3.60 (s, 6H; COOMe), 4.6 (m, 2H;
aCH), 7.26 (m, 16H; Ar-H), 8.62 (br, 2H; CONH), 9.22 ppm, (brd, 2H;
CONH); 13C NMR (75.47 MHz, [D]6DMSO): d=35.42, 37.23, 50.30,
51.71, 126.89, 128.51, 134.66, 135.36, 138.64, 168.44, 169.51, 170.09 ppm;
IR (KBr): n˜ =3243, 1742, 1640, 1539 cmꢀ1; MS (MALDI-TOF): m/z (%):
840 (100) [M+Li+]; HRMS calcd for C40H40N4O8S4: 832.1807; found:
832.1812; elemental analysis calcd (%) for C40H40N4O8S4 (832.1807): C
57.67, H 4.84, N6.73, S 15.40; found: C 57.51, H 4.97, N6.46, S 15.53.
VI. Reaction of
1 with cystamine: preparation of 6: Compound 1
(0.558 g, 2.49 mmol) and cystamine·2HCl (0.304 g, 1.349 mmol), if pro-
cessed as described in procedure I, gave 0.269 g (36%) of 6. M.p. 130–
1358C; 1H NMR (300 MHz, CDCl3): d=2.38 (m, 4H; S-CH2), 3.43 (m,
4H; N-CH2), 7.35 (m, 16H; aromatic), 7.90 ppm (d, J=6.7 Hz, 2H;
CONH); IR (KBr): n˜ =3427, 1705, 1633, 1547, 1298 cmꢀ1; MS (FAB):
X(B). Reaction of 2 with cystamine: preparation of 9: The reaction of 2
(0.400 g, 0.558 mmol) and cystamine dihydrochloride (0.138 g,
0.613 mmol), as described in procedure III, gave 0.500 g (ꢁ100%) of
foamy solid. The crude product was subjected to chromatography on
Chem. Eur. J. 2007, 13, 4253 – 4263
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4261

I. L. Karle, S. Ranganathan et al.
silica gel. Elution with benzene/ethyl acetate (1:1) afforded 0.090 g
N. R. Champness, A. Garau, V. Lippolis, C. Wilson, M. Schroder,
Chem. Commun. 2003, 312–313.
[16] C. Liang, K. Mislow, J. Am. Chem. Soc. 1994, 116, 3588–3592.
[17] T. Sekiya, H. V. Ormondt, H. G. Khorana, J. Biol. Chem. 1975, 250,
1087–1098.
[18] a) F. J. Schmitz, M. B. Ksebati, J. S. Chang, J. L. Wang, M. B. Hos-
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Sefler, J. Am. Chem. Soc. 1998, 120, 4105–4112.
(19%) of 9. Rf =0.32 (PhH/EtOAc 1:1); m.p. 130–1358C; [a]D31:6
=
ꢀ4.5000 (c=0.28 in CHCl3); 1H NMR (300 MHz, CDCl3): d=2.30 (m,
12H; CH2S (8H), CH2N(4H)), 3.68 (m, 6H; COOMe), 4.80 (m, 2H;
aCH), 7.50 ppm (m, 20H; Ar-H+CONH); IR (KBr): n˜ =3239, 1744,
1639, 1538 cmꢀ1; MS (ESI): m/z (%): 833 (45) [M+H+].
XI. Reaction of 9 with AgBF4: preparation of a monosilver complex:
The reaction of silver (I) tetrafluoro borate (15.3 mg, 0.0793 mmol) and 9
(22 mg, 0.0264 mmol), as described in procedure IV, afforded the com-
plex. M.p. 150–1558C; MS (ESI): m/z (%): 939, 941 (5) [M+Ag+].
[19] M. B. Hossain, D. Helm, J. Antel, G. M. Sheldrick, S. K. Sanduja,
A. J. Weinheimer, Proc. Natl. Acad. Sci. USA 1988, 85, 4118–4122.
[20] a) M. Mascal, I. G. Wood, M. J. Begley, A. S. Batsanov, T. Wals-
grove, A. M. Z. Slawin, D. J. Williams, A. F. Drake, G. Siligardi, J.
Chem. Soc. Perkin Trans. 1 1996, 2427–2433; b) M. Mascal, C. J.
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Soc. 1993, 115, 813–814.
Acknowledgements
I.L.K. is grateful to the National Institutes of Health Grant GM-30902
and to the Office of Naval Research for financial support. P.V. and S.R.
are grateful to the Council of Scientific and Industrial Research, New
Delhi, for the award of a Fellowship and financial assistance.
[21] F. R. Fronczek, S. T. Davis, L. M. B. Gehrig, R. D. Gandour, Acta
Crystallogr. Sect. C 1987, C43, 1615–1618.
[22] Cystine, harboring generally an orthogonally disposed S–S bridge,
plays a major role in the crafting of topological features in proteins.
An attractive goal would be to design bihelical structures containing
an S–S bridge in the hybrid peptide backbone that can assemble to
nanotubes.
[1] a) D. L. An, T. Nakano, A. Orita, J. Otera, Angew. Chem. 2002, 114,
179–181; Angew. Chem. Int. Ed. 2002, 41, 171–173; b) U. Guo, J. D.
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4170–4179; d) K. Nozaki, T. Terakawa, H. Takaya, T. Hiyama,
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131–133; e) I. L. Karle, D. Ranganathan, V. Haridas, J. Am. Chem.
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Nagaraj, I. L. Karle, J. Org. Chem. 2000, 65, 4415–4422.
[2] J. K. Judice, S. J. Keipert, D. J. Cram, J. Chem. Soc. Chem. Commun.
1993, 1323–1325.
[23] The desired 4 has diphenic acid and cystine in the ratio of 2:2. De-
tailed chromatography of the reaction mixture afforded, in addition
to 4 (34%), minor products, in which this ratio was 1:1 (i; 4.5%),
3:3 (ii; 3.5%) and 4:4 (iii; 2.3%). i: (Rf =0.38 (PhH/EtOAc 8:2);
m.p. 215–218o C; [a]D27 =ꢀ266.688 (c=0.16 in CHCl3); 1H N MR
(200 MHz, CDCl3): d=3.00 (m, 2H; bCH2), 3.45 (dd, J=13.3,
3.1 Hz, 2H; bCH2), 3.80 (s, 6H; COOMe), 4.75 (m, 2H; aCH), 7.35
(m, 8H; Ar-H), 7.75 ppm (d, J=7.0 Hz, 2H; CONH); 13C N MR
(75.47 MHz, CDCl3): d=41.25, 52.45, 52.86, 126.67, 127.42, 130.59,
131.12, 132.66, 141.62, 168.15, 170.48 ppm; IR (KBr): n˜ =3396, 3341,
1744, 1733, 1666, 1644, 1523, 1219 cmꢀ1; MS (ESI): m/z (%): 475
(100) [M+H+], 497 (60) [M+Na+]; HRMS calcd for C22H22N2O6S2:
474.543; found: 474.0921; elemental analysis calcd (%) for
C22H22N2O6S2 (474.543): C 55.68, H 4.67, N5.90, S 13.51; found: C
55.58, H 4.94, N5.71, S 13.15). Compound i afforded rigid crystals
from methanol. Crystal structure was established by X-ray crystal-
lography. In the absence of any usual interactions, the rigid structure
is suggested to be maintained by weak attractive forces, disposed in
all the three directions (I. L. Karle, P. Venkateshwarlu, S. Rangana-
than, Peptide Science 2006, 84, 502–507). ii: (Rf =0.49 (PhH/EtOAc
1:4); m.p. 115–1188C; 1H NMR (200 MHz, CDCl3 +[D]6DMSO):
d=2.75 (m, 12H; bCH2), 3.59 (m, 18H; COOMe), 4.54 (m, 6H;
aCH), 7.29 (m, 24H; Ar-H), 8.72 ppm (m, 6H; CONH); MS
(MALDI-TOF): m/z (%): 1446 (100) [M+Na+], 1462 (30) [M+K+]).
iii: (Rf =0.25 (PhH/EtOAc 1:4); m.p. 115–1208C; 1H N MR
(300 MHz, CDCl3): d=2.93 (br, 16H; bCH2), 3.69 (m, 24H;
COOMe), 4.55 (br, 8H; aCH), 7.59 ppm (m, 40H; Ar-H+CONH);
MS (MALDI-TOF): m/z (%): 1921 (17) [M+Na+]). Efforts to
secure crystals of ii and iii did not succeed.
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[24] a) Initial efforts to incorporate the second cystine residue by the
linking of 2 presented problems. DCC/SuOH afforded 32% of bis-
imide (iv). Rf =0.37 (PhH/EtOAc 96:4); m.p. 120–1258C; [a]D31:6
=
ꢀ353.630 (c=0.135 in DMSO); 1H NMR (300 MHz, CDCl3): d=
3.46 (dd, J=15.0, 10.5 Hz, 2H; bCH2), 3.55 (dd, J=15.0, 4.5 Hz, 2H;
bCH2), 3.75 (s, 6H; COOMe), 5.82 (dd, J=10.5, 4.5 Hz, 2H; aCH),
7.65 ppm (m, 16H; aromatic); 13C NMR (75.47 MHz, [D]6DMSO):
d=38.05, 52.42, 58.16, 128.78, 130.77, 132.71, 133.39, 133.88, 168.44,
170.25 ppm; IR (KBr): n˜ =3054, 2943, 2358, 1743, 1693, 1654, 1587,
1241 cmꢀ1; MS (FAB): m/z (%): 681 (32) [M+H+], 340 (34) [(M/2)+];
HRMS: calcd for C36H28N2O8S2: 680.1365; found: 680.1380. Com-
pound iv afforded colorless needles from chloroform/hexane. X-ray
crystallography confirmed the structure assigned. The reaction af-
forded only 3.7% of iv . b) Activation of the acid with ethyl chloro-
formate followed by addition with cystine di-OMe gave a complex
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4262
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Chem. Eur. J. 2007, 13, 4253 – 4263

Bihelical Structures
FULL PAPER
mixture of products containing the bischloroformate ester and cys-
tine di-OMe engaged in a single amide-bond formation. Various at-
tempts to correct these to give desired cyclic products did not suc-
ceed.
son, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Ha-
segawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M.
Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma,
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[33] These findings are in agreement with those reported, whereby the
bihelical topology in a chiral compound becomes open if this ligand
is absent (ref. [20a,b]).
[34] 2: 2-[2-(2-2-[2-(2-carboxyphenyl)phenylcarboxamido]-2-methyloxy-
carbonylethyldisulfanyl-1-methyloxycarbonylethylcarbamoyl)phen-
[25] Further chromatography of the reaction mixture afforded an isomer-
ic compound (13%); Rf =0.33 (CHCl3/MeOH 95:5); m.p. 135–
1378C. In spite of the difference in the m.p., the 1H-NMR data and
mass spectrum clearly showed it was isomeric. 1H NMR (200 MHz,
CDCl3 +[D]6DMSO): d=2.30 (m, 8H; S-CH2), 3.30 (m, 8H; N-
CH2), 7.20 (m, 16H; Ar-H), 8.57 ppm (brs, 4H; CONH); IR (KBr):
n˜ =3243, 2922, 1637, 1535, 1306 cmꢀ1; MS (ESI): m/z (%): 739 (100)
[M+Na+], 717 (20) [M+H+]; HRMS: calcd for C36H36N4O4S4:
716.1697; found: 716.1666. The CD spectrum showed a random pro-
file.
AHCTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
AHCTREUNG
carboxyphenyl)phenylcarboxamido]ethyldisulfanylethylcarbamoyl)-
phenyl]benzoic acid; 7: methyl 2-[2-(2-2-[2-(2-methyloxycarbonyl-
phenyl)phenylcarboxamido]ethyldisulfanylethylcarbamoyl)phenyl]-
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benzoate;
hexadecahydrotetrabenzo
8:
9,10,11,12,15,16,17,18,27,28,29,30,33,34,35,36-
[g,i,u,w][1,2,15,16,5,12,19,26]tetrathiate-
AHCTREUNG
traazacyclooctacosine-9,18,27,36-tetraone; 9: dimethyl 9,18,27,36-tet-
raoxo-9,10,11,12,15,16,17,18,27,28,29,30,33,34,35,36-hexadeca-
A
N
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1988, 31, 77–86.
AHCTREUNG
[35] CCDC-609597 and CCDC-609598 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[29] E. Bunenberg, C. Djerassi, K. Mislow, A. Moscowitz, J. Am. Chem.
Soc. 1962, 84, 2823–2826.
[30] Although induced chirality is possible in the crystal structure of 8, it
showed a random CD profile similar to its achiral precursor 7.
[31] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V.
Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Peters-
Received: September 28, 2006
Revised: January 11, 2007
Published online: March 8, 2007
Chem. Eur. J. 2007, 13, 4253 – 4263
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4263