Bio-inspired Herringbone Foldamers: Strategy for Changing the Structure of Helices

Article abstract of DOI:10.1021/acs.joc.7b00185

Cyclic oligomers of azole peptides were isolated from a multitude of marine organisms and were used for a large number of molecular machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we show that a minor change, the introduction of a methyl group in the δ position, results in a significant change in the secondary structure of the corresponding oligomers. Instead of a canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the helix changes its sign at least twice per turn. This strategy allows a remarkable change of the secondary structure via a small modification. By means of enantiomerically pure amino acids, we were able to control, for the first time, both the helicity of the helix and the form of the herringbone. The investigation of the underlying herringbone basic element and its folding to a noncanonical helix were conducted by NMR and CD spectroscopy, as well as by X-ray crystallography and quantum chemical calculations.

Full text of DOI:10.1021/acs.joc.7b00185

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Article
Bio-Inspired Herringbone Foldamers:
Strategy for Changing the Structure of Helices
Abdulselam Adam, Gebhard Haberhauer, and Christoph Wölper
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00185 • Publication Date (Web): 30 Mar 2017
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The Journal of Organic Chemistry
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Bio-Inspired Herringbone Foldamers: Strategy for Changing the Structure of
Helices
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Abdulselam Adam, Gebhard Haberhauer* and Christoph Wölper
Institut für Organische Chemie, Universität DuisburgꢀEssen, Universitätsstr. 7, Dꢀ45117
Essen, Germany
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Email: gebhard.haberhauer@uniꢀdue.de
TOC/Abstract graphic:
ABSTRACT: Cyclic oligomers of azole peptides were isolated from a multitude of marine
organisms and were used for a large number of molecular machines. As shown previously,
oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we
show that a minor change – the introduction of a methyl group in the
δ position – results in a
significant change in the secondary structure of the corresponding oligomers. Instead of a
canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the
helix changes its sign at least twice per turn. This strategy allows a remarkable change of the
secondary structure via a small modification. By means of enantiomeric pure amino acids,
we were able to control – for the first time – both the helicity of the helix and the form of the
herringbone. The investigation of the underlying herringbone basic element and their folding
to a noncanonical helix were conducted by NMR and CD spectroscopy as well as by Xꢀray
crystallography and quantum chemical calculations.
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Introduction
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Peptides and proteins play a major role in living organisms. Due to their specific and highly
organized structures, they are the most important molecular machines in cells.1ꢀ2 In this
context, the information about the superior structure is of utmost importance: controlling the
form of the structure means controlling its function.3ꢀ5 Through a specific structural change, it
is possible to influence the selectivity and the effect of bioactive substances enormously.1ꢀ2,5
Therefore, a great deal of effort has been invested in manipulating the secondary structure of
peptides and proteins in a highly directed and effective way. One basic structural element
found in peptides and proteins is helicity.6 It has been shown that – beside the naturally
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occurring αꢀamino acids – synthetic α/β/γꢀamino acids also form oligomers exhibiting helixꢀ
like structures.7ꢀ22 The incorporation of azoleꢀcontaining units in these amino acids reduce
the backbone flexibility and enhance the stability of the helical secondary structure.23ꢀ24
Almost all of these helical structures have a canonical form.
An upꢀtoꢀdate, but scarcely investigated issue is the formation and control of noncanonical
helices. Huc et al. were able to show that oligomers bearing aliphaticꢀaromatic δꢀamino acids
are prone to form a noncanonical helix with a herringbone form.25ꢀ26 The helicity of a
noncanonical helix can be induced by incorporating a single chiral carbon of the Nꢀterminal
moiety.27 However, the control of the type of helix, the helicity and the form of the
herringbone has – to the best of our knowledge – never been investigated and described. In
this context, controlling the form of the helix is crucial for biological functions.
Recently, we synthesized oligomers from imidazole containing δꢀamino acids which fold into
canonical helices.28 These compounds are congeners of naturally occurring marine
metabolites29ꢀ32 and can be used to transfer chirality to further stereogenic elements33ꢀ35
making the design of unidirectional molecular machines possible.36ꢀ38 The helices formed by
oligomers of this imidazole
dispersion interactions.28 It is interesting to note that in these helices hydrogen bonds are
arranged almost orthogonally to the axis of the helix. In naturally occurring helices of ꢀamino
acids, the hydrogen bonds are arranged parallel to the axis of the helix.16 Here we show that
the introduction of a single methyl group in the imidazoleꢀcontaining ꢀamino acid leads to a
δꢀamino acids are stabilized both by hydrogen bonds and
α
δ
significant change in the secondary structure and its properties. Instead of a canonical helix,
a noncanonical helix with a herringbone form is observed. Due to the use of enantiomeric
pure amino acids, the chiral information at the stereogenic centers predetermines the helicity
and the form of the herringbone.
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Results and Discussion
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a) Concept for Changing the Structure and the Determination of the Herringbone Form
in Noncanonical Helices
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In the case of canonical helices, the building blocks are connected in such a way that the
slope along the helix does not change significantly, neither in size nor in sign (see Figure 1a).
In a noncanonical helix, an additional superior structure exists; one example of this is the
herringbone form (see Figure 1a). This herringbone form changes the helix in such a way
that the slope along the helix changes its sign at least twice per turn. The combination of two
superior structures (helix and herringbone) results in the existence of six different
conformations, which are described by the following descriptors: M and P for the helicity and
V and A for the herringbone form. In order to correctly use the descriptors V and A for the
herringbone form, the orientation of the helix has to be specified. In the following, the
discussed helices should be orientated in such a way that the Nꢀtermini are on the top and
the Cꢀtermini on the bottom (Figure 1a). If we order the helices in that way, the apex of the
herringbone building block is orientated downwards in the herringbone form V with the
opposite being true for the herringbone form A. In Figure 1a, a canonical M helix as well as
two noncanonical M helices showing herringbone form V and A, respectively, are depicted
schematically. The blue dots on the tops represent the Nꢀtermini, the red dots at the bottoms
the Cꢀtermini.
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Figure 1. a) Schematic representation of a canonical M helix as well as two noncanonical M
helices showing herringbone form V and A, respectively. The blue dots at the top represent
the Nꢀtermini, the red dots at the bottom the Cꢀtermini. b) The dihedral angle θ(C1ꢀN2ꢀC3ꢀ
C4) in a dimer of two achiral imidazole amino acids amounts to about 180°. The
corresponding oligomer adopts a canonical M helix (left). c) In a dimer of chiral imidazole
amino acids the absolute value of the dihedral angle θ(C1ꢀN2ꢀC3ꢀC4) is significantly smaller
than 180°. The corresponding oligomers should fold into noncanonical helices either with V
or with A herringbone form.
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Our aim was to change the structure of a helical oligopeptide into a noncanonical
herringbone helix by introduction of a small group. Whereby, we intended to govern both the
helicity (M or P) and the herringbone form (V or A) of the helix by the introduction of chiral
information into monomers. Recently, we were able to show that oligomers derived from
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imidazole peptides form canonical helices. In these
parts of the imidazole rings with the centers as aliphatic carbon atoms. With exception of
the Nꢀtermini, the foldamers consists of only achiral units; in other words, the carbon atoms
possess two hydrogen atoms as substituents and the corresponding amino acid can be
considered as being equivalent to the ꢀamino acid glycine. In Figure 1b, a dimer of such
achiral imidazole amino acids is shown. As the carbon atom (C3 in Figure 1b) has two
equivalent substituents (hydrogen atoms), the dihedral angle (C1ꢀN2ꢀC3ꢀC4) should be
δꢀamino acids the α, β and γ centers are
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δ
δ
α
δ
θ
about 180° resulting in an almost flat dimer. If a couple of these dimers are formed as an
oligomer, the resulting secondary structure represents a canonical helix. The helicity of this
helix can be determined by a single chiral imidazole amino acid located at the Nꢀterminus.
In order to obtain a noncanonical helix, we used the following approach: The introduction of
an alkyl group at the
δ carbon atom should result in a bending of the corresponding dimer
(Figure 1c). This dimer can be considered as a herringbone unit. In previous studies, we
were able to show that an alkyl group (e.g. a methyl or isopropyl group) leads to a significant
deviation of the dihedral angle
that an imidazole with a methyl group attached to the
thereof shows a dihedral angle (C1ꢀN2ꢀC3ꢀC4) of ꢀ156°, the strongly bent one has a
θ
(C1ꢀN2ꢀC3ꢀC4) from 180°.39ꢀ40 Model studies have shown
position have two minima: one
δ
θ
dihedral angle of ꢀ102°. The first conformation is stabilized by interaction between the σ(C3ꢀ
Me) orbital and the π*imidazole orbital; the second one exhibits a stabilizing interaction between
the σ*(C3ꢀN2) orbital and the πimidazole orbital.41
If a couple of these dimers are formed into an oligomer, the latter should fold into a
noncanonical helix with an additional herringbone form (Figure 1c). A critical point is the size
of the alkyl group. On the one hand, they should be large enough to cause a bending of the
dimer as previous investigations showed that the larger the alkyl groups are, the larger is the
bending of the corresponding dimer.40 On the other hand, the size of the alkyl groups must
not be too large: in the noncanonical helix, the alkyl groups are orientated parallel to the helix
axis. If they are too bulky, the attractive interactions between the turns will probably be
inhibited resulting in no helix formation. Therefore, we chose methyl groups as substituents.
If the achiral imidazole amino acid is considered as equivalent to glycine (see above), the
imidazole amino acid showing one methyl group at the
δ carbon atom is an analogue to
alanine. Furthermore, we intended to use a chiral imidazole amino acid which should allow
us to determine both the helicity and the herringbone form.
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b) Synthesis of the Oligomers
The synthesis of the oligomers is shown in Scheme 1. The first step is the synthesis of the
corresponding imidazole amino acid starting from the Bocꢀprotected alanine 1 and the amino
ketone 2. The resulting diprotected imidazole amino acid can be transformed into both the
free acid 4a and into the ammonium salt 5b. Starting from these two building blocks the
dimer 6a, the trimer 7, the tetramer 10a, the heptamer 11 and also the decamer 13a can be
synthesized by stepwise coupling (reaction condition C), Bocꢀdeprotection (reaction condition
A) and benzyl esterꢀdeprotection (reaction condition B) (see Scheme 1).
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Additionally to the linear oligomers 6a, 7, 10a, 11, and 13a, the cyclic oligomers 15, 16 and
22 were prepared (Scheme 2). These were done for the following two reasons: firstly, by
means of these cyclic compounds, the above mentioned thesis, that the absence of an alkyl
group leads to a dihedral angle
θ
(C1ꢀN2ꢀC3ꢀC4) of about 180° whereas the presence of a
(C1ꢀN2ꢀC3ꢀC4) « 180°), should be verified.
methyl group results in a bending of the dimer (
θ
Secondly, cyclic peptides are known to crystallize better, allowing for an additional
investigation of the conformation in solid state. In the first step, the free amino acids 14 and
21 were synthesized (Scheme 2). The oneꢀpot cyclization of the amino acid 14 leads to the
trimer 15 and the tetramer 16 in moderate yields. The macrotrimerization of the amino acid
21 result in the cyclic trimer 22; the corresponding tetramer could only be detected in traces.
Scheme 1. Synthesis of the decamer 13a. Reaction conditions: i) THF, NMM, ClCOOiBu,
88%; ii) xylene, MeNH2, AcOH, ꢀ, 85 %; iii) MeOH, dioxane, NaOH, 83 %; iv) MeOH, H2O,
Cs2CO3, PhCH2Br, DMF, 79 %; general procedures: A) EtOAc, HCl; B) MeOH, Pd(OH)2/C,
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H2; C) CH3CN, iPr2NEt, FDPP. FDPP = pentafluorophenyldiphenylphosphinate, NMM = Nꢀ
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methylmorpholine.
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Scheme 2. Synthesis of the cyclic trimers 15 and 22 as well as the cyclic tetramer 16.
Reaction conditions: i) THF, Boc2O, Pd(OH)2/C, 93 %; ii) DMF, NaH, PhCH2Br, 51 %; iii)
MeOH, dioxane, NaOH, 96 %; general procedures: A) EtOAc, HCl; C) CH3CN, iPr2NEt,
FDPP.
c) Investigation of the Secondary Structure
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For structural investigations, the H NMR spectra of the linear oligomers showing different
chain lengths were recorded in chloroform. A section of these spectra is depicted in Figure 2.
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Additionally, the H NMR spectrum of decamer 23, which consists of nine achiral imidazole
amino acids (the only one chiral unit is at the Nꢀterminus and accordingly unimportant for the
shape of the helix), is also given. This decamer is known to form a canonical helix in
solution.28
While the amide signals are found at 7.6ꢀ8.5 ppm for the short oligomers (up to the tetramer
10a), these are shifted to lower field for the higher oligomers (heptamer 11 and decamer
13a). The NH resonances are found at values of up to 10.2 ppm. This strong shift is an
unambiguous hint for the formation of hydrogen bridges. The extent of the hydrogen bond
formation is comparable to that of the decamer 23 showing a canonical helix.28 The 1H NMR
coupling constants of the amide protons in 13a ranges in the area from 6.9 to 8.5 Hz, which
corresponds to dihedral angles θ
(HꢀN2ꢀC3ꢀH) with absolute values from 140 to 153°.42
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N
N
H
N
N
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OBn
N
N
Boc NH
O
O
O
O
9
23
H
N
OBn
N
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Boc NH
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13a
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1
Figure 2. H NMR spectra of the oligomers dependent on their chain length in CDCl3: a)
decamer 23, b) decamer 13a, c) heptamer 11, d) tetramer 10a, e) trimer 7, f) dimer 6a, g)
monomer 4.
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An interesting aspect in H NMR spectra of the linear oligomers is the broadening of the
signals and thus the dynamic of the systems. In the case of the short oligomers (dimer 6a to
tetramer 10a) and the decamer 13a the peaks are sharp. Accordingly, the exchange is fast
(dimer 6a to tetramer 10a) or slow (decamer 13a) with respect to the NMR timescale. In the
case of heptamer 11, exchange is neither slow nor fast (Figure 2). It corresponds to an
intermediate regime where different species coexist that exchange at a rate of the same
order than the frequency difference of the NMR signals. The first hint for the existence of a
noncanonical helix of decamer 13a can be found through a comparison to the decamer 23.
Both have the same number of hydrogen bridges, but show a completely different dynamic.
For decamer 23, a slow dynamic with respect to the NMR time scale can be observed.
Whereby, the flexibility inside the helix is slower than that at the outer sides.28 In the decamer
13a, also the monomers at the termini hardly show any dynamic indicating the whole
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secondary structure is equally frozen. Based on the concentrationꢀindependent H NMR
spectra, it can be definitively excluded that these observations are caused by intermolecular
processes like aggregation.28
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Variable temperature H NMR measurements of the oligomers in CDCl3 and C2D2Cl4 show
that the secondary structures collapse at higher temperatures. In the case of the heptamer
11, the hydrogen bonds are broken even at 50 °C resulting in a shift of the amide protons to
the range of 7.6 ppm (Supporting Information). In the case of the decamer 13a, a
temperature increase leads to only a slight high field shift of the NH signals (Supporting
Information). Only from 80 °C the amide signals become extremely broadened indicating a
high dynamic of the secondary structure. At temperatures above 100 °C, the NH signals are
found at about 7.6 ppm.
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Furthermore, NOESY experiments were performed for the decamer 13a (see Supporting
Information, Figures S13ꢀ15). Since the decamer 13a is constituted of the same monomer,
the signals of the relevant nucleus appear in such narrow range that a distinction and exact
assignment is not possible. This behavior is maybe a hint that folding of decamer 13a is not
very compact. However, an important conclusion can be drawn when the coupling range
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between the amide protons and the methyl groups attached to the
δ position is considered
(Figure S14): some amide hydrogen atoms (e.g. at 9.16 and 9.65 ppm) are in close proximity
(<3.0 Å) to two methyl groups.
The hydrogen/deuterium exchange experiments (HDX) of the decamer 13a confirm that the
secondary structure is very stable. The exchange is slow despite the addition of a large
excess of methanol (see Supporting Information). While the shorter oligomers (trimer 7 and
tetramer 10a) reach equilibrium within 10 minutes, more than 5 hours are required in the
case of decamer 13a. The reason for this difference is the rigidity of the folded framework in
decamer 13a.
A further investigation of the secondary structure of the oligomers was conducted by means
of ECD spectroscopy. In Figure 3a, the CD spectra of the oligomers are shown. For a better
comparison, the CD spectra are divided by the number of chiral units. Therefore, a change in
the spectra dependent on the chain length should provide information about the secondary
structure. The observed effects are all of intramolecular nature as we obtained concentrationꢀ
independent spectra (see Supporting Information).
a)
b)
Figure 3. a) CD spectra (per chiral unit) of monomer 4 (red), dimer 6a (green), trimer 7
(blue), tetramer 10a (brown), heptamer 11 (light blue), and decamer 13a (yellow) in
acetonitrile. b) CD spectra (per chiral unit) of decamer 13a in acetonitrile in the range from ꢀ
10 to 80 °C in steps of 10 °C.
If the negative Cotton effect at 260 nm is considered, it can be seen, that – going from the
monomer to the decamer – a significant decrease of the signals is found up to the trimer. At
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210 nm only the higher oligomers (heptamer and decamer) show a positive Cotton effect.
Furthermore, for the higher oligomers a slight bathochromic shift for the positive Cotton
effects at 235 and 260 nm are observed (Figure 3a). Our interpretation for this observation is
the following: starting from a trimer, subordinate structural elements are formed which may
correspond to a herringbone basic element (see Figure 1b). In higher oligomers the
herringbone basic elements arrange to an organized superordinate structure which can be
considered as a herringbone helix. This hypothesis is supported by variable temperature CD
measurements of the decamer 13a (Figure 3b): increasing the temperature leads to the
decrease of the organized helical structure. The positive Cotton effect at 210 nm diminishes
and a hypsochromic shift of the band at 240 nm is observed. The CD spectrum of the
decamer 13a at a temperature of 80 °C resembles those of the trimer 7 and the tetramer 10a
at 20 °C. This means that the herringbone basic elements also remain at higher
temperatures. A similar behavior is also found for the heptamer 11 (see Supporting
Information). In the case of the smaller oligomers (dimer, trimer and tetramer), an only limited
breakup of the herringbone basic elements is observed (see Supporting Information).
CD measurements in different organic solvents and in aqueous solution show that both the
herringbone basic elements and the helix remain, which is of particular importance for
applications in medicinal chemistry (see Supporting Information). Furthermore, water titration
experiments display a parabolic dependence of secondary structure on the water content of
the solvent. This is a known effect and represents that in aqueous solutions the folding is
caused by dispersion interactions.28
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A comparison of the CD spectrum of decamer 13a with the CD spectrum of 23, which folds
into a canonical
two differences. Firstly, the CD spectrum of 13a exhibits a negative Cotton effect at 260 nm.
Accordingly, decamer 13a should adopt a helix in solution. Secondly, and of even greater
P
helix in solution and shows a positive Cotton effect at 260 nm,28 reveals
M
relevance, the Cotton effect at 260 nm of 23 virtually disappears at higher temperatures,
whereas there is no significant change in the Cotton effect at 260 nm of 13a.
To prove that there is a direct relation between the Cotton effects at about 235 and 260 nm
and the structure of the herringbone basic element, the following issue was considered: in a
cyclic trimer and tetramer a helical structure is not possible. The only superordinate structural
element is the relative orientation of the azole cycles to each other. If the dihedral angle
between the azole groups amounts to a value which is significant smaller than 180°, the
resulting structure corresponds to several combined herringbone basic elements (Figure 1c).
By means of the CD spectra of these systems, the Cotton effects for the herringbone basic
element can be identified.
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Figure 4. Molecular structure of the dimer 24, the cyclic trimers 15, 22 and 25 and the cyclic
tetramer 16. All hydrogen atoms and solvent molecules are omitted for the sake of clarity.
For the structural study, single crystals of the dimer 24, the cyclic trimers 15 and 22 and the
cyclic tetramer 16 were grown and investigated using Xꢀray crystallography. The thus
obtained structures are depicted together with the already known structure of 2543 in Figure
4. Regarding the dihedral angle θ(C1ꢀN2ꢀC3ꢀC4), there is no difference between the nonꢀ
cyclic dimer 24 and the cyclic trimer 22. In both cases, the average dihedral angle is about
180° (ꢀ176° in 24 and ꢀ170° in 22). In the 1H NMR of 22, the coupling constants for the amide
protons have a value of 3.3 Hz, which corresponds to a dihedral angle
θ(HꢀN2ꢀC3ꢀH) of
about 115°. The methyl and the isopropyl groups attached at the carbon atoms in the cyclic
δ
trimers 15 and 25 are responsible for a deviation from the planarity. The average dihedral
1
angle amounts to ꢀ157° for 15 and ꢀ126° for 25. In the H NMR of 15 and 25, the coupling
constants for the amide protons have a value of 7.0 and 8.9 Hz, which corresponds to a
dihedral angle
cyclic trimers 15, 22 and 25 clearly demonstrates that alkyl groups in
imidazole systems leads to a bending of the dihedral angle (C1ꢀN2ꢀC3ꢀC4).
In the molecular structure of the tetramer 16, two types of differently bent imidazole units
θ
(HꢀN2ꢀC3ꢀH) of about 141° and 156°, respectively. The comparison of the
δ
position of such
θ
were found: one has a dihedral angle
ꢀ71 °.
θ(C1ꢀN2ꢀC3ꢀC4) of about ꢀ120°, the other one of about
The CD spectra of 15, 16 and 25 are illustrated in Figure 5. Additionally, the corresponding
CD spectra obtained by quantum chemical calculations are shown. In order to receive these
spectra, the structures of the oligomers 15, 16 and 25 were optimized by means of B3LYPꢀ
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D344ꢀ48 functional and the 6ꢀ31G*49ꢀ50 basis set. On the thus obtained geometries, TDꢀ
B3LYP51ꢀ53 calculations were performed for the first 50 transitions. A comparison shows that
the experimentally determined are very similar to the simulated ones. Furthermore, it
becomes obvious that the trimers (with calculated average dihedral angles of ꢀ159° for 15
and ꢀ125° for 25) show a negative Cotton effect at 250 nm, whereas the corresponding
negative Cotton effect of the tetramer (with a calculated average dihedral angle of ꢀ85°) is
shifted to 260 nm. In other words, a bending of the imidazole units leading to a herringbone
basic element appears in the CD spectrum by a negative Cotton effect at about 260 nm.
Therefore, greater bending can be seen by the shift of this signal to higher wavelengths.
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a)
b)
Figure 5. a) Experimentally determined CD spectrum of the cyclic trimers 15 (red) and 25
(green) as well as the cyclic tetramer 16 (blue) in acetonitrile at 20 °C. b) Simulated (TDꢀ
B3LYP/6ꢀ31G*) CD spectra of the cyclic trimers 15 (red) and 25 (green) as well as the cyclic
tetramer 16 (blue).
To study the superior structure of the herringbone basic elements, molecular modeling
calculations were conducted for the decamer 13b (R1 = Moc, R2 = Me). First, Montecarlo
simulations were performed, where a canonical helixꢀlike structure and an almost linear
structure were assumed.54 As force fields, OPLS 2005 and Amber* were used in different
environments (vacuum, water and chloroform). The thus obtained helical geometries and
further preꢀorientated conformations were used as starting geometries for additional quantum
chemical calculations. The optimization were performed using the B3LYP functional, the
empirical D3 dispersion correction and the 6ꢀ31G* basis set. Although all possible helical
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structures (canonical M and P helix, noncanonical M and P helix with herringbone form V and
A) were used as starting geometries for the B3LYPꢀD3 calculations, only four types of helical
structures were verified as end structures during the optimization process. These helices are
depicted in Figure 6 with their relative energies. Furthermore, the helical structures were
calculated in solution using the continuum solvation model COSMO55. However, the
calculations in solution (B3LYPꢀD3/6ꢀ31G* − COSMO) leads to no significant changes in
either the structure or in the relative energies (Figure 6).
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canonical M helix
noncanonical M helix with
herringbone form V
0.0 kcal/mol
canonical P helix
noncanonical P helix
with herringbone form V
+44.9 kcal/mol
+34.8 kcal/mol
+50.9 kcal/mol
(+31.4 kcal/mol)
(0.0 kcal/mol)
(+49.1 kcal/mol)
(+37.3 kcal/mol)
Figure 6. Molecular structures (B3LYPꢀD3/6ꢀ31G*) of decamer 13b (R1 = Moc, R2 = Me)
exhibiting different helicities. All hydrogen atoms were omitted for the sake of clarity. The
relative energies (B3LYPꢀD3/6ꢀ31G*) are also given. The values in brackets stem from
B3LYPꢀD3/6ꢀ31G* − COSMO calculations; as solvent acetonitrile was used.
Beside the canonical M and P helices, the noncanonical M and P helices with herringbone
form V were found. Please note, that the orientation of the helix (N terminus is at the top; cf.
Figure 1) is essential for the denotation V or A. The by far most stable conformation is,
according to the calculations, the noncanonical M helix with herringbone form V (see Figure
6); the second most stable secondary structure is the canonical M helix. The two other
helices are so energetically unfavored (>37 kcal/mol) that we will exclude them from a further
discussion.
In the case of the canonical M helix, a turn consists of about 3.5 imidazole amino acids. This
was already found for the canonical helices of the achiral amino acids.28 The pitch –
calculated as the distance measured between the C(3) atom of the iꢀth imidazole unit and the
carbonyl carbon atom (C1) of the (i+3)ꢀrd unit – is about 4.1 Å (numbering see Figure 1b).
This is in the range of typical πꢀπ stacking interactions56; however, it is higher than that in the
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helices composed of achiral imidazole amino acids (3.4 Å).28 This is due to the additional
methyl groups in the M helix of decamer 13b, which are placed between the turns preventing
effective πꢀπ stacking interactions. The methyl groups at the stereogenic centers point
outside the helix and are accordingly far away (>3.5 Å) from the amide hydrogen atoms.
For the noncanonical M helix with herringbone form V, a full turn consists of 4.5 imidazole
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amino acids. The dihedral angle θ(C1ꢀN2ꢀC3ꢀC4) (see Figure 1b) adopt two different values
in the helix: Within the herringbone basic element (consisting of two imidazole amino acids) a
value of about ꢀ105° is found (Figure 7). At the interface between two herringbone basic
elements, it amounts to ca. ꢀ152°. Please note, that accordingly the noncanonical M helix
with herringbone form V can consists in two different conformers: The helix can start at the
Cꢀterminus either with a strongly (θ(C1ꢀN2ꢀC3ꢀC4) ≈ ꢀ105°) or with a weakly bent (θ(C1ꢀN2ꢀ
C3ꢀC4) ≈ ꢀ150°) unit. The former one is energetically more favored (Figure S19 and S21).
The methyl groups (C5, see Figure 7) at the stereogenic centers point alternating to the
inside and the outside of the helix. The methyl groups pointing inside the helix are in close
proximity to two different amide hydrogen atoms, which is in agreement with the NOESY
experiments of 13a (Figure 7).
5''
4''
N
3''
7''
2''
N
O
N
H
1''
O
7'''
H
N
6iv
H
N
d(H6ivꢀH7''') = 2.34 Å
d(H6ivꢀH7'') = 2.41 Å
d(C5'ꢀC5''') = 4.30 Å
d(C5ivꢀC5') = 5.12 Å
d(C5ivꢀC5''') = 3.90 Å
d(C5ꢀC5'') = 13.10 Å
5'
5'''
N
5iv
*
4'
H
3'
*
H
2'
N
H
N
O
N
1'
H
N
4
1
θ
θ
θ
(C1ꢀN2ꢀC3ꢀC4) = ꢀ141°
(C1'ꢀN2'ꢀC3'ꢀC4') = ꢀ103°
(C1''ꢀN2''ꢀC3''ꢀC4'') = ꢀ154°
N
2
3
N
O
5
Figure 7. Molecular structure of an extract of decamer 13b showing a noncanonical M helix
with herringbone form V. The distances between a methyl group (C5iv) pointing inside the
helix and two amide hydrogen atoms (H7'' and H7''') as well as further characteristic data are
listed.
The methyl groups are arranged in such a pattern that repulsive interactions between methyl
groups from different turns are avoided. The attractive interactions between the aromatic
systems of different turns are not disturbed by them. The smallest distances between nonꢀ
hydrogen atoms of neighboring turns amount to values lower than 3.3 Å. This is a possible
reason for the energetic stabilization of this conformation compared to all other calculated
helix structures of decamer 13b. In view of the large energy difference (>31 kcal/mol), it can
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be assumed that only the noncanonical M helix with herringbone form V is the dominant
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secondary structure in solution.
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b)
Figure 8. a) Experimentally determined CD spectrum of 13a in acetonitrile at 20 °C. b)
Simulated (TDꢀB3LYP/6ꢀ31G*) CD spectra of different conformations of 13b. Only the
simulated CD spectrum of the isomer showing a noncanonical M helix with herringbone form
V matches with the experimentally determined CD spectrum of 13a. Due to the different
width of the spectra, the experimentally determined and simulated spectra are depicted in
different areas.
Further evidence for the noncanonical M helix with herringbone form V and its dominance in
solution is the comparison between the experimentally determined CD spectrum of the
decamer 13a and the simulated CD spectra of the conformers of 13b (Figure 8). For the
simulation, the energy of the 250 lowest singlet excitations were calculated using the TDꢀ
B3LYP/6ꢀ31G* approach. In the simulated area, the shapes of the experimentally measured
and the calculated CD spectrum of the isomer showing a noncanonical M helix with
herringbone form V match well: the energyꢀlowest band is negative; it follows a positive one
and the energyꢀhighest band is negative again. The calculated spectra of the other
conformers match either very poorly or not at all with the experimentally determined CD
spectrum.
Furthermore, the CD spectra were calculated in solution using the continuum solvation model
COSMO. However, the consideration of this approximation (B3LYPꢀD3/6ꢀ31G* − COSMO)
leads to no significant changes in the simulated CD spectra (Figure S19).
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Conclusion
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In sum we were able to synthesize novel nonꢀcyclic oligomers derived from imidazole amino
acids. Whereas achiral imidazole amino acids were utilized in previous work, here the
corresponding chiral congeners were used. They differ only in the formal introduction of a
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methyl group in the
δ position. However, the thus caused impact is remarkable: Whereas
oligomers derived from achiral imidazole amino acids fold into canonical helices, the
oligomers derived from chiral imidazole amino acids form noncanonical helices. These
helices exhibit an additional structural element: a herringbone form which enlarged the family
of helices. By the use of enantiomeric pure amino acids, we were able to predetermine both
the helicity of the helix and the form of the herringbone. The investigation of the underlying
herringbone basic element and their folding to a noncanonical helix were conducted by NMR
and CD spectroscopy in different solvents and temperatures. Quantum chemical calculations
support both the formation of the herringbone basic element and the folding into a superior
noncanonical helix. The formation of the herringbone basic element was further supported by
the Xꢀray analysis of the cyclic oligomer. Furthermore, we demonstrate that the foldamers
show a high stability in organic as well as in aqueous media, which is of particular
importance for applications in medicinal chemistry.
As the corresponding imidazole amino acids are easy accessible and modifiable, this
approach allows the access to a wide diversity of enantiopure secondary structures showing
completely different forms. Moreover, as short cyclic oligomers from azoleꢀcontaining
pseudopeptides are also present in marine organisms29,31ꢀ32, the question arises, if
noncanonical helices could be found in nature and if they are biologically active
intermediates.
Experimental Section
General Remarks: All chemicals were reagent grade and were used as purchased.
Reactions were monitored by TLC analysis with silica gel 60 F254 thinꢀlayer plates. Flash
chromatography was carried out on silica gel 60 (230ꢀ400 mesh). H and 13C NMR spectra
1
were measured with Bruker Avance DRX 300, Avance DRX 500 and Avance HD 600
spectrometers. All chemical shifts (d) are given in ppm. The spectra were referenced to the
peak for the protium impurity in the deuterated solvents indicated in brackets in the analytical
data. HRꢀMS spectra were recorded with a Bruker BioTOF III Instrument. UV/Vis absorption
spectra were obtained with Jasco Jꢀ815 and Vꢀ550 spectrophotometers. CD absorption
spectra were recorded with a Jasco Jꢀ815 spectrophotometer. IR absorption spectra were
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recorded with a Varian 3100 FTꢀIR spectrophotometer. Melting points were measured using
a Büchi Bꢀ540 melting point apparatus.
General Procedure (A) for the Cleavage of the Boc Group. The Bocꢀprotected compound (1
equiv.) was dissolved in ethyl acetate (7 ml/mmol starting material) and the solution was
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cooled to 0 °C. HCl in EtOAc (4 M; 2.5 ml/mmol starting material) was added at that
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temperature. The ice bath was removed after 30 min and stirring was continued at room
temperature until all starting material was consumed which was detected by thin layer
chromatography. The mixture was concentrated in vacuo to provide a quantitative yield of the
hydrochloride, which was used in the next step without further purification.
General Procedure (B) for the Cleavage of the Benzyl Ester Group. Palladium hydroxide (80
mg/mmol starting material) was added at room temperature to a solution of the protected
compound (1 equiv.) in methanol (40 ml/mmol starting material). The mixture was stirred
under H2 atmosphere until all starting material was consumed which was detected by thin
layer chromatography. Then, the mixture was filtered and concentrated in vacuo to give the
acid compound, which was used in the next step without further purification.
General Procedure (C) for the Peptide Coupling. To a solution of the acid (1 equiv.) and the
aminohydrochloride (1.2 mmol/mmol starting material) in acetonitrile (40 ml/mmol starting
material) N,NꢀDiisopropylethylamine (7.3 mmol/mmol starting material) was added dropwise
at room temperature. After 30 min pentafluorophenyldiphenylphosphinate (FDPP; 1.2
mmol/mmol starting material) was added and the solution was stirred at room temperature
until all starting material was consumed which was detected by thin layer chromatography
(several days). Afterwards, the solvent was evaporated and the residue was purified by
chromatography on silica gel to provide the peptide.
Experimental Procedures and Analytical Data. Amido ketone 3a (R1 = Boc, R2 = Me, R3 =
Me)57. Bocꢀ
LꢀalanineꢀOH (1, 16.934 g, 89.50 mmol) was dissolved under argon in absolute
tetrahydrofuran (THF) (250 mL) and then one equivalent Nꢀmethylmorpholine (NMM) (9.85
mL, 89.50 mmol) was added. The solution was cooled to ꢀ25 °C and isobutyl chloroformate
(11.6 mL, 89.50 mmol) was added, while the reaction mixture was maintained at ꢀ25 °C. After
2 h, aminoketone 2 (15.000 g, 89.50 mmol) and the second equivalent of NMM (9.85 mL,
89.50 mmol), were added at ꢀ25 °C. Stirring was continued for 15 h while the solution was
allowed to warm to room temperature. The solvent was evaporated and the residue was
dissolved in DCM and then washed with water and brine. The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash column
chromatography with silica gel (DCM/EtOAc 90:10 → 75:25) to yield 3a (23.834 g, 78.834
mmol, 88.1%) as a white solid. 1H NMR (600 MHz, CDCl3):
δ = 7.33–7.19 (m, 2 H), 5.23 (d, J
= 6.6 Hz, 1 H), 5.23 (d, J = 6.6 Hz, 1 H), 4.99 (brs, 2 H), 4.33–4.19 (m, 2 H), 3.81 (s, 6 H),
2.37 (s, 3 H), 2.37 (s, 3 H), 1.45 (s, 9 H), 1.45 (s, 9 H), 1.38 (d, J = 7.1 Hz, 3 H), 1.38 ppm (d,
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J = 7.1 Hz, 3 H). 13C NMR (151 MHz, CDCl3):
δ
= 198.4, 198.2, 172.7, 166.5, 166.4, 155.6,
4
5
155.5, 80.5, 63.0, 53.5, 50.1, 50.0, 28.4, 28.1, 28.0, 18.2, 18.1 ppm.
Imidazole 4b (R1 = Boc, R2 = Me). To a solution of amido ketone 3a (18.0 g, 59.538 mmol) in
xylenes (390 mL), acetic acid (43.5 mL) and methylamine (8 M in EtOH, 35.0 mL, 279.829
mmol) were added at room temperature. The mixture was stirred at 170 °C with azeotropic
removal of water for 3.5 h and then cooled to room temperature. The solvent was
concentrated in vacuo, the residue was dissolved in DCM and washed with saturated
NaHCO3 solution. The aqueous solution was extracted with DCM, the combined organic
layers were dried over MgSO4, concentrated in vacuo and the residue was purified by flash
column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:0 → 75:25:3) to yield
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imidazole 4b (15.122 g, 50.856 mmol, 85.4%) as a white solid. mp: 65ꢀ66 °C. H NMR (600
MHz, CDCl3):
δ = 5.34 (d, J = 7.7 Hz, 1 H), 4.99–4.89 (m, 1 H), 3.86 (s, 3 H), 3.54 (s, 3 H),
2.51 (s, 3 H), 1.55 (d, J = 7.0 Hz, 3 H), 1.40 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3):
δ
=
=
164.2, 155.2, 148.8, 136.9, 127.2, 79.9, 51.7, 42.6, 30.4, 28.4, 20.6, 10.2 ppm. IR (ATR): νꢀ
3348, 2966, 2975, 2936, 1694, 1678, 1570, 1516, 1438, 1366, 1325, 1246, 1221, 1201,
1157, 1074, 1061, 1030 cmꢀ1. UV/VIS (MeOH): λmax (log
ε) = 244 nm (4.03). HRMS (ESIꢀ
TOF) m/z: [M + H]+ calcd for C14H24N3O4 298.1761; found 298.1772; [M + Na]+ calcd for
+
C14H23N3O4Na+ 320.1581; found 320.1584.
Imidazole 4a (R1 = Boc, R2 = H). Imidazole 4b (5.579 mg, 18.7624 mmol) was dissolved in a
mixture of methanol (208 mL) and dioxane (145 mL) followed by slow addition of NaOH
solution (2
continued until TLC showed consumption of all starting material (24 hours). Then, the
solution was poured onto an ice/DCM mixture and acidified with 2 HCl to pH = 1. The
M, 94 mL, 187.6240 mmol) at 0 °C. The ice bath was removed and stirring was
M
layers were separated, the aqueous layer was saturated with NaCl and then repeatedly
extracted with DCM. The organic layers were combined, dried over MgSO4 and concentrated
in vacuo to give 4.407 g (15.5543 mmol, 82.9%) of the free acid 4a as a white solid, which
1
was used in the next step without further purification. mp: 107ꢀ108 °C. H NMR (600 MHz,
CDCl3):
H), 1.75 (d, J = 6.4 Hz, 3 H), 1.36 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3):
155.8, 149.5, 136.1, 123.0, 80.4, 42.5, 31.8, 28.4, 19.5, 10.0 ppm. IR (ATR): = 3384, 2976,
δ
= 10.11 (brs, 1 H), 7.24–7.05 (m, 1 H), 5.15–5.04 (m, 1 H), 3.78 (s, 3 H), 2.57 (s, 3
δ
= 161.5,
νꢀ
2931, 2877, 1698, 1636, 1509, 1449, 1367, 1248, 1161, 1067 cmꢀ1. UV/VIS (MeOH): λmax
+
(log
ε
) = 228 nm (4.05). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C13H22N3O4 284.1605;
found 284.1611; [M + Na]+ calcd for C13H21N3O4Na+ 306.1424; found 306.1431; [M ꢀ H]ꢀ calcd
ꢀ
for C13H20N3O4 282.1448; found 282.1542.
Imidazole 5a (R1 = Boc, R2 = Bn). Imidazole 4a (500 mg, 1.7647 mmol) was dissolved in a
mixture of methanol (7.4 mL) and water (1 mL) followed by the addition of Cs2CO3 (604 mg,
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1.8529 mmol). The solution was evaporated to dryness and the residue reevaporated twice
from DMF (65 °C). The solid was dissolved in DMF and benzyl bromide (315 ꢁL, 2.6471
mmol) was added. The solvent was evaporated after stirring at room temperature for 24
hours. The crude product was taken up in water, extracted several times with DCM, dried
over MgSO4, concentrated in vacuo and the residue was purified by flash column
chromatography with silica gel (DCM/EtOAc/MeOH 75:25:0 → 75:25:10) to yield imidazole
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5a (519 mg, 1.3906 mmol, 78.8%) as a white solid. mp: 106ꢀ107 °C. H NMR (600 MHz,
CDCl3):
4.98–4.89 (m, 1 H), 3.53 (s, 3 H), 2.48 (s, 3 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.42 ppm (s, 9 H).
13C NMR (151 MHz, CDCl3):
= 163.7, 155.3, 149.0, 136.74, 136.71, 128.6, 128.4, 128.0,
127.4, 79.9, 66.0, 42.7, 30.4, 28.5, 20.8), 10.5 ppm. IR (ATR): = 3359, 2980, 2933, 2867,
1680, 1566, 1514, 1447, 1393, 1328, 1224, 1202, 1159, 1064, 1047, 1036, 727, 692 cmꢀ1.
δ = 7.47–7.41 (m, 2 H), 7.37–7.32 (m, 2 H), 7.32–7.27 (m, 1 H), 5.44–5.32 (m, 3 H),
δ
νꢀ
UV/VIS (CH3CN): λmax (log ε
) = 198 (4.18), 248 nm (4.05). HRMS (ESIꢀTOF) m/z: [M + H]+
calcd for C20H28N3O4 374.2074; found 374.2077; [M + Na]+ calcd for C20H27N3O4Na+
+
396.1894; found 396.1898.
Imidazole 5b (R1 = HCl*H, R2 = Bn). This compound was synthesized according to the
general procedure (A) for the cleavage of the Boc group from imidazole 5a (729 mg, 1.9521
1
mmol) to yield 5b (605 mg, 1.9521 mmol, quantitative) as a white solid. mp: 171ꢀ172 °C. H
NMR (600 MHz, MeOD):
= 7.0 Hz, 1 H), 3.79 (s, 3 H), 2.60 (s, 3 H), 1.77 ppm (d, J = 7.0 Hz, 3 H). 13C NMR (151 MHz,
MeOD): = 161.6, 145.5, 140.2, 137.1, 130.0, 129.9, 129.8, 125.0, 68.4, 43.7, 32.7, 18.2,
10.3 ppm. IR (ATR): = 3445, 3357, 3050, 2841, 2787, 2647, 2590, 1743, 1723, 1623, 1435,
1377, 1284, 1224, 1188, 1085, 757, 702 cmꢀ1. UV/VIS (MeOH):
max (log ) = 211 (4.05), 242
δ = 7.51–7.45 (m, 2 H), 7.42–7.32 (m, 3 H), 5.40 (s, 2 H), 5.04 (q, J
δ
νꢀ
λ
ε
nm (4.02). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C15H20N3O2+ 274.1550; found 274.1566;
[M + Na]+ calcd for C15H19N3O2Na+ 296.1369; found 296.1372.
Dimer 6a (R1 = Boc, R2 = Me, R3 = Bn). This compound was synthesized according to the
general procedure (C) for the peptide coupling from 4a (503 g, 1.7753 mmol) and 5b. After
flash column chromatography with silica gel (DCM/MeOH 99:1 → 93:7) 6a was obtained as a
1
white solid (528 mg, 0.9800 mmol, 55.2%). mp: 87ꢀ88 °C. H NMR (600 MHz, CDCl3):
δ =
7.61 (brs, 1 H), 7.46–7.41 (m, 2 H), 7.36–7.31 (m, 2 H), 7.31–7.27 (m, 1 H), 5.51–5.43 (m, 1
H), 5.39 (d, J = 12.5 Hz, 1 H), 5.32 (d, J = 12.5 Hz, 1 H), 5.17 (brs, 1 H), 4.93–4.84 (m, 1 H),
3.58 (s, 3 H), 3.48 (s, 3 H), 2.52 (s, 3 H), 2.48 (s, 3 H), 1.70 (d, J = 7.0 Hz, 3 H), 1.49 (d, J =
7.0 Hz, 3 H), 1.42 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3):
147.3, 136.9, 136.7, 133.5, 128.9, 128.5, 128.4, 128.1, 127.4, 80.0, 66.0, 42.7, 39.9, 30.5,
30.1, 28.5, 20.8, 19.9, 10.5, 9.9 ppm. IR (ATR): = 3304, 2978, 2934, 1698, 1647, 1589,
δ = 163.7, 162.9, 155.2, 148.8,
νꢀ
1506, 1497, 1456, 1366, 1190, 1157, 1061, 737, 698 cmꢀ1. UV/VIS (CH3CN): λmax (log
ε
) =
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+
196 (4.40), 246 nm (4.35). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C28H39N6O5 539.2976;
4
5
6
7
8
9
found 539.2937; [M + Na]+ calcd for C28H38N6O5Na+ 561.2796; found 561.2750.
Dimer 6b (R1 = HCl*H, R2 = Me, R3 = Bn). This compound was synthesized according to the
general procedure (A) for the cleavage of the Boc group from imidazole 6a (959 mg, 1.7804
1
mmol) to yield 6b (846 mg, 1.7804 mmol, quantitative) as a white solid. mp: 198ꢀ199 °C. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (600 MHz, MeOD):
H), 5.42 (s, 2 H), 4.86 (q, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 3.65 (s, 3 H), 2.61 (s, 3 H), 2.49 (s, 3
H), 1.79 (d, J = 7.3 Hz, 3 H), 1.71 ppm (d, J = 6.8 Hz, 3 H). 13C NMR (151 MHz, MeOD):
164.6, 159.6, 151.1, 145.1, 139.6, 137.6, 136.7, 130.1, 130.0, 129.9, 128.6, 120.9, 68.9,
44.5, 42.9, 32.9, 31.4, 19.0, 18.1, 10.1, 9.9 ppm. IR (ATR): = 3362, 2812, 2717, 1723,
1662, 1654, 1636, 1542, 1516, 1456, 1338, 1318, 1294, 1191, 1168, 1076, 755, 700 cmꢀ1.
δ = 7.51–7.45 (m, 2 H), 7.42–7.32 (m, 3 H), 5.45 (q, J = 7.3 Hz, 1
δ
=
νꢀ
UV/VIS (MeOH): λmax (log ε
) = 209 (4.23), 243 nm (4.31). HRMS (ESIꢀTOF) m/z: [M + H]+
+
calcd for C23H31N6O3 439.2452; found 439.2460; [M + Na]+ calcd for C23H30N6O3Na+
461.2272; found 461.2269.
Trimer 7. This compound was synthesized according to the general procedure (C) for the
peptide coupling from 4a (472 g, 1.6649 mmol) and 6b. After flash column chromatography
with silica gel (DCM/MeOH 98:2 → 95:5) 7 was obtained as a white solid (518 mg, 0.7360
mmol, 44.2%). mp: 94ꢀ95 °C. 1H NMR (600 MHz, CDCl3):
δ = 7.74–7.61 (m, 1 H), 7.47–7.40
(m, 2 H), 7.38–7.30 (m, 3 H), 7.29–7.23 (m, 1 H), 5.53–5.44 (m, 1 H), 5.44–5.36 (m, 2 H),
5.32 (d, J = 12.5 Hz, 1 H), 5.15 (brs, 1 H), 4.93–4.81 (m, 1 H), 3.58 (s, 3 H), 3.48 (s, 3 H),
3.48 (s, 3 H), 2.52 (s, 3 H), 2.51 (s, 3 H), 2.47 (s, 3 H), 1.70 (d, J = 7.0 Hz, 3 H), 1.61 (d, J =
7.0 Hz, 3 H), 1.47 (d, J = 7.0 Hz, 3 H), 1.38 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3):
δ =
163.8, 163.1, 162.8, 155.1, 148.8, 147.3, 147.0, 136.9, 136.7, 133.8, 133.6, 129.0, 128.5,
128.4, 128.3, 128.0, 127.4, 79.9, 65.9, 42.6, 40.0, 39.8, 30.5, 30.2, 30.1, 28.4, 20.6, 19.9,
19.7, 10.5, 9.88, 9.85 ppm. IR (ATR):
νꢀ
= 3253, 2980, 2935, 1699, 1645, 1587, 1497, 1367,
1158, 1061, 737, 698 cmꢀ1. UV/VIS (CH3CN):
λ
max (log ) = 194 (4.63), 245 nm (4.57). HRMS
ε
(ESIꢀTOF) m/z: [M + H]+ calcd for C36H50N9O6+ 704.3879; found 704.3879; [M + Na]+ calcd for
ꢀ
C36H49N9O6Na+ 726.3638; found 726.3694; [M ꢀ H]ꢀ calcd for C36H48N9O6 702.3722; found
702.3712.
Trimer
cleavage of the Boc group from imidazole 7 (216 mg, 0.3069 mmol) to yield 8 (197 mg,
0.3096 mmol, quantitative) as a white solid. mp: 212ꢀ213 °C. 1H NMR (600 MHz, MeOD):
8. This compound was synthesized according to the general procedure (A) for the
δ
=
7.48–7.44 (m, 2 H), 7.42–7.33 (m, 3 H), 5.49–5.38 (m, 4 H), 4.78 (q, J = 6.8 Hz, 1 H), 3.88 (s,
3 H), 3.85 (s, 3 H), 3.61 (s, 3 H), 2.61 (s, 3 H), 2.57 (s, 3 H), 2.48 (s, 3 H), 1.81 (d, J = 7.2 Hz,
3 H), 1.78 (d, J = 7.2 Hz, 3 H), 1.65 ppm (d, J = 6.8 Hz, 3 H). 13C NMR (151 MHz, MeOD):
δ
= 165.7, 160.2, 159.8, 150.6, 150.4, 145.6, 139.8, 138.6, 137.4, 136.8, 130.2, 130.14,
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130.07, 129.9, 122.4, 121.3, 69.1, 45.0, 43.8, 42.6, 33.1, 32.7, 31.1, 19.4, 18.8, 17.9, 10.2,
4
5
6
7
8
9
10.0, 9.9 ppm. IR (ATR):
ν
ꢀ
= 3361, 3219, 2922, 2850, 1724, 1660, 1542, 1515, 1455, 1325,
1295, 1195, 1168, 1077, 738, 700 cmꢀ1. UV/VIS (MeOH):
(ESIꢀTOF) m/z: [M + H]+ calcd for C31H42N9O4+ 604.3354; found 604.3342; [M + Na]+ calcd for
C31H41N9O4Na+ 626.3174; found 626.3143; [M + Cl]ꢀ calcd for C31H41ClN9O4 638.2965; found
λ
max (log ) = 243 nm (4.73). HRMS
ε
ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
638.2963.
Trimer 9. This compound was synthesized according to the general procedure (B) for the
cleavage of the Benzyl Ester Group from imidazole 7 (290 mg, 0.4120 mmol) to yield 9 (212
1
mg, 0.3454 mmol, 83.8%) as a white solid. mp: 310ꢀ312 °C. H NMR (600 MHz, MeOD):
δ =
5.74–5.24 (m, 2 H), 4.86–4.65 (m, 1 H), 3.65 (s, 3 H), 3.54 (s, 6 H), 2.71–2.28 (m, 9 H),
1.72–1.25 ppm (m, 18 H). 13C NMR (151 MHz, MeOD):
= 165.5, 165.1, 165.0, 157.3,
149.3, 149.1, 148.9, 136.0, 135.9, 135.8, 129.7, 129.4, 129.3, 80.5, 44.0, 41.9, 41.6, 31.0,
30.6, 30.5, 28.7, 19.8, 19.42, 19.36, 9.8, 9.6 ppm. IR (ATR): = 3385, 3308, 2980, 2935,
δ
νꢀ
1698, 1635, 1588, 1506, 1471, 1367, 1235, 1163, 1054 cmꢀ1. UV/VIS (MeOH):
λmax (log ε) =
261 nm (4.83). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C29H44N9O6 614.3409; found
614.3401; [M ꢀ H]ꢀ calcd for C29H42N9O6 612.3253; found 612.3249.
Tetramer 10a (R1 = Boc, R2 = Bn). This compound was synthesized according to the general
+
ꢀ
procedure (C) for the peptide coupling from 4a (82 mg, 0.2890 mmol) and 8. After flash
column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:9) 10a was obtained as a
1
white solid (169 mg, 0.1945 mmol, 67.3%). mp: 150ꢀ151 °C. H NMR (600 MHz, CDCl3):
δ =
8.53–7.26 (m, 8 H), 5.54–5.06 (m, 6 H), 4.89 (brs, 1 H), 3.58 (s, 3 H), 3.57–3.44 (m, 9 H),
2.58–2.50 (m, 9 H), 2.48 (s, 3 H), 1.73 (d, J = 7.0 Hz, 3 H), 1.69–1.56 (m, 6 H), 1.54–1.35
ppm (m, 12 H). 13C NMR (151 MHz, CDCl3):
δ = 164.0, 163.3, 163.20, 163.16, 155.3, 148.9,
147.6, 147.2, 147.0, 137.3, 137.0, 134.4, 134.11, 134.07, 128.8, 128.6, 128.5, 128.2, 127.7,
127.62, 127.58, 80.4, 66.1, 42.8, 42.3, 40.20, 40.17, 30.8, 30.6, 30.3, 30.0, 28.7, 20.7, 20.0,
19.8, 19.8, 10.8, 10.2, 10.12, 10.09 ppm. IR (ATR):
νꢀ
= 3252, 2980, 2934, 1699, 1636, 1587,
1506, 1497, 1465, 1456, 1367, 1160, 1053, 738, 699 cmꢀ1. UV/VIS (CH3CN): λmax (log
196 (4.67), 244 nm (4.66). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C44H61N12O7+ 869.4781;
found 869.4767; [M+Na]+ calcd for C44H60N12O7Na+ 891.4600; found 891.4587.
Tetramer 10b (R1 = HCl*H, R2 = Bn). This compound was synthesized according to the
general procedure (A) for the cleavage of the Boc group from imidazole 10a (159 mg, 0.1830
mmol) to yield 10b (147 mg, 0.1830 mmol, quantitative) as a white solid. mp: 234ꢀ235 °C. 1H
ε
) =
NMR (500 MHz, MeOD):
4.81–4.75 (m, 1 H), 3.93–3.80 (m, 9 H), 3.60 (s, 3 H), 2.65–2.53 (m, 9 H), 2.49 (s, 3 H), 1.86–
1.73 (m, 9 H), 1.66 ppm (d, J = 5.5 Hz, 3 H). 13C NMR (126 MHz, MeOD):
= 165.4, 160.2,
δ = 7.49–7.44 (m, 2 H), 7.42–7.34 (m, 3 H), 5.54–5.38 (m, 5 H),
δ
160.0, 159.7, 150.5, 150.1, 149.4, 145.4, 139.7, 138.5, 138.0, 137.2, 136.7, 130.04, 129.99,
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129.95, 129.8, 122.64, 122.58, 121.2, 69.0, 45.0, 43.8, 43.7, 42.6, 33.3, 32.91, 32.86, 31.2,
4
5
6
7
19.3, 18.8, 18.4, 18.0, 10.3, 10.11, 10.06, 10.0 ppm. IR (ATR): νꢀ = 3384, 3226, 2922, 2826,
2718, 1727, 1653, 1542, 1515, 1456, 1328, 1197, 1170, 739, 701 cmꢀ1. UV/VIS (MeOH): λmax
+
(log ε
) = 212 (4.40), 250 nm (4.68). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C39H53N12O5
8
9
769.4256; found 769.4256.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Heptamer 11. This compound was synthesized according to the general procedure (C) for
the peptide coupling from 9 (106 mg, 0.1729 mmol) and 10b. After flash column
chromatography with silica gel (DCM/EtOAc/MeOH 75:25:12) 11 was obtained as a white
1
solid (197 mg, 0.1444 mmol, 83.5%). mp: 217ꢀ218 °C. H NMR (500 MHz, CDCl3):
δ =
10.02–6.05 (m, 12 H), 5.60–4.37 (m, 9 H), 3.67–2.89 (m, 21 H), 2.62–2.11 (m, 21 H) 1.70–
0.99 ppm (m, 30 H). 13C NMR (126 MHz, CDCl3):
= 164.2, 163.6, 163.2, 163.0, 162.9,
δ
154.9, 146.7, 146.3, 145.8, 145.1, 144.8, 144.5, 137.3, 136.9, 136.5, 134.8, 134.2, 133.7,
128.8, 128.6, 128.4, 128.1, 127.9, 127.5, 126.7, 126.2, 78.7, 65.5, 43.1, 41.5, 41.1, 40.5,
39.8, 30.4, 30.2, 30.0, 29.9, 29.6, 28.3, 28.0, 19.3, 19.2, 18.6, 10.3, 10.1, 9.7, 9.5, 9.3 ppm.
IR (ATR): νꢀ = 3391, 3201, 2982, 2934, 1703, 1633, 1584, 1494, 1464, 1368, 1227, 1158,
1115, 1068, 1051, 739, 698 cmꢀ1. UV/VIS (CH3CN): λmax (log
ε) = 194 (4.79), 247 nm (4.86).
+
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C68H94N21O10 1364.7487; found 1364.7463; [M +
Na]+ calcd for C68H93N21O10Na+ 1386.7306; found 1386.7285.
Heptamer 12. This compound was synthesized according to the general procedure (A) for
the cleavage of the Boc group from imidazole 11 (178 mg, 0.1304 mmol) to yield 12 (170 mg,
0.1304 mmol, quantitative) as a white solid. mp: 245ꢀ247 °C. 1H NMR (600 MHz, MeOD):
δ =
7.50–7.44 (m, 2 H), 7.43–7.33 (m, 3 H), 5.56–5.38 (m, 8 H), 4.80 (q, J = 6.6 Hz, 1 H), 3.97–
3.77 (m, 18 H), 3.61 (s, 3 H), 2.72–2.53 (m, 18 H), 2.49 (s, 3 H), 1.90–1.69 (m, 18 H), 1.66
ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz, MeOD):
δ = 165.4, 160.2, 160.1, 160.0, 159.7,
150.5, 150.0, 149.4, 149.3, 149.18, 149.16, 145.4, 139.7, 138.6, 138.14, 138.05, 138.00,
137.97, 137.2, 136.7, 130.02, 129.99, 129.9, 129.7, 123.0, 122.9, 122.8, 122.6, 122.5, 121.1,
68.9, 44.9, 43.72, 43.67, 43.65, 43.6, 42.5, 33.1, 32.83, 32.75, 32.7, 31.1, 19.3, 18.7, 18.34,
18.31, 18.26, 17.9, 10.22, 10.18, 10.13, 10.08, 10.0, 9.9 ppm. IR (ATR):
νꢀ = 3362, 3219,
3030, 2921, 2850, 1732, 1717, 1660, 1653, 1541, 1519, 1508, 1456, 1328, 1201, 736, 701
cmꢀ1. UV/VIS (MeOH): λmax (log
ε) = 207 (4.59), 258 nm (4.97). HRMS (ESIꢀTOF) m/z: [M +
+
H]+ calcd for C63H86N21O8 1264.6963; found 1264.6934; [M + Na]+ calcd for C63H85N21O8Na+
ꢀ
1286.6782; found 1286.6759; [M + Cl]ꢀ calcd for C63H85ClN21O8 1298.6573; found
1298.6558.
Decamer 13a. This compound was synthesized according to the general procedure (C) for
the peptide coupling from 9 (41 mg, 0.0662 mmol) and 12. After flash column
chromatography with silica gel (DCM/MeOH 9:1) 13a was obtained as a white solid (90 mg,
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0.0484 mmol, 73.1%). mp: 222ꢀ223 °C. 1H NMR (600 MHz, CDCl3):
δ = 9.85 (d, J = 7.8 Hz, 1
4
5
6
7
8
9
H), 9.82 (d, J = 7.8 Hz, 2 H), 9.80 (d, J = 7.9 Hz, 2 H), 9.76 (d, J = 7.7 Hz, 1 H), 9.67 (d, J =
7.9 Hz, 1 H), 9.65 (d, J = 8.5 Hz, 1 H), 9.16 (d, J = 6.9 Hz, 1 H), 7.43–7.31 (m, 5 H), 5.43–
5.05 (m, 12 H), 4.98–4.89 (m, 1 H), 3.58–3.29 (m, 27 H), 2.97 (s, 3 H), 2.57–2.40 (m, 24 H),
2.21 (s, 3 H), 2.08 (s, 3 H), 1.62–1.11 ppm (s, 39 H). 13C NMR (151 MHz, CDCl3):
δ = 170.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
164.21, 164.17, 164.1, 162.7, 154.8, 146.7, 146.4, 145.2, 144.6, 144.5, 144.44, 144.40
137.4, 135.7, 135.0, 134.81, 134.76, 134.6, 134.2, 128.9, 128.8, 128.7, 128.6, 128.44,
128.35, 128.3, 128.1, 125.8, 78.6, 65.8, 41.5, 41.4, 40.9, 39.9, 31.8, 30.3, 30.1, 30.0, 29.8,
29.6, 29.2, 29.0, 28.3, 27.9, 27.8, 22.8, 22.6 19.3, 19.22, 19.15, 19.1 18.7, 18.3 10.2, 9.8,
9.67, 9.66, 9.2 ppm. IR (ATR):
νꢀ = 3396, 3237, 2984, 2933, 1716, 1705, 1630, 1627, 1583,
1506, 1497, 1456, 1406, 1370, 1158, 1117, 1069, 751, 699 cmꢀ1. UV/VIS (CH3CN):
λmax (log
+
ε
) = 193 (4.99), 249 nm (5.00). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C92H127N30O13
1860.0193; found 1860.0220; [M + Na]+ calcd for C92H126N30O13Na+ 1882.0013; found
1882.0062.
Imidazole 14. This compound was synthesized according to the general procedure (A) for the
cleavage of the Boc group from imidazole 4a (250 mg, 0.8824 mmol) to yield 14 (194 mg,
0.8824 mmol, quantitative) as a white solid. mp: 234ꢀ235 °C. 1H NMR (600 MHz, MeOD):
5.09 (q, J = 7.0 Hz, 1 H), 3.83 (s, 3 H), 2.64 (s, 3 H), 1.81 ppm (d, J = 7.0 Hz, 3 H). 13C NMR
(151 MHz, MeOD): = 162.2, 144.9, 139.8, 125.0, 43.4, 32.9, 17.9, 10.1 ppm. IR (ATR):
3566, 3348, 2801, 2710, 1716, 1705, 1567, 1397, 1386, 1252, 1235, 1183, 1136, 1097, 889
δ =
δ
νꢀ =
cmꢀ1. UV/VIS (MeOH): λmax (log
ε) = 245 (4.06), 270 nm (4.01). HRMS (ESIꢀTOF) m/z: [M +
H]+ calcd for C8H14N3O2 184.1081; found 184.1089; [M + Na]+ calcd for C8H13N3O2Na+
+
206.0900; found 206.0896.
Cyclic trimer 15. This compound was synthesized according to the general procedure (C) for
the peptide coupling from 14 (184 mg, 0.8376 mmol). After flash column chromatography
with silica gel (DCM/MeOH 92:8) 15 was obtained as a white solid (73 mg, 0.1473 mmol,
1
52.8%). mp: >350 °C. H NMR (600 MHz, CDCl3):
δ = 8.90 (d, J = 7.0 Hz, 1 H), 5.23–5.14
(m, 1 H), 3.48 (s, 3 H), 2.55 (s, 3 H), 1.53 ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz,
CDCl3): = 162.7, 147.2, 132.9, 129.0, 41.8, 29.8, 21.8, 9.4 ppm. IR (ATR): = 3376, 2980,
2926, 1644, 1591, 1526, 1505, 1464, 1366, 1221, 1205, 1050, 916 cmꢀ1. UV/VIS (CH3CN):
δ
νꢀ
λmax (log
ε
) = 192 (4.76), 237 nm (4.62). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for
+
C24H34N9O3 496.2779; found 496.2799; [M + Na]+ calcd for C24H33N9O3Na+ 518.2599; found
518.2604.
Cyclic tetramer 16. This compound was synthesized according to the general procedure (C)
for the peptide coupling from 14 (184 mg, 0.8376 mmol). After flash column chromatography
with silica gel (DCM/MeOH 92:8) 16 was obtained as a white solid (30 mg, 0.0454 mmol,
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6
7
8
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21.7%). mp: >350 °C. H NMR (600 MHz, CDCl3):
3.59 (s, 3 H), 2.49 (s, 3 H), 1.66 ppm (d, J = 6.6 Hz, 3 H). 13C NMR (151 MHz, CDCl3):
162.9, 147.8, 132.9, 128.9, 39.7, 30.1, 20.2, 9.7 ppm. IR (ATR): = 3385, 2981, 2933, 1645,
1636, 1588, 1506, 1497, 1466, 1368, 1226, 1123, 1030 cmꢀ1. UV/VIS (CH3CN):
max (log ) =
δ = 7.70 (brs, 1 H), 5.42–5.33 (m, 1 H),
δ
=
νꢀ
λ
ε
9
195 (5.26), 274 nm (4.99). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C32H45N12O4+ 661.3681;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
found 661.3707; [M + Na]+ calcd for C32H44N12O4Na+ 683.3501; found 683.3586.
Amido ketone 3b (R1 = Z, R2 = H, R3 = Me)58. ZꢀglycineꢀOH (14.040 g, 67.13 mmol) was
dissolved under argon in absolute tetrahydrofuran (THF) (410 mL) and one equivalent
Nꢀmethylmorpholine (NMM) (7.38 mL, 67.13 mmol) was added. The solution was cooled to ꢀ
25 °C and isobutyl chloroformate (8.73 mL, 67.13 mmol) was added, while the reaction
mixture was maintained at ꢀ25 °C. After 2 h, aminoketone 2 (11.250 g, 67.13 mmol) and the
second equivalent of NMM (7.38 mL, 67.13 mmol) were added at ꢀ25 °C. Stirring was
continued for 14 h while the solution was allowed to warm to room temperature. The solvent
was evaporated and the residue was dissolved in EtOAc and then washed with water and
brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography with silica gel (nꢀHexane/EtOAc 1:1) to yield 3b
1
(16.980 g, 52.68 mmol, 78.5%) as a white solid. mp: 78 °C. H NMR (500 MHz, CDCl3):
δ =
7.40–7.29 (m, 5 H), 7.27–7.14 (m, 1 H), 5.61–5.50 (m, 1 H), 5.27 (d, J = 6.5 Hz, 1 H), 5.13 (s,
2 H), 3.96 (d, J = 5.4 Hz, 2 H), 3.80 (s, 3 H), 2.36 ppm (s, 3 H). 13C NMR (126 MHz, CDCl3):
δ
= 198.2, 169.1, 166.5, 156.7, 136.3, 128.7, 128.3, 128.2, 67.4, 63.0, 53.5, 44.3, 28.1 ppm.
IR (ATR): = 3396, 3315, 3034, 2957, 1741, 1725, 1652, 1522, 1438, 1361, 1282, 1253,
1153, 1044, 749, 698 cmꢀ1. UV/VIS (MeOH):
max (log ) = 216 (3.28), 274 nm (3.08). HRMS
νꢀ
λ
ε
(ESIꢀTOF) m/z: [M + Na]+ calcd for C15H18N2O6Na+ 345.1068; found 345.1063.
Imidazole 17. To a solution of amido ketone 3b (7.091 g, 22.0 mmol) in xylenes (300 mL),
trifluoroacetic acid (3.3 mL, 44.0 mmol) and ammonia (7 M in MeOH, 6.3 mL, 44.0 mmol)
were added at room temperature. The mixture was stirred at 175 °C with azeotropic removal
of water for 20 h and then cooled to room temperature. The solvent was concentrated in
vacuo, the residue was dissolved in EtOAc, washed with brine and saturated NaHCO3
solution and dried over MgSO4. The solution was concentrated in vacuo and the residue was
purified by flash column chromatography with silica gel (nꢀHexane/EtOAc 2:3 → 1:10) to
1
yield imidazole 17 (4.838 g, 16.0 mmol, 73.0%) as a white solid. mp: 140 °C. H NMR (500
MHz, CDCl3):
Hz, 2 H), 3.83 (s, 3 H), 2.48 ppm (s, 3 H). 13C NMR (126 MHz, CDCl3):
145.5, 139.0, 136.1, 128.7, 128.4, 128.1, 124.5, 67.5, 51.6, 38.6, 12.2 ppm. IR (ATR):
3392, 3304, 3250, 3021, 2960, 1715, 1692, 1650, 1522, 1439, 1408, 1356, 1282, 1250,
δ
= 7.35–7.27 (m, 5 H), 6.03 (t, J = 6.0 Hz, 1 H), 5.09 (s, 2 H), 4.34 (d, J = 6.0
δ
= 163.2, 157.8,
νꢀ =
1213, 1115, 1042, 748, 691 cmꢀ1. UV/VIS (MeOH): λmax (log
ε
) = 214 (3.80), 245 nm (3.89).
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3
+
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C15H18N3O4 304.1292; found 304.1298; [M + Na]+
4
5
calcd for C15H17N3O4Na+ 326.1111; found 326.1115.
Imidazole 18. To a solution of imidazole 17 (2.832 g, 9.34 mmol) in absolute tetrahydrofuran
(THF) (100 mL), diꢀtertꢀbutyl dicarbonate (2.24 mL, 10.27 mmol) and palladium hydroxide
(0.330 g) were added at room temperature. The mixture was stirred under H2 atmosphere
overnight. Then, the mixture was filtered, concentrated in vacuo and the residue was purified
by flash column chromatography with silica gel (nꢀHexane/EtOAc 1:1 → 1:4) to yield
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
imidazole 18 (2.342 g, 8.73 mmol, 93.2%) as a white solid. mp: 176 °C. H NMR (500 MHz,
CDCl3):
ppm (s, 9 H). 13C NMR (126 MHz, CDCl3):
38.2, 28.5, 12.2 ppm. IR (ATR): = 3351, 3053, 2978, 2933, 1710, 1687, 1598, 1513, 1435,
δ
= 5.71–5.61 (m, 1 H), 4.31 (d, J = 6.1 Hz, 2 H), 3.85 (s, 3 H), 2.51 (s, 3 H), 1.43
δ
= 163.0, 157.4, 146.1, 138.7, 124.3, 80.8, 51.6,
νꢀ
1367, 1320, 1280, 1251, 1211, 1163, 1100, 1040, 1025 cmꢀ1. UV/VIS (MeOH):
λmax (log ε) =
+
245 nm (4.05). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C12H20N3O4 270.1448; found
270.1453; [M + Na]+ calcd for C12H19N3O4Na+ 292.1268; found 292.1272.
Imidazole 19. To a solution of imidazole 18 (2.279 g, 8.46 mmol) in dimethylformamide
(DMF) (85 mL), sodium hydride (60wtꢀ%, 0.440 g, 11.00 mmol) was added at 0 °C. After 1 h,
benzyl bromide (1.33 mL, 11.00 mmol) was added and the mixture was stirred at that
temperature for 2 h and at room temperature overnight. The mixture was poured into water,
the precipitated white solid was washed with water and the crude product was dissolved in
DCM. The aqueous solution was extracted with DCM. The combined organic layers were
dried over MgSO4, concentrated in vacuo and the residue was purified by flash column
chromatography with silica gel (cyclohexane/EtOAc 1:1 → 1:2) to yield imidazole 19 (1.544
1
g, 4.30 mmol, 50.8%) as a white solid. mp: 141 °C. H NMR (500 MHz, CDCl3):
δ = 7.33–
7.24 (m, 3 H), 6.93–6.88 (m, 2 H), 5.33–5.18 (m, 3 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.90 (s, 3 H),
2.43 (s, 3 H), 1.32 ppm (s, 9 H). 13C NMR (126 MHz, CDCl3):
= 163.8, 155.6, 145.6, 137.4,
135.3, 129.3, 128.1, 127.6, 125.8, 80.1, 51.8, 47.3, 37.0, 28.3, 10.3 ppm. IR (ATR): = 3361,
2957, 2939, 1698, 1681, 1570, 1525, 1455, 1436, 1389, 1362, 1340, 1250, 1222, 1164,
δ
νꢀ
1082, 729, 694 cmꢀ1. UV/VIS (MeOH):
λmax (log ε) = 243 nm (4.01). HRMS (ESIꢀTOF) m/z: [M
+
+ H]+ calcd for C19H26N3O4 360.1918; found 360.1924; [M + Na]+ calcd for C19H25N3O4Na+
382.1737; found 382.1742.
Imidazole 20. Imidazole 19 (2.157 mg, 6.00 mmol) was dissolved in a mixture of methanol
(73 mL) and dioxane (54 mL) followed by slow addition of NaOH solution (2
M, 30 mL, 60.00
mmol) at 0 °C. The ice bath was removed and stirring was continued until TLC showed
consumption of all starting material (24 hours). Then, the solution was poured onto an
ice/DCM mixture and acidified with 2
M HCl to pH = 1. The layers were separated, the
aqueous layer was then repeatedly extracted with DCM. The organic layers were combined,
dried over MgSO4 and concentrated in vacuo to give 1.988 g (5.80 mmol, 95.9%) of the free
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acid 20. mp: 240 °C. 1H NMR (500 MHz, [D6]ꢀDMSO):
δ
= 7.40–7.23 (m, 4 H), 7.06–6.93 (m,
4
5
2 H), 5.26 (s, 2 H), 4.20 (d, J = 5.7 Hz, 2 H), 2.27 (s, 3 H), 1.26 ppm (s, 9 H). 13C NMR (126
6
7
8
MHz, [D6]ꢀDMSO):
δ
= 164.7, 155.4, 145.2, 136.5, 136.4, 128.8, 127.5, 127.4, 126.0, 78.2,
46.4, 36.8, 28.1, 10.0 ppm. IR (ATR):
ν
ꢀ
= 3430, 2978, 2930, 2857, 1708, 1524, 1488, 1452,
9
1391, 1364, 1277, 1247, 1164, 1011, 747, 694 cmꢀ1. UV/VIS (MeOH): λmax (log
ε) = 233 nm
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(3.96). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C18H24N3O4 346.1761; found 346.1770; [M
+ Na]+ calcd for C18H23N3O4Na+ 368.1581; found 368.1593.
Imidazole 21. This compound was synthesized according to the general procedure (A) for the
cleavage of the Boc group from imidazole 20 (1.250 g, 3.62 mmol) to yield 21 (1.020 g, 3.62
1
mmol, quantitative) as a white solid. mp: 178 °C. H NMR (500 MHz, [D6]ꢀDMSO):
δ = 8.60
(brs, 3 H), 7.42–7.37 (m, 2 H), 7.36–7.31 (m, 1 H), 7.08–7.04 (m, 2 H), 5.34 (s, 2 H), 4.10 (s,
2 H), 2.40 ppm (s, 3 H). 13C NMR (126 MHz, [D6]ꢀDMSO):
= 164.0, 141.2, 137.1, 135.7,
129.0, 127.9, 127.6, 126.3, 46.5, 34.8, 10.0 ppm. IR (ATR): = 3419, 2930, 2786, 2700,
1712, 1614, 1548, 1499, 1467, 1383, 1335, 1262, 1225, 1180, 1039, 732, 714, 696 cmꢀ1.
δ
νꢀ
UV/VIS (MeOH): λmax (log ε
) = 235 nm (3.95). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for
C13H16N3O2 246.1237; found 246.1241; [M + Na]+ calcd for C13H15N3O2Na+ 268.1056; found
+
268.1060.
Cyclic trimer 22. This compound was synthesized according to the general procedure (C) for
the peptide coupling from 21 (451 g, 1.601 mmol). After flash column chromatography with
silica gel (cyclohexane/EtOAc/MeOH 1:2:0 → 1:9:1), 22 was obtained as a white solid (36
1
mg, 0.053 mmol, 9.9%). mp: >350 °C. H NMR (500 MHz, CDCl3):
δ = 8.87 (t, J = 3.3 Hz, 1
H), 7.32–7.23 (m, 3 H), 6.96–6.89 (m, 2 H), 5.07 (s, 2 H), 4.45 (d, J = 3.3 Hz, 2 H), 2.54 ppm
(s, 3 H). 13C NMR (126 MHz, CDCl3):
δ
= 163.8, 142.8, 134.8, 133.7, 129.7, 129.3, 128.3,
125.8, 46.5, 36.8, 9.6 ppm. IR (ATR):
ν
ꢀ = 3376, 3061, 2943, 1651, 1596, 1539, 1504, 1467,
1455, 1434, 1372, 1345, 1219, 1115, 1028, 931, 756, 731, 696 cmꢀ1. UV/VIS (DCM): λmax
(log ε
) = 244 (4.28), 289 nm (3.64). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C39H40N9O3
+
682.3245; found 682.3249; [M + Na]+ calcd for C39H39N9O3Na+ 704.3069; found 704.3068.
1,10-Phenanthroline 1-oxide59-60. 1,10ꢀPhenanthroline (1.000 g, 5.5491 mmol) was dissolved
in glacial acetic acid (5.0 mL) followed by slow addition of hydrogen peroxide (30%, 0.6 mL).
The mixture was heated to 75 °C for 3 h, cooled to rt and again hydrogen peroxide (30%, 0.6
mL) was added. After 3 h the reaction mixture was cooled to rt and basified to pH = 10 with a
saturated potassium hydroxide solution. The solids were dissolved with water and extracted
repeatedly with chloroform. The organic layers were combined, dried over MgSO4 and
concentrated in vacuo to give 0.675 g (3.4404 mmol, 61.7%) of 1,10ꢀPhenanthroline 1ꢀoxide
1
as a pale yellow solid, which was used in the next step without further purification. H NMR
(300 MHz, CDCl3):
δ
= 9.29 (dd, J = 1.9 Hz, 4.4 Hz, 1 H), 8.72 (dd, J = 1.1 Hz, 6.4 Hz, 1 H),
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8.22 (dd, J = 1.9 Hz, 8.1 Hz, 1 H), 7.80–7.67 (m, 3 H), 7.63 (dd, J = 4.4 Hz, 8.1 Hz, 1 H),
7.43 ppm (dd, J = 6.4 Hz, 8.3 Hz, 1 H).
2-Chloro-1,10-phenanthroline61,60. 1,10ꢀPhenanthroline 1ꢀoxide (1.200 g, 6.1162 mmol) and
NaCl (7.280 g, 123.7802 mmol) were dissolved under argon in absolute DMF (21.8 mL). The
mixture was cooled to 0 °C, POCl3 (1.7 mL, 18.2758 mmol) was slowly added and the
reaction mixture was heated to 100 °C for 20 h. After cooling to rt, water (49 mL) was added
and the solution was basified with aqueous ammonia to pH = 10. The aqueous layer was
saturated with NaCl, the solids were filtered and the solution was repeatedly extracted with
chloroform. The organic layers were combined, washed with brine, dried over MgSO4,
concentrated in vacuo and the residue was purified by flash column chromatography with
silica gel (DCM/cyclohexane/EtOAc 7:3:1 → 7:3:3) to yield 2ꢀchloroꢀ1,10ꢀphenanthroline
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(0.750 g, 3.3776 mmol, 55.2%) as a white solid. 1H NMR (300 MHz, CDCl3):
δ = 9.23 (dd, J =
1.7 Hz, 4.3 Hz, 1 H), 8.26 (dd, J = 1.7 Hz, 8.1 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.83 (d, J =
8.8 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 4.3 Hz, 8.1 Hz, 1 H), 7.63 ppm (d, J = 8.4
Hz,1 H).
N-(1,10-Phenanthroline-2-yl)acetamide62. Sodium hydride (60%, 1.082 g, 27.0721 mmol)
was slowly added to a solution of acetamide (1.631 g, 27.5566 mmol) in xylene (50 mL) at
100 °C. After 1 h, 2ꢀChloroꢀ1,10ꢀphenanthroline (0.650 g, 3.0282 mmol) was added and the
solution was heated to 140 °C. After 16 h, the mixture was cooled to rt, the solids were
filtered and dissolved in methanol. The solvent was removed in vacuo and the residue was
purified by flash column chromatography with silica gel (DCM/EtOAc/MeOH 75:25:5 →
75:25:10). After separation of the acetamide by sublimation, Nꢀ(1,10ꢀPhenanthrolineꢀ2ꢀ
yl)acetamide (0.465 g, 1.9592 mmol, 64.7%) was obtained as a white solid which was used
1
in the next step without further purification. H NMR (300 MHz, CDCl3):
δ = 9.20–9.01 (m, 2
H), 8.62 (d, J = 8.8 Hz, 1 H), 8.25 (d, J = 8.8 Hz, 1 H), 8.23 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 7.77
(d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.61 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 2.27 ppm (s,
3 H).
2-Amino-1,10-phenanthroline60. Sodium hydroxide (835 mg, 20.8845 mmol) was added to a
solution of Nꢀ(1,10ꢀPhenanthrolineꢀ2ꢀyl)acetamide (398 mg, 1.6775 mmol) in methanol (11.9
mL) and water (4.0 mL) and the mixture was refluxed for 1 h. Then, methanol was
evaporated in vacuo, solids were filtered, washed with water and the crude product was
purified by flash column chromatography with silica gel (DCM /MeOH 95:5 → 85:15) to yield
1
2ꢀAminoꢀ1,10ꢀphenanthroline (295 mg, 1.5111 mmol, 90.1%) as a white solid. H NMR (300
MHz, CDCl3):
δ = 9.11 (dd, J = 1.7 Hz, 4.4 Hz, 1 H), 8.19 (dd, J = 1.7 Hz, 8.1 Hz, 1 H), 7.98
(d, J = 8.8 Hz, 1 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.55 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 7.53 (d, J =
8.8 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 5.17 ppm (brs, 2 H).
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1,10-Phenanthroline dimer 24. To a solution of dimer 6c (R1 = Boc, R2 = H, R3 = H)28 (50 mg,
0.1189 mmol) in acetonitrile (20 mL), N,NꢀDiisopropylethylamine (147 ꢁL, 0.8644 mmol) was
added
dropwise
under
argon
at
room
temperature.
After
1
h,
6
7
8
9
pentafluorophenyldiphenylphosphinate (FDPP; 69 mg, 0.1796 mmol) was added and the
solution was stirred at room temperature until all starting material was consumed which was
detected by thin layer chromatography (7 days). Afterwards, the solvent was evaporated, the
residue was dissolved in absolute toluene (12 mL) and 2-Amino-1,10-phenanthroline (27 mg,
0.1383 mmol) was added to the solution. The mixture was stirred at 110 °C for 2 days, then
the solvent was removed in vacuo and the residue was purified by flash column
chromatography with silica gel (DCM/MeOH/triethylamine 85:15:0 → 85:15:10) to yield 24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(49 mg, 0.0820 mmol, 69.0%) as a white solid. mp: 141ꢀ142 °C. H NMR (600 MHz, CDCl3):
δ
= 10.29 (brs, 1 H), 9.17–9.10 (m, 1 H), 8.79 (d, J = 8.1 Hz, 1 H), 8.27–8.18 (m, 2 H), 7.77–
7.71 (m, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.59 (dd, J = 4.4 Hz, 8.1 Hz, 1 H), 5.53 (brs, 1 H),
4.64 (d, J = 5.7 Hz, 2 H), 4.40 (d, J = 5.7 Hz, 2 H), 3.56 (s, 3 H), 3.51 (s, 3 H), 2.58 (s, 3 H),
2.54 (s, 3 H), 1.37 ppm (s, 9 H). 13C NMR (151 MHz, CDCl3):
149.6, 145.2, 144.6, 143.5, 138.2, 136.2, 135.2, 133.8, 129.3, 129.1, 129.0, 126.3, 125.8,
124.2, 122.8, 115.5, 79.7, 37.0, 34.9, 30.2, 20.0, 28.2, 9.9, 9.7 ppm. IR (ATR): = 3498,
3376, 3254, 3044, 2957, 2924, 2852, 1703, 1641, 1584, 1504, 1476, 1386, 1268, 1163, 848,
δ = 163.5, 162.6, 155.6, 151.8,
νꢀ
734, 718 cmꢀ1. UV/VIS (CH3CN):
λmax (log
ε
) = 193 (4.50), 232 (4.50), 290 (4.42), 338 (3.77),
354 nm (3.54). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C31H36N9O4 598.2885; found
+
598.2885; [M + Na]+ calcd for C31H35N9O4Na+ 620.2704; found 620.2691; [M ꢀ H]ꢀ calcd for
ꢀ
C31H34N9O4 596.2728; found 596.27418.
Acknowledgments
This work was generously supported by the Professor WerdelmannꢀStiftung
(T167/23664/2013). The authors thank Dr. Felix Niemeyer, Dr. Torsten Schaller and Udo
Kranz for helpful support.
Supporting Information
NMR and CD spectra, calculated molecular structures and crystal structure data of 15, 16,
22, and 24, 1H NMR and 13C NMR spectra of the new compounds, cartesian coordinates and
absolute energies of all calculated compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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References
3
4
(1) Whitford, D. Proteins: Structure and Function; John Wiley & Sons: Chichester, 2013.
(2) Sewald, N.; Jakubke, H.ꢀD. Peptides: Chemistry and Biology; WileyꢀVCH: Weinheim,
2015.
5
6
7
8
9
(3) Milburn, M. V.; Tong, L.; DeVos, A. M.; Brunger, A.; Yamaizumi, Z.; Nishimura, S.; Kim,
S.ꢀH. Science 1990, 247, 939ꢀ945.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Browne, W. R.; Feringa, B. L. Nature Nanotech. 2006, 1, 25ꢀ35.
(5) Lerch, M. M.; Hansen, M. J.; van Dam, G. M.; Szymanski, W.; Feringa, B. L. Angew.
Chem., Int. Ed. 2016, 55, 10978ꢀ10999.
(6) Martinek, T. A.; Fülöp, F. Chem. Soc. Rev. 2012, 41, 687ꢀ702.
(7) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem.
Soc. 1996, 118, 13071ꢀ13072.
(8) Seebach, D.; Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.;
Widmer, H. Helv. Chim. Acta 1996, 79, 913ꢀ941.
(9) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173ꢀ180.
(10) Hanessian, S.; Luo, X.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569ꢀ
8570.
(11) Hintermann, T.; Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998, 81, 983ꢀ
1002.
(12) Pengo, B.; Formaggio, F.; Crisma, M.; Toniolo, C.; Maria, B. G.; Kamphuis, J.; Saviano,
M.; Iacovino, R.; Rossi, F.; Benedetti, E. J. Chem. Soc., Perkin Trans. 2 1998, 1651ꢀ1657.
(13) Inai, Y.; Kurokawa, Y.; Hirabayashi, T. Biopolymers 1999, 49, 551ꢀ564.
(14) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101,
3893ꢀ4012.
(15) Inai, Y.; Kurokawa, Y.; Kojima, N. J. Chem. Soc., Perkin Trans. 2 2002, 1850ꢀ1857.
(16) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252ꢀ
262.
(17) Hecht, S.; Huc, I. Foldamers: Structure, Properties and Applications; WileyꢀVCH:
Weinheim, 2007.
(18) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399ꢀ1408.
(19) Clayden, J.; Castellanos, A.; Solà, J.; Morris, G. A. Angew. Chem., Int. Ed. 2009, 48,
5962ꢀ5965.
(20) Sola, J.; Helliwell, M.; Clayden, J. J. Am. Chem. Soc. 2010, 132, 4548ꢀ4549.
(21) Grison, C. M.; Miles, J. A.; Robin, S.; Wilson, A. J.; Aitken, D. J. Angew. Chem., Int. Ed.
2016, 55, 11096ꢀ11100.
(22) Grison, C. M.; Robin, S.; Aitken, D. J. Chem. Commun. 2016, 52, 7802ꢀ7805.
28
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
(23) Mathieu, L.; Legrand, B.; Deng, C.; Vezenkov, L.; Wenger, E.; Didierjean, C.; Amblard,
4
5
M.; Averlant‐Petit, M. C.; Masurier, N.; Lisowski, V.; Martinez, J.; Maillard, L. T. Angew.
Chem., Int. Ed. 2013, 52, 6006ꢀ6010.
6
7
8
9
(24) Zhao, W.; Wang, Y.; Shang, J.; Che, Y.; Jiang, H. Chem. Eur. J. 2015, 21, 7731ꢀ7735.
(25) Delsuc, N.; Godde, F.; Kauffmann, B.; Léger, J.ꢀM.; Huc, I. J. Am. Chem. Soc. 2007,
129, 11348ꢀ11349.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26) Kudo, M.; Carbajo López, D.; Maurizot, V.; Masu, H.; Tanatani, A.; Huc, I. Eur. J. Org.
Chem. 2016, 2457ꢀ2466.
(27) Akazome, M.; Ishii, Y.; Nireki, T.; Ogura, K. Tetrahedron Letters 2008, 49, 4430ꢀ4433.
(28) Adam, A.; Haberhauer, G. Chem. Eur. J. 2015, 21, 4333ꢀ4339.
(29) Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1ꢀ23.
(30) Wipf, P. Chem. Rev. 1995, 95, 2115ꢀ2134.
(31) Wipf, P. Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Elsevier:
Amsterdam, 1998.
(32) Comba, P.; Dovalil, N.; Gahan, L. R.; Hanson, G. R.; Westphal, M. Dalton Trans. 2014,
1935ꢀ1956.
(33) Haberhauer, G.; Oeser, T.; Rominger, F. Chem. Commun. 2005, 2799ꢀ2801.
(34) Pintér, Á.; Haberhauer, G.; HylaꢀKryspin, I.; Grimme, S. Chem. Commun. 2007, 3711ꢀ
3713.
(35) Haberhauer, G.; Kallweit, C. Angew. Chem., Int. Ed. 2010, 49, 2418ꢀ2421.
(36) Haberhauer, G. Angew. Chem., Int. Ed. 2008, 47, 3635ꢀ3638.
(37) Haberhauer, G. Angew. Chem., Int. Ed. 2010, 49, 9286ꢀ9289.
(38) Haberhauer, G. Angew. Chem., Int. Ed. 2011, 50, 6415ꢀ6418.
(39) Haberhauer, G.; Pintér, Á.; Oeser, T.; Rominger, F. Eur. J. Org. Chem. 2007, 1779ꢀ
1792.
(40) Haberhauer, G.; Drosdow, E.; Oeser, T.; Rominger, F. Tetrahedron 2008, 64, 1853ꢀ
1859.
(41) Pintér, Á.; Haberhauer, G. Modeling of Molecular Properties; Comba, P., Ed.; Wileyꢀ
VCH: Weinheim, 2011.
(42) Karplus, M. J. Chem. Phys. 1959, 30, 11ꢀ15.
(43) Haberhauer, G.; Rominger, F. Tetrahedron Lett. 2002, 43, 6335ꢀ6338.
(44) Becke, A. D. Phys. Rev. A 1988, 38, 3098ꢀ3100.
(45) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785ꢀ789.
(46) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200ꢀ206.
(47) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104.
(48) Grimme, S. Chem. Eur. J. 2012, 18, 9955ꢀ9964.
(49) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724ꢀ728.
29
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