The effect of backbone stereochemistry on the folding of acyclic β2,3-aminoxy peptides

Article abstract of DOI:10.1002/chem.200901471

As a new type of foldamer, β-aminoxy peptides have the ability to adopt novel β N-O turns or β N-O helices in solution. Herein, we describe a new subclass of β-aminoxy peptide, that is, peptides of acyclic β^2,3-aminoxy acids (NH₂OCHR₁CHR ₂COOH), in which the presence of two chiral centers provides insight into the effect of backbone stereochemistry on the folding of β-aminoxy peptides. Acyclic β^2,3aminoxy peptides with syn and anti configurations have been synthesized and their conformations investigated by NMR, IR, and circular dichroism (CD) spectroscopic, and X-ray crystallographic analysis. The ss N-O turns or β N-O helices, which feature ninemembered rings with intramolecular hydrogen bonds and have been identified previously in peptides of β³- and β^2,2-aminoxy acids, are also predominantly present in the acyclic β^2,3- aminoxy peptides with a syn configuration and N-O bonds gauche to the C _a-Cβ bonds in both solution and the solid state. In the acyclic β^2,3-aminoxy peptides with an anti configuration, an extended strand (i.e., non-hydrogenbonded state) is found in the solid state, and several conformations including non-hydrogen-bonded and intramolecular hydrogen-bonded states are present simultaneously in nonpolar solvents. These results suggest that the backbone stereochemistry does affect the folding of the acyclic β^2,3-aminoxy peptides. Theoretical calculations on the conformations of model acyclic β^2,3-aminoxy peptides with different backbone stereochemistry were also conducted to elucidate structural characteristics. Our present work may provide useful guidelines for the design and construction of new foldamers with predicable structures.

Full text of DOI:10.1002/chem.200901471

FULL PAPER
DOI: 10.1002/chem.200901471
The Effect of Backbone Stereochemistry on the Folding of Acyclic
b2,3-Aminoxy Peptides
Yu-Hui Zhang,[a, b] Kesheng Song,[a] Nian-Yong Zhu,[a] and Dan Yang*[a]
ꢀ
Abstract: As a new type of foldamer,
b-aminoxy peptides have the ability to
b N O helices, which feature nine-
membered rings with intramolecular
hydrogen bonds and have been identi-
fied previously in peptides of b3- and
bonded state) is found in the solid
state, and several conformations in-
cluding non-hydrogen-bonded and in-
tramolecular hydrogen-bonded states
are present simultaneously in nonpolar
solvents. These results suggest that the
backbone stereochemistry does affect
the folding of the acyclic b2,3-aminoxy
peptides. Theoretical calculations on
the conformations of model acyclic
ꢀ
ꢀ
adopt novel b N O turns or b N O
helices in solution. Herein, we describe
a new subclass of b-aminoxy peptide,
that is, peptides of acyclic b2,3-aminoxy
acids (NH2OCHR1CHR2COOH), in
which the presence of two chiral cen-
ters provides insight into the effect of
backbone stereochemistry on the fold-
b
2,2-aminoxy acids, are also predomi-
nantly present in the acyclic b2,3-amino-
xy peptides with a syn configuration
ꢀ
ꢀ
and N O bonds gauche to the Ca Cb
bonds in both solution and the solid
state. In the acyclic b2,3-aminoxy pep-
tides with an anti configuration, an ex-
tended strand (i.e., non-hydrogen-
ing of b-aminoxy peptides. Acyclic b2,3
-
b
2,3-aminoxy peptides with different
aminoxy peptides with syn and anti
configurations have been synthesized
and their conformations investigated
by NMR, IR, and circular dichroism
(CD) spectroscopic, and X-ray crystal-
backbone stereochemistry were also
conducted to elucidate structural char-
acteristics. Our present work may pro-
vide useful guidelines for the design
and construction of new foldamers
with predicable structures.
Keywords:
conformation analysis · foldamers ·
peptidomimetics · stereochemistry
aminoxy
acids
·
ꢀ
lographic analysis. The b N O turns or
Introduction
antibiotic activity, molecular recognition, and anion chan-
nels.[2] In an effort to develop novel peptidomimetic foldam-
ers, we found that peptides made of aminoxy acids can
adopt fascinating, rigid, yet predictable secondary structures.
Up to this point, our studies primarily focused on two types
of aminoxy peptide, a-aminoxy acids[3] and b-aminoxy
acids[4] (Scheme 1). In comparison with natural amino acids,
In recent years, various unnatural oligomers with well-de-
fined secondary structures (termed “foldamers”) have been
created and their conformational characteristics intensely
studied[1] to reveal attractive architectures that could serve
promising biological functions, such as cellular penetration,
ꢀ
the N O bond in aminoxy acids has unusual torsional char-
acteristics that arise from repulsion between the lone pairs
of electron on the N and O atoms. Thus, the backbone of
aminoxy peptides is more rigid than that of natural peptides.
[a] Prof. Dr. Y.-H. Zhang, Dr. K. Song, Dr. N.-Y. Zhu, Prof. Dr. D. Yang
Department of Chemistry
ꢀ
For a-aminoxy peptides, 1.88 helices (i.e., a N O helices
ꢀ
that comprise a N O turns; Scheme 1) were observed in
The University of Hong Kong
peptides that contain as few as two residues and were inde-
pendent of side chains.[3] a-Aminoxy peptides have been
successfully used in the construction of anion receptors and
channels.[5] Compared with a-aminoxy peptides, b-aminoxy
peptides have extra b-carbon atoms in the backbone, thus
leading to greater variations in substitution patterns
(Scheme 2). Previous studies by our group indicated that b-
Pokfulam Road, Hong Kong (China)
Fax : (+852)2859-2159
E-mail: yangdan@hku.hk
[b] Prof. Dr. Y.-H. Zhang
Britton Chance Center for Biomedical Photonics
Wuhan National Laboratory for Optoelectronics
Huazhong University of Science and Technology
1037 Luoyu Road, Wuhan 430074 (China)
ꢀ
ꢀ
aminoxy peptides can adopt novel b N O turns or b N O
helices, which involve nine-membered rings with hydrogen
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901471.
Chem. Eur. J. 2010, 16, 577 – 587
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
577

bonds, independent of the ring
size, thus indicating that the ali-
phatic rings increase the rigid-
ness of the backbone.[6]
Another factor that is impor-
tant in determining the folding
of foldamers is the backbone
stereochemistry; for example,
Scheme 1. a-Aminoxy acids[3] and b-aminoxy acids.[4]
b
2,3-peptides constructed with
trans-2-aminocyclopentanecar-
boxylic acid (ACPC) favor a
12-helix structure,[7] whereas
those constructed with cis-
Scheme 2. b-Aminoxy peptides.
ACPC favor
a strand struc-
ture.[8] Studies on acyclic disub-
stituted b2,3-peptides have indi-
cated that a 14-helix structure is
present in a,b-anti-dialkyl b2,3
-
peptides[9] (with the same con-
figuration at the a- and b-
carbon atoms), and sheet struc-
tures are favored in a,b-syn-di-
alkyl b2,3-peptides (with differ-
ent configurations at the a- and
b-carbon atoms).[10] For g2,4
-
peptides with different configu-
rations, reverse turns and heli-
ces are found.[11]
To investigate whether the
backbone stereochemistry af-
fects the secondary structures
of b-aminoxy peptides, we pre-
pared and characterized a novel
subclass of b-aminoxy peptide,
acyclic
b
2,3-aminoxy peptides
(4-oxa-g-peptides). The pres-
Scheme 3. Synthesis of 1, 3, and 4. Reagents and conditions: a) Bakerꢁs yeast, petroleum ether/H2O (63%
ence of two chiral centers in
ꢀ
yield, 93% ee); b) LDA, BnBr or CH3CH2I, THF, HMPA (60–70% yield); c) PhthN OH, Ph3P, DIAD,
the monomer unit (acyclic b2,3
-
CH2Cl2 (58–64% yield); d) 1. TFA, CH2Cl2; 2. EDCI, HOBt, CH2Cl2, cyclohexylamine (65–71% overall
yield); e) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. 10% NaHCO3, (CH3)3CHCOCl, CH3OH, CH2Cl2 (59% overall
yield); f) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. EDCI, HOAt, CH2Cl2 (63–73% overall yield);
g) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. 10% NaHCO3, (CH3)3CHCOCl, CH3OH, CH2Cl2 (61–68% overall
yield). DIAD=diisopropyl azodicarboxylate, EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride, HMPA=hexamethylphosphoramide, LDA=lithium diisopropylamide, HOBt = 1-hydroxybenzotria-
zole, HOAt = 1-hydroxyazabenzotriazole, TFA=trifluoroacetic acid.
aminoxy acid; Scheme 2) allows
us to examine the effect of
backbone stereochemistry on
the folding of b-aminoxy pep-
tides. NMR, IR, and circular di-
chroism (CD) spectroscopic,
and X-ray crystallographic anal-
bonds between the neighboring residues, and that the local
ysis with computer simulation were used to elucidate the
structural features of these acyclic b2,3-aminoxy peptides.
Our results lay the groundwork for predicting the conforma-
tion of b-aminoxy peptides and may help to guide efforts in
constructing new foldamers with useful functions.
ꢀ
ꢀ
structures of the b N O turns and b N O helices vary
slightly for different subclasses of b-aminoxy peptide
(Scheme 2).[4] For example, the N O bonds are anti to the
ꢀ
Ca Cb bonds in b2,2-aminoxy peptides, whereas these bonds
ꢀ
can be either anti or gauche in b3-aminoxy peptides, depend-
ing on the size of the side chains (Scheme 2). Therefore, the
extra b-carbon atoms in acyclic b-aminoxy peptides permit
considerable conformational flexibility. For cyclic b2,3-ami-
noxy peptides (Scheme 2), in which the a- and b-carbon
atoms are part of an aliphatic ring (either a cyclopentane or
Results and Discussion
Synthesis of acyclic b2,3-aminoxy peptides 1–7: Peptides 1–7
were synthesized as shown in Schemes 3–5 (see the Support-
ing Information for further details).
ꢀ
ꢀ
cyclohexane unit), the N O bonds are anti to the Ca Cb
578
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Chem. Eur. J. 2010, 16, 577 – 587

Foldamers of b-Aminoxy Peptides
FULL PAPER
1) the concentration depend-
ence of the chemical shifts of
the amide protons[12] and 2) the
gradual addition of a strong hy-
drogen-bond acceptor, such as
deuterated dimethyl sulfoxide
([D6]DMSO), to a dilute solu-
tion of the peptide in a non-hy-
drogen-bonding solvent, such as
CDCl3,[13] are commonly used
to probe the formation of intra-
molecular hydrogen bonds by
amide protons in linear pep-
tides in solution. We applied
these two methods to the char-
acterization of the intramolecu-
lar hydrogen bonds present in
Scheme 4. Synthesis of 2. Reagents and conditions: a) CH3OH, H2SO4, ClCH2CH2Cl; b) LDA, CH3CH2I, THF,
ꢀ
HMPA (52% yield); c) 1. LiOH, CH3OH, H2O; 2. 20% Cs2CO3, BnBr, DMF (88% overall yield); d) PhthN
the peptides of acyclic b2,3
-
OH, Ph3P, DIAD, CH2Cl2 (35% yield); e) 1. Pd/C, H2, CH3OH, CHCl3; 2. EDCI, HOBt, CH2Cl2, cyclohexyl-
amine (65% overall yield); f) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. 10% NaHCO3, (CH3)3CHCOCl, CH3OH,
CH2Cl2 (61% overall yield).
aminoxy acids.
Table 1
summarizes
the
chemical shifts of the amide
1
protons in the H NMR spectra
of 1–7 at room temperature,
among which 1–4 have a syn
configuration and 5–7 have an
anti configuration (Scheme 6).
The protons of the N-oxy
amide unit NHb of 3 and 4 and
the regular amide unit NHc of
1–4 appeared unusually down-
field and showed little change
when the solutions were diluted
from 50 to 1.56 mm in CDCl3
(Dd=0.05–0.16 ppm) or when
[D6]DMSO was added gradual-
ly to a 5 mm solution of 1–4 in
CDCl3
(Dd=0.07–0.30 ppm;
Table 1). In contrast, the signals
of the N-oxy amide unit NHa of
1–4 were found rather upfield
and changed dramatically upon
dilution in CDCl3 (Dd=0.17–
0.74 ppm) or upon addition of
[D6]DMSO
(Dd=1.70–
2.22 ppm; Table 1). These re-
sults suggest that the amide
protons NHb of 3 and 4 and
NHc of 1–4 form intramolecular
hydrogen bonds, whereas the
amide protons NHa of 1–4 are
accessible to the solvent.
For compounds 5–7 with an
anti configuration, the signals
from the amide protons NHa
were located at about d=
Scheme 5. Synthesis of 5–7. Reagents and conditions: a) LDA, CH3CH2I or CH3I, THF, HMPA (43–52%
yield); b) 4-NO2C6H4COOH, Ph3P, DEAD, THF (50–71% yield); c) NaN3, CH3OH, 458C (45–65% yield);
ꢀ
d) LiAlH4, Et2O; e) TrCl, DMAP, DMF, Et3N (73–95% overall yield); f) PhthN OH, PPh3, DIAD, CH2Cl2
(80–85% yield); g) HCOOH, CH2Cl2 (60–73% yield); h) NaIO4, RuO2·H2O, CH3CN/CCl4/H2O/acetone
1:1:1.4:0.3; 1. EDCI, HOAt, CH2Cl2, cyclohexylamine or isobutylamine (55–78% overall yield);
j) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. 10% NaHCO3, (CH3)3CHCOCl, CH3OH, CH2Cl2 (65% overall yield);
k) 1. NH2NH2·H2O, CH3OH, CH2Cl2; 2. EDCI, HOAt, CH2Cl2, (CH3)2CHCOOH (56–60% overall yield).
DEAD = diethyl azodicarboxylate, DMAP=4-dimethylaminopyridine, TrCl=triphenymethyl chloride.
1
Conformational studies of compounds 1–7 by H NMR spec-
8.6 ppm and were shifted substantially in the dilution studies
and [D6]DMSO addition studies. This outcome reveals that
troscopy: Two 1H NMR spectroscopic methods based on
Chem. Eur. J. 2010, 16, 577 – 587
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579

D. Yang et al.
1
1H NMR spectra usually repre-
Table 1. Chemical shifts (d) and changes in the chemical shift (DdNH) of the amide protons of 1–7 in H NMR
spectroscopic dilution (dilu.) and in [D6]DMSO addition studies (DMSO).
sents
average
a
population-weighted
of non-hydrogen-
NHa [ppm]
NHb [ppm]
NHc [ppm]
Comp.
d[a]
Dd[b]
(dilu.)
Dd[c]
(DMSO)
d[a]
Dd[b]
(dilu.)
Dd[c]
(DMSO)
d[a]
Dd[b]
(dilu.)
Dd[c]
(DMSO)
bonded and hydrogen-bonded
states to account for the rapid
exchange between these states.
In contrast, the timescale of IR
spectroscopic measurements is
short enough to clearly distin-
G
G
G
G
G
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8.21
8.35
8.24
8.43
8.67
8.59
8.34
0.17
0.24
0.45
0.74
0.15
0.51
1.82
1.70
2.22
2.08
1.20
1.81
1.91
8.00
7.76
7.79
7.89
6.31
6.83
7.07
0.054
0.097
0.070
0.14
0.13
0.25
0.33
0.42
0.068
0.098
1.05
1.06
0.96
11.42
11.48
0.093
0.16
0.30
0.26
ꢀ
guish the N H stretching sig-
nals of the hydrogen-bonded
[a] d=Chemical shift of the amide NH protons obtained from the 1H NMR spectrum of the indicated com-
pound (5 mm, CD2Cl2, room temperature; there was little change in the chemical shift of the amide protons of
1–7 below 5 mm). [b] Dilution study: solutions of 1–7 in CDCl3 were diluted from 50 to 1.56 mm at room tem-
perature (DdDilution =d50 mMꢀd1.56 mM). [c] [D6]DMSO addition study: [D6]DMSO (50 mL) was added gradually to
a solution of 1–7 (5 mm) in CDCl3 (0.5 mL) at room temperature (DdDMSO =d50 mL of DMSOꢀd0 mL of DMSO).
and
non-hydrogen-bonded
states. Therefore, the data from
ꢀ
the N H stretching region of
the IR spectra provide insight
into the degree of hydrogen-
bond existence in nonpolar sol-
vents.[3,4]
Previous studies have shown
that the IR absorption peaks of
the
non-hydrogen-bonded
amide NH appear between n˜ =
3400 and 3450 cmꢀ1 and the
peaks of the non-hydrogen-
bonded N-oxy amide NH are
between
n˜ =3340
The absorption
and
3400 cmꢀ1.
peaks that correspond to the
hydrogen-bonded normal
amide and N-oxy amide appear
around n˜ =3300 and 3200 cmꢀ1,
respectively.[3,4]
ꢀ
Figure 1 presents the N H
stretching region of the FTIR
spectra of 1–7. The spectra
were recorded at a very low
concentration (2 mm), such that
intermolecular hydrogen bond-
ing is unlikely to occur
Scheme 6. Compounds 1–7 with syn or anti configurations.
the protons of the N-oxy amide unit NHa are solvent ex-
posed, similar to the NHa protons in 1–4. Compared with
the NHc protons in 1–4, the NHc protons in 5–7 appeared
relatively upfield (d=6.31–7.07 ppm), thus suggesting that
non-hydrogen-bonded states exist partially in each case
(Table 1). This conclusion is further supported by the evi-
dence that a relatively large Dd shift for the amide protons
NHc in 5–7 was observed in the dilution studies and
[D6]DMSO addition studies (Table 1). When the protecting
groups of the C or N terminus were changed from large to
small groups (as in 5 and 6, respectively) or when the sub-
stituent at Ca was changed from an ethyl to a methyl group
(as in 6 and 7, respectively), the amide proton NHc shifted
downfield gradually, thus implying a slight increase in the
populations of the hydrogen-bonded states.
(Table 1). We observed three major peaks for 1 and 2 and
four major peaks for 3 and 4 (Figure 1): the absorptions
peaks in the region n˜ =3399–3405 cmꢀ1 correspond to the
non-hydrogen-bonded N-oxyamide NHa groups at the N ter-
mini; the large peaks in the region n˜ =3281–3295 cmꢀ1 are
due to the stretching of the hydrogen-bonded C-terminal
amide NHc groups; the small shoulder peaks at n˜ =3430–
3432 cmꢀ1 are assigned to the N H stretching bands of the
ꢀ
non-hydrogen-bonded amide NHc groups at the C termini;
and the fourth peak in the IR spectra of 3 and 4 at n˜ =
3201 cmꢀ1 comes from the stretching of intramolecular hy-
drogen-bonded NHb unit. The small peaks at n˜ =3430–
3432 cmꢀ1 indicate that negligible populations of the non-hy-
drogen-bonded conformation of 1–4 are present in CH2Cl2.
For 5–7, the peaks in the regions n˜ =3395–3399 and 3308–
3326 cmꢀ1 are assigned to the stretching of the non-hydro-
gen-bonded NHa and weakly hydrogen-bonded NHc units,
respectively (Figure 1), and the large peaks at n˜ =3430–
Conformational studies of compounds 1–7 by IR spectrosco-
py: The observed value of each amide proton in the
580
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Foldamers of b-Aminoxy Peptides
FULL PAPER
ꢀ
Figure 1. The N H stretching region of the FTIR spectra of 1–7 (2 mm, CH2Cl2, at room temperature) after subtraction of the spectrum of pure CH2Cl2.
3442 cmꢀ1 suggest a substantial population of non-hydrogen-
whether intramolecular hydrogen bonds are formed and to
what extent hydrogen-bond existence is achieved was ob-
tained, but the structural features of these intramolecular
hydrogen bonds, such as ring size and dihedral angles of the
bonds, are still unknown. To clarify the characteristics of the
secondary structures formed in acyclic b2,3-aminoxy pep-
tides, we attempted to grow crystals. Fortunately, suitable
bonded NHc units, especially in 5. These results are in good
1
agreement with the observations from the H NMR spectro-
scopic studies.
X-ray crystallographic analysis of 1 and 5: From our
1H NMR and IR spectroscopic studies, information about
Chem. Eur. J. 2010, 16, 577 – 587
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581

D. Yang et al.
Figure 2. The solid-state structures of a) 1 and b) 5. The solid-state packing patterns of c) 1 containing three molecules and d) 5 containing four mole-
cules. Dotted lines in yellow indicate intermolecular hydrogen bonds and dotted lines in green indicate intramolecular hydrogen bonds.
crystals of 1 and 5 for single-crystal X-ray structural analysis
were obtained from CH2Cl2/n-hexane. The X-ray crystallo-
graphic structure shown in Figure 2a reveals that 1 adopts a
Table 2. Torsional angles[a] of 1 and 5 of b2,3-aminoxy acids and model
8[4b] of b3-aminoxy acids in their solid-state structures.
Compound
f [8]
q [8]
f [8]
y [8]
ꢀ
b N O turn structure, thus bearing high similarity to that
1
ꢀ113.50
ꢀ115.85
123.84
77.95
70.42
178.48
160.67
73.30
77.49
ꢀ70.47
ꢀ70.10
ꢀ112.07
135.26
8[a]
formed in compound 8 of b3-aminoxy acid, which involves a
nine-membered ring with hydrogen bonds between the C=
Oi and NHi+2, and is stabilized further by another six-mem-
bered ring with hydrogen bonds between the NHi+2 and
conformation A
conformation B
ꢀ44.39
5
108.69
ꢀ66.30
[a]
NOi+1 units.[4b] The N O bond in 1 is gauche to the Ca Cb
bond with a dihedral angle aNOCbCa of 77.958 (Table 2).
The molecules of 1 pack in an antiparallel fashion with an
intermolecular hydrogen bond between two adjacent mole-
cules (Figure 2c).
ꢀ
ꢀ
ꢀ
For compound 5, there are two molecules present in each
asymmetric unit of the crystal but with slightly different con-
formations (Table 2). No intramolecular hydrogen bonds are
observed in the crystal structures (Figure 2b). Three inter-
molecular hydrogen bonds are observed between these two
molecules in the same unit, and one unit is connected to an
adjacent unit by the fourth intermolecular hydrogen bond.
A water molecule also forms a hydrogen bond with an
amide proton in each unit (Figure 2d). All the molecules
adopt “extended” strand conformations with the N O bond
ꢀ
anti to the Ca Cb bond (dihedral angle aNOCbCa: 178.48
or 160.678). These findings are in contrast with the results of
the H NMR and IR spectroscopic studies, which indicated
1
that both intramolecular hydrogen-bonded or non-hydro-
gen-bonded conformations of 5 exist simultaneously in solu-
tion, possibly because the “extended” strand is more favora-
ble in the solid state in which the molecules are packed at
an exceedingly “high concentration”. A disagreement be-
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Foldamers of b-Aminoxy Peptides
FULL PAPER
tween the structures in solution and in the solid state was
the conformation in the solid state. The NOE pattern for 6
with a small protecting group at the N terminus is similar to
the pattern for 5. However, there is a different NOE pattern
for 7, which has a smaller substituent (methyl group) at the
Ca position than 5 and 6 (which have an ethyl group at this
position), compared to 5 and 6, that is, a weak NOE interac-
tion between the NHa and CHb protons and a medium NOE
interaction between the NHc and CHb protons (Figure 3).
This difference suggests that the substituent at the Ca posi-
tion slightly affects the conformations of b2,3-aminoxy pep-
tides with an anti configuration.
also noted in the b3-aminoxy peptides, in which the sheet
ꢀ
structures (with intermolecular hydrogen bonds) and b N O
turns (with intramolecular hydrogen bonds) are formed in
the solid state and in solution, respectively.[4b]
2D NOESY studies of 1–7: The 2D NOESY spectroscopic
method was used to investigate the secondary structures of
1–7 in solution (Figure 3). Similar NOE patterns were ob-
CD studies of 2 and 4–7: CD spectroscopy has been success-
fully employed on an extensive scale to characterize the sec-
ondary structures of foldamers.[3,4,14] We used CD spectros-
copy as an additional tool to determine the conformation of
the homochiral peptides of acyclic b2,3-aminoxy acids. The
CD spectra of 2 and 4–7 in CF3CH2OH are shown in
Figure 4; however, CD spectra of 1 and 3 in CF3CH2OH
Figure 3. Summary of the NOE interactions observed (s=stronger, m=
medium, w=weaker NOE interactions) in the NOESY spectra of 1–7
(5 mm, CD2Cl2, room temperature).
tained for 1 and 2: stronger NOE interactions between the
NHa and CHb protons and weaker NOE interactions be-
tween the NHc and CHb protons. This observation agrees
well with the evidence that the H···H distance between the
NHa and CHb units in the solid-state structure of 1 is ap-
proximately 2.68 ꢂ, which is shorter than the distance be-
tween the NHc and CHb units (ca. 3.80 ꢂ; Figure 2a). The
similarity of the NOE patterns observed for 1 and 2 also
suggest that the difference in the side chain at the Ca posi-
tion has a limited effect on the secondary structures of 1
and 2. It is most likely that both 1 and 2 preferentially adopt
Figure 4. A) CD spectra of 2 and 4 (CF3CH2OH, room temperature): a) 2
at 0.5 mm, b) 4 at 0.5 mm, and c) 4 at 5 mm. B) CD spectra of 2 and 5–7
(CF3CH2OH, room temperature): a) 2 at 0.5 mm, b) 5 at 0.5 mm, c) 5 at
5 mm, d) 5 at 10 mm, e) 6 at 0.2 mm, f) 7 at 0.5 mm, and g) 7 at 5 mm. The
spectra have been normalized for the concentration of the compound
and the number of backbone amide residues.
ꢀ
ꢀ
a b N O turn conformation with the N O bond gauche to
ꢀ
the Ca Cb bond in solution and the solid state. The NOE
patterns observed for 3 and 4 are analogous to those for 1
ꢀ
and 2; therefore, the b N O helices with two consecutive b
could not be obtained due to poor solubility. The CD curves
of 2 and 4 in CF3CH2OH, which constitute nearly mirror
images of each other for their opposite chirality, are very
similar to those of b3-aminoxy peptides[4b] with a maximum
absorption at approximately l=202 nm (Figure 4A), thus
ꢀ
N O turns are the dominant conformations of 3 and 4 in so-
lution.
The NOE interactions obtained for 5 reveal a distinct pat-
tern: a medium NOE interaction between the NHa and CHb
protons and a medium NOE interaction between the NHc
and CHb protons (Figure 3). The NOE pattern does not
agree with the crystal structure of 5, in which the H···H dis-
tance between the NHa and CHb protons (ca. 2.72 ꢂ) is
much shorter than the distance between the NHc and CHb
protons (ca. 64.26 ꢂ; Figure 2b). This result also suggests
that the conformation of 5 in solution is a little different to
ꢀ
ꢀ
suggesting that the b N O turn and b N O helix are adopt-
ed predominantly in 2 and 4, respectively. The CD absorp-
tion peaks of 5 and 7 determined at different concentrations
showed negligible changes, thus implying that there was no
aggregation (Figure 4B). The CD curves observed for 5–7
(Figure 4B) are similar to each other with a maximum ab-
sorption at approximately l=198 nm and zero crossing at
Chem. Eur. J. 2010, 16, 577 – 587
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583

D. Yang et al.
approximately l=217 nm, but differ slightly from the curves
of 2 and 4, thus suggesting that the secondary structures in
5–7 are, to some extent, different from the structures in 2
and 4.
Theoretical calculations: We carried out theoretical calcula-
tions to elucidate the conformational features of acyclic b2,3
-
Scheme 7. Models 8–11.
aminoxy peptides with different backbone stereochemistry
and different substituents at the Ca positions. All the calcu-
lations were conducted with the Gaussian98 program.[15] The
geometry of each structure was fully optimized by the
B3LYP/6-311G** method,[16] and vibration-frequency calcu-
lations were subsequently performed. The energies were
evaluated by the MP2/6-311G** method[17] based on
B3LYP/6-311G** geometries. Solvent effects were estimated
from the SCIPCM model[18] by the B3LYP/6-311G**
method. The final relative energies of the different confor-
mations were estimated by using Equation (1) , which has
been shown to be highly robust for other peptide system-
s.[4a,19]
bered-ring intramolecular hydrogen bonding and a gauche
dihedral angle q. The H···H distances NHa···CbH and
NHb···CbH in 8a are approximately 2.71 and 4.03 ꢂ, respec-
tively, which are in good agreement with the solid-state
structure (Figure 2a) and the strong/weak NOE pattern ob-
served for 1 (Figure 3).
Figure 6 shows the five stable conformations of model 9.
The nine-membered-ring intramolecular hydrogen-bonded
conformation 9a, which is similar to 8a, is the most stable
and in agreement with the strong/weak NOE pattern ob-
served for 2 in the 2D NOESY spectrum (Figure 3). The re-
sults suggest that changing the substituent at Ca from a
benzyl group to an ethyl group does not affect the secon-
dary structures of b2,3-aminoxy peptides with syn configura-
tions.
The structural features of compounds 5–7 with anti config-
urations were calculated for models 10 and 11 (Scheme 7),
respectively. Compared with 10, 11 has a smaller substituent
(methyl group) at Ca. The differences between the free ener-
gies of the calculated conformations for 10 and 11 (Figure 7
and 8, respectively) are much less than those energies for
models 8 and 9 (Figure 5 and 6, respectively), thus suggest-
DG ¼ DEðMP2Þ þ ½DEðB3LYP, solventÞꢀDEðB3LYP, gasÞꢁ
þenthalpy correctionꢀTDS
ð1Þ
Model structures 8 and 9 (Scheme 7) are the simulations
of 1 and 2 (Scheme 6), respectively, which have the same
configuration (syn), but a different substituent at the Ca po-
sition. Figure 5 displays the five stable conformations of
model 8. In consideration of relative energies, structure 8a,
which features strong, nine-
membered-ring intramolecular
hydrogen bonding, is the most
stable conformation. Com-
pound 8b is distinguished from
8a by its dihedral angles q of
approximately 79.28 in 8a
(gauche) and ꢀ161.48 in 8b
(anti) (Scheme 7). Thus, 8b is
less stable than 8a due to a
geometrical distortion. Struc-
tures 8c and 8d also possess
nine-membered-ring intramo-
lecular
hydrogen
bonding,
though they are much less
stable as a result of weaker hy-
drogen bonding and geometri-
cal distortions. Structure 8e has
seven-membered-ring intramo-
lecular hydrogen bonding and is
less stable in CH2Cl2 than 8a by
approximately
2.5 kcalmolꢀ1.
The calculations, therefore, sug-
gest that the dominant confor-
mation of model 8 in CH2Cl2 is
Figure 5. Calculated conformations of model 8. The relative free energies (kcalmolꢀ1) were calculated at the
MP2/6-311G** level in the gas phase and in CH2Cl2 (given in parentheses). The H···H distances of the
NHa···CbH and NHb···CbH interactions, the hydrogen-bond lengths, and the angles of the NHb···O interactions
8a, which features nine-mem- (ꢂ) are indicated.
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Chem. Eur. J. 2010, 16, 577 – 587

Foldamers of b-Aminoxy Peptides
FULL PAPER
ing that 10 and 11 are much
more flexible in their conforma-
tions. Thus, unlike 8, which
favors a single dominant con-
formation (i.e., 8a), 10 and 11
possibly have
a tendency to
exist simultaneously in several
variant conformations in solu-
tion. This interpretation was
supported by the evidence that
the weak/medium NOE pattern
observed for 7 does not agree
with any of the calculated con-
formations for 11 alone. Taken
together, for 5–7, several con-
formations may coexist in solu-
tion, whereas the percentages
of these conformations may
vary for each of these com-
pounds, thus resulting in the
different NOE patterns ob-
served for 5,
6
(medium/
medium NOE pattern), and 7
(weak/medium NOE pattern).
This outcome may explain why
the CD spectra of 5–7 are dif-
ferent from those spectra of 2
and 4, in which only one domi-
nant conformation is favored.
Figure 6. Calculated conformations of model 9. The relative free energies (kcalmolꢀ1) were calculated at the
MP2/6-311G** level in the gas phase and in CH2Cl2 (given in parentheses). The H···H distances of the
NHa···CbH and NHb···CbH interactions, the hydrogen-bond lengths, and angles of the NHb···O interactions (ꢂ)
are indicated.
Conclusions
In summary, we have synthe-
sized and investigated the con-
formational preferences of acy-
clic b2,3-aminoxy peptides with
different backbone stereochem-
istry. For acyclic b2,3-aminoxy
peptides with syn configura-
1
tions, the results from H NMR,
2D NOESY, IR, and CD spec-
troscopic, and X-ray crystallo-
graphic studies agree well with
each other and show consisten-
cy with theoretical calculations.
ꢀ
In addition, the b N O turns or
ꢀ
b N O helices, which have pre-
viously been found in the pep-
tides of b3- and b2,2-aminoxy
acids featuring nine-membered-
ring intramolecular hydrogen
bonding, are present predomi-
nantly in these acyclic b2,3-ami-
noxy peptides with syn configu-
rations. However, the local
ꢀ
Figure 7. Calculated conformations of 10. The relative free energies (kcalmolꢀ1) were calculated at the MP2/6-
311G** level in the gas phase and in CH2Cl2 (given in parentheses). The H···H distances of the NHa···CbH and
NHb···CbH interactions, the hydrogen-bond lengths, and angles of the NHb···O interactions (ꢂ) are indicated. structures of the b N O turns
Chem. Eur. J. 2010, 16, 577 – 587
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585

D. Yang et al.
Acknowledgements
This study was supported by The Uni-
versity of Hong Kong and the Re-
search Grants Council of Hong Kong
(HKU 06/2C and HKU 7654/06M).
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Received: June 2, 2009
Revised: August 24, 2009
Published online: October 28, 2009
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