Conformational studies on peptides of α-aminoxy acids with functionalized side-chains

Article abstract of DOI:10.1002/asia.200900636

Peptides of homochiral α- aminoxy acids of nonpolar side chains can form a 1.8₈-helix. In this paper, we report the conformational studies of α- aminoxy peptides 1-3, which have functionalized side chains, in both non- polar and polar solvents.

Full text of DOI:10.1002/asia.200900636

FULL PAPERS
DOI: 10.1002/asia.200900636
Conformational Studies on Peptides of a-Aminoxy Acids with Functionalized
Side-Chains
[
a, b]
[a]
[b]
[b]
[b]
Dan Yang,*
Guo-Jun Liu, Yu Hao, Wei Li, Ze-Min Dong,
[a] [b]
Dan-Wei Zhang, and Nian-Yong Zhu
Abstract: Peptides of homochiral a-
aminoxy acids of nonpolar side chains
bered-ring intramolecular hydrogen
bonds (the N-O turns) in nonpolar sol-
vents as well as in methanol. CD stud-
ies of peptides 1–3 in different solvents
indicate that a substantial degree of
helical content is retained in methanol
and acidic aqueous buffers. The intro-
duction of functionalized side chains in
a-aminoxy peptides provides opportu-
nities for designing biologically active
peptides.
can form a 1.8 -helix. In this paper, we
8
report the conformational studies of a-
aminoxy peptides 1–3, which have
functionalized side chains, in both non-
Keywords: circular dichroism
·
conformation analysis helical
·
1
polar and polar solvents. H NMR,
structures · hydrogen bonds · pep-
tides
XRD, and FTIR absorption studies
confirm the presence of the eight-mem-
Introduction
functionalized side chains and still maintain their well-de-
fined secondary structures (314 helices, 2.512 helices, 12/10
helices, or 14/15 helices, and so forth), and even quaternary
structures, in methanol or in aqueous solutions. The intro-
duction of various functional groups into b-peptides has
stimulated investigations into the biological applications of
Naturally occurring peptides and proteins are polymers of
a-amino acids. It is challenging to investigate the relation-
ship between the three-dimensional structures of the pep-
[1–7]
tides and their biological activities
because short peptides
[13–15,21,51–58]
seldom maintain well-defined secondary structures as a con-
these peptides in aqueous solutions.
a-Aminoxy acids are analogues of b-amino acids in which
[8]
sequence of their conformational flexibility. In recent
years, much attention has been paid to unnatural oligomers
that are capable of forming stable folded conformations in
[59–61]
an oxygen atom replaces the b-carbon atom.
Because of
the repulsion between the lone pair of electrons of the nitro-
gen and oxygen atoms, the backbones of a-aminoxy acids
are more rigid, and so they can form stable secondary struc-
[9–15]
solutions (so-called “foldamers”).
Among those oligo-
mers, b-peptides, which are composed of b-amino acid build-
ing blocks, are particularly appealing; they have been dem-
onstrated to adopt helix, sheet, reverse turn, and hairpin
conformations similar to those commonly observed in pro-
[60–69]
tures in solution.
We have reported previously that
when an a-aminoxy acid having a nonpolar side chain is in-
corporated into a peptide backbone, strong eight-mem-
[
16–21]
[21–35]
[36–43]
teins.
Most notably, Gellman,
Seebach,
and
bered-ring intramolecular hydrogen bonds (the N-O turn)
[44–50]
[59–63]
others
have developed some b-peptides that feature
could be induced between the adjacent residues.
Fur-
thermore, oligomers of homochiral a-aminoxy acids that
have hydrophobic side chains can form 1.8 helical confor-
8
[
a] Prof. D. Yang, G.-J. Liu, Prof. D.-W. Zhang
Department of Chemistry, Fudan University
Shanghai 200433 (P.R. China)
Fax : (+852)28592159
Fax : (+8621)65643576
E-mail: yangdan@hku.hk
mations (or a twisted 2 helix with two residues per helical
8
[60,65,66]
turn) in nonpolar solvents.
When designing aminoxy
peptides for biological applications, it is necessary to incor-
porate aminoxy acids featuring functionalized side chains;
the question then arises regarding whether the N-O turns
[
b] Prof. D. Yang, Dr. Y. Hao, Dr. W. Li, Dr. Z.-M. Dong, Dr. N.-Y. Zhu
Department of Chemistry
and 1.8 helical conformations of those peptides are retained
8
in protic solvents. In this paper, we report the results of our
conformational studies, in both nonpolar and polar solvents
of short oligomers of homochiral a-aminoxy acids that have
functionalized side chains.
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900636.
1356
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1356 – 1363

Results and Discussion
We prepared the N-pivalyl a-aminoxy dipeptide alkyl
amides 1–3, which have functionalized side chains, by fol-
lowing literature procedures. Compound 1 contains neutral
polar functional group such as ꢀOH, whereas ꢀCOOH and
1
ꢀ
NH groups are found in compounds 2 and 3, respectively.
Figure 1. H NMR spectroscopic chemical shifts of the amide protons of
a) 1 and b) 2 in CDCl at 258C as a function of the logarithm of solution
2
3
We used compound 4 as a reference compound in our con-
formational studies.
concentration (from 200 mm to 0.8 mm).
We performed the conformational studies of compounds 1
and 2 in nonpolar solvents, as well as in polar solvents, by
using H NMR, FTIR absorption, X-ray diffraction (XRD),
1
ꢀ1
mately 3100–3200 cm , corresponding to the intramolecular
and circular dichroism (CD) spectroscopic methods. As
compound 3 was not very soluble in nonpolar solvents, we
only performed the relative conformational studies in polar
hydrogen-bonded forms of these amide bonds. Furthermore,
ꢀ
1
we assigned the peaks at approximately 3430 cm for 1 to
the stretching of the intramolecular hydrogen-bonded OꢀH
solvents.
bond, forming a six-membered ring structure (Figure 4).
1
H NMR spectra of 1 and 2 in CDCl (Figure 1) indicated
Figure 5 presents 2D NOESY spectra of compounds 1
3
that the chemical shifts of NH at the N-terminus moved up-
and 2 in a nonpolar solvent (5 mm in CDCl ) at room tem-
a
3
field distinctly upon dilution with CDCl , whereas the sig-
nals of other amide protons changed very little. Similarly,
perature. For a typical N-O turn formed by a homochiral a-
aminoxy peptide, strong nuclear Overhauser effects (NOEs)
are observed between NH and C H , with weak NOEs exist-
3
the chemical shifts of NH of 1 and 2 (5 mm in CDCl ) at
a
3
i
a
60]
i
[
the N-terminus underwent a dramatic downfield shift upon
ing between NHi+1 and C H .
The same NOE patterns
a
i
addition of [D ]DMSO, whereas the signals of the other
amide protons showed little change (Figure 2). These results
were also found in the N-O turns at the N-terminus of 1 and
2. However, in the N-O turns at the C-terminus of 1 and 2,
6
strongly suggest that the amide protons at the N-terminus of
the NOEs between NHb and H showed similar intensity
2
1
and 2 (NH ) are solvent accessible, whereas other amide
when compared with those between NH and H . According
a
c
2
protons are hydrogen-bonded intramolecularly.
to theoretical calculations, there are two most stable con-
formers (5a and 5b) for model compound 5 (Figure 6).
While the eight-membered-ring hydrogen bond is present in
[65]
Figure 3 presents the FTIR absorption spectra (NꢀH
stretching region) of compounds 1 and 2 recorded at a con-
centration of 2 mm in CH Cl . The FTIR absorption spectra
both of these conformers, the C ꢀC bond is anti to the Nꢀ
2
2
a
b
of 1 and 2 revealed some similarities. The stretching of free
O bond in 5a but gauche in 5b. The observed NOE patterns
of the residues containing polar side chains in 1 and 2 indi-
cate that they may adopt a conformation similar to that of
5b in CDCl3.
aminoxy amide NꢀH bond of both compounds resulted in a
a
ꢀ
1
peak at approximately 3382–3383 cm , whereas the C-ter-
minal isobutyl (iBu) amide units (NꢀH ) displayed peaks at
c
ꢀ
1
around 3280–3320 cm , assigned to the intramolecular hy-
A single crystal of 2 was obtained by recrystallization
from its chloroform solution. The XRD structure of 2
(Figure 7) confirmed the NOE patterns observed in the non-
[61]
drogen-bonded moieties.
The stretching frequencies of
aminoxy-amide NꢀHb bonds of 1 and 2 were at approxi-
Chem. Asian J. 2010, 5, 1356 – 1363
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www.chemasianj.org
1357

D. Yang et al.
FULL PAPERS
Figure 4. Hydrogen-bonding pattern of the side-chain OH group and of
the C=O···HꢀN within one residue of compound 1 in CH
2 2
Cl .
3
Figure 5. Summary of the NOE patterns of 1 and 2 (5 mm in CDCl ) at
room temperature (s, strong NOEs; w, weak NOEs).
1
Figure 2. H NMR spectroscopic chemical shifts of the amide protons of
a) 1 and b) 2 (5 mm in CDCl
]DMSO were added.
3
) at 258C when increasing amounts of
[
65]
Figure 6. HF/6-31G** optimized conformers of model compound 5.
[
D
6
Figure 7. The crystal-state structure of 2 as determined by X-ray diffrac-
tion.
polar solvents. The aminoxy residue bearing the isopropyl
(
iPr) side chain maintains a typical a N-O turn similar to
that of conformer 5a, with an H···O distance of 2.00 ꢁ,
N···O=C distance of 2.83 ꢁ, and an NꢀH···O angle of 160.28
(
Table 1). The distance between NH and C H (2.53 ꢁ) is
a 1
a
shorter than that between NH and C H (3.21 ꢁ) (Table 2).
b
a
1
For the aminoxy residue bearing the acid side chain, we ob-
Table 1. Hydrogen-bond distances and angles found in the crystal struc-
ture of 2.
H bond
Distance H···O [ꢁ]
Distance N···O [ꢁ]
Angle NHO [8]
N
N
b
H
b
···O
···O
1
2.00
2.22
2.83
3.04
160.2
160.0
Figure 3. The NꢀH-stretch region of the FTIR absorption spectra for
compounds a) 1 and b) 2 in CH Cl (2 mm).
c
H
c
2
2
2
1358
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Chem. Asian J. 2010, 5, 1356 – 1363

Conformational Studies on Peptides of a-Aminoxy Acids
Table 2. Summary of H-H distances found in the crystal structure of pep-
tide 2.
downfield than that of reference compound 4 (8.12 ppm),
which cannot form any obvious intramolecular hydrogen
bond. Furthermore, the signals of NHb were at least
0.90 ppm more downfield than those of the aminoxy-amide
H
a
ꢀH
2.53
1
H
b
ꢀH
3.21
1
H
b
ꢀH
3.01
2
H
c
ꢀH
2.51
2
Distance [ꢁ]
protons NH at the N-terminus. These differences of chemi-
a
cal shift values indicate that NH and NH protons of 1–3
c
b
served an N-O turn structure similar to that of conformer
b, with an H···O bond length of 2.22 ꢁ. The NꢀO bond is
gauche to the C ꢀC bond and the distance between NH
form intramolecular hydrogen bonds, whereas NH protons
a
[61]
5
do not. These hydrogen-bond patterns suggest that com-
pounds 1–3 adopt a helix structure with two consecutive N-
O turns as observed in our previous studies on a-aminoxy
peptides of nonpolar side chains. However, the 2D NOESY
a
b
b
and C H (3.01 ꢁ) is slightly longer than that between NH
c
a
2
and C H (2.51 ꢁ). The backbone torsion angles of com-
a
2
pound 2 are summarized in Table 3. Comparing with the
data of the two most stable conformers 5a and 5b of model
compound 5 (Table 4), we conclude that the N-terminal
studies in CD OH at room temperature could not be per-
3
formed because of the fast exchange between the aminoxy-
amide protons and solvent molecules. Thus, we performed
the NOESY studies at ꢀ608C to slow down the exchange
process (Figure 8). Interestingly, the same NOE pattern
were found for all of these compounds: weaker NOEs be-
[65]
Table 3. The backbone torsion angles of compound 2.
tween NH and C H relative to those between NH and
i+1
i
a
i
C H , which suggests that all of the residues maintain their
a
i
5
b-like conformation in methanol at ꢀ608C, independent of
the side-chain functionality.
Compound 2
f
q
y
Figures 9–11 display CD spectra for 1–3. To facilitate
direct comparisons, the data have been normalized for the
concentration and the number of backbone N-O turns. In
N-terminal residue
C-terminal residue
ꢀ120.88
ꢀ85.88
94.38
143.38
7.68
ꢀ51.48
2
,2,2-trifluoroethanol (TFE), the CD curves of 1–3 display a
positive maximum, with similar intensities, at 196 nm, a neg-
ative maximum at 230 nm, and a zero crossing in the range
of 215–223 nm (Figure 9a). This CD pattern agrees well
with those of a-aminoxy peptides with nonpolar side chains
Table 4. The backbone torsion angles of HF/6-31G** optimized conform-
ers 5a and 5b.
[
65]
Conformer
f
q
y
[60,61]
reported previously by our group.
peptides 1–3 in methanol (Figure 9b) and acidic buffers
pH<6.00; Figure 10) maintain a similar shape as those re-
The CD curves of
5
5
a
b
129.68
110.08
ꢀ77.78
ꢀ19.88
30.28
ꢀ136.98
(
residue of 2 is 5a-like, whereas
the C-terminal one is 5b-like.
These data agree well with the
NOE results for compounds 1
and 2 and therefore, a close cor-
relation exists between the crys-
Figure 8. Summary of the NOE patterns of peptides 1–3 (10 mm in CD
3
OH) at ꢀ608C (s, strong NOEs; m,
tal-state structure and the solu- medium NOEs).
tion structure.
1
H NMR spectroscopic values
of all the amide protons of 1–4 in CD OH were obtained at
room temperature (Table 5). The chemical shift values of
corded in TFE, but with lower intensity (ca.
3
2
ꢀ1
ꢀ1
ꢀ1
42000 deg·cm ·dmol
in MeOH and ca. 20000–
in acidic buffer vs ca.
2
regular amide NH protons at the C-terminus of 1–3 ap-
30000 deg·cm ·dmol
c
2
peared in the range 8.57–8.82 ppm, at least 0.45 ppm more
50000 deg·cm ·dmol in TFE) and a slightly red-shifted pos-
itive maximum, which suggests that 1–3 can form a helical
conformation even in polar solvents, such as methanol and
acidic buffers, and the helical content decreases with the in-
crease of the polarity of solvent. To investigate the confor-
mational stability of 1–3 in buffers, we performed a series of
CD studies upon variation of pH value and temperature of
buffers (Figure 10 and Figure 11). In Figure 10, the CD pat-
tern of 1–3 basically remained unchanged until the pH value
of buffers was higher than 7.00. This change reflects the di-
minution of helical conformations of 1–3 arising from the
3
Table 5. Chemical shifts (ppm) of the amide protons of 1–4 in CD OH
[
a]
(
10 mm) at room temperature.
NH
a
NH
b
NH
c
1
2
3
4
11.12
11.03
11.25
12.08
12.00
12.15
8.57
8.82
8.61
8.12
[
a] Chemical shifts of aminoxy-amide protons are in italics.
Chem. Asian J. 2010, 5, 1356 – 1363
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www.chemasianj.org
1359

D. Yang et al.
FULL PAPERS
Figure 9. CD spectra of 1–3 in a) 2,2,2-trifluoroethanol (0.4 mm); b) meth-
anol.
deprotonation of aminoxy-amide protons on the backbone
when the solution becomes basic. Nevertheless, the helical
conformations of 1–3 still remained under acidic condition
even when the temperature reached 858C (Figure 11).
Conclusions
We have developed a new family of a-aminoxy-acid oligo-
mers with functionalized side chains. The conformations of
1
these oligomers have been investigated by H NMR, FTIR
absorption, CD spectroscopy, and XRD analysis. We have
found that the formation of N-O turn is independent of
side-chain variations when functionalized side chains were
incorporated into the peptide backbone, although an alter-
native N-O turn conformation, in which the C ꢀC bonds
Figure 10. CD spectra of a)1, b)2, c)3 in different buffers of different pH
values (4 mm). For the details of buffers, see the Supporting Information.
a
b
were gauche to the NꢀO bonds, is observed for some cases
in nonpolar solvents. In methanol, this alternative N-O turn
conformation is found at low temperature in all aminoxy-
acid residues, regardless of the nature of side chains. Sub-
stantial helical contents are also observed for those peptides
in acidic and neutral buffers. The conformational stability of
the aminoxy peptides in acidic and neutral environment is
an important feature, which makes them potential scaffolds
for biological applications.
Experimental Section
General Methods
All reagents and solvents for the reactions were of analytical grade, and
were dried and distilled as necessary. Melting points (m.p.) were deter-
mined with a Reichert Thermovar Kofler microscope and the values
were uncorrected. Optical rotations were measured with an AUTO POL
IV automatic polarimeter. NMR spectra were recorded on Jeol ECA-400
1360
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1356 – 1363

Conformational Studies on Peptides of a-Aminoxy Acids
Figure 11. CD spectra of a)1, b)2, c)3 in buffers (pH 6.00) at different temperatures (8C) and diagrams of molar ellipticity (Mol. Ellip.) at 200 nm versus
temperature. For the details of buffers, see the Supporting Information.
or Bruker Avance DRX 400, 500, and 600 MHz Fourier Transform spec-
trometers. IR absorption spectra were recorded on a NICOLET FTIR-
polarimeter. UV absorptions were recorded on an Agilent HP8453 spec-
trometer.
3
60 spectrophotometer as a thin film unless otherwise noted. Mass spec-
Characterization of Compounds 1–4
tra were recorded with a Finnigan MAT 95 mass spectrometer for both
low resolution and high resolution mass spectra. Circular dichroism spec-
troscopic studies were carried out with the use of a Jasco J-715 spectro-
20
D
Compound 1: an oil; ½aꢁ =+138.68 (c=0.50, CH
3
OH); IR (CH
2
Cl
2
): n˜ =
): d=
ꢀ1
1
3
436, 3384, 3318, 3170, 1727, 1683 cm ; H NMR (400 MHz, CDCl
3
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D. Yang et al.
FULL PAPERS
1
4
6
1
0
1
1
2.01 (s, 1H), 8.88 (s, 1H), 7.84 (t, J=5.4 Hz, 1H), 4.29 (dd, J=5.5,
.6 Hz, 1H), 4.11 (d, J=3.9 Hz, 1H), 3.97–3.91 (m, 2H), 3.67 (t, J=
.0 Hz, 1H, OH), 3.20–3.06 (m, 2H), 2.33–2.23 (m, 1H), 1.87–1.80 (m,
H), 1.21 (s, 9H), 1.09 (d, J=6.9 Hz, 3H), 0.95 (d, J=7.0 Hz, 3H),
[8] J. W. Payne, N. J. Marshall, B. M. Grail, S. Gupta, Curr. Org. Chem.
2002, 6, 1221–1246.
[9] S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180.
[10] D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem.
Rev. 2001, 101, 3893–4011.
[11] a) A. R. Sanford, B. Gong, Curr. Org. Chem. 2003, 7, 1649–1659;
b) R. Sanford, K. Yamato, X. Yang, L. Yuan, Y. Han, B. Gong, Eur.
J. Biochem. 2004, 271, 1416–1425; c) B. Gong, Acc. Chem. Res.
1
3
3
.94 ppm (d, J=6.7 Hz, 6H); C NMR (100 MHz, CDCl ): d=180.0,
70.6, 168.7, 91.6, 87.0, 61.5, 46.6, 38.1, 30.8, 28.4, 27.0, 20.1, 19.0,
+
6.4 ppm; LRMS (EI, 20 eV): m/z (%): 375 (33) M , 128 (100); HRMS
+
(
EI): m/z (%) calcd for C17
H
33
N
3
O
6
: 375.2369 [M ]; found: 375.2371.
2
D
0
2
008, 41, 1376–1386.
Compound 2: an oil; ½aꢁ =+112.68 (c=0.68, CHCl
3
); IR (CH
2 2
Cl ): n˜ =
ꢀ
1
1
3
384, 3286, 3108, 1736, 1682 cm ; H NMR (400 MHz, CDCl
3
): d=12.04
[12] R. P. Cheng, Curr. Opin. Struct. Biol. 2004, 14, 512–520.
[13] C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem.
Biol. 2007, 3, 252–262.
(s, br, 1H), 8.86 (br t, 1H), 8.61 (s, 1H), 4.67 (t, J=6.6 Hz, 1H), 4.13 (d,
J=3.9 Hz, 1H), 3.22–3.02 (m, 3H), 2.85 (dd, J=16.1, 7.8 Hz, 1H), 2.32–
2
0
1
1
.25 (m, 1H), 1.90–1.78 (m, 1H), 1.21 (s, 9H), 1.08 (d, J=6.8 Hz, 3H),
.95 ppm (d, J=6.8 Hz, 9H); C NMR (100 MHz, CDCl ): d=179.6,
3
[14] a) I. Huc, Eur. J. Org. Chem. 2004, 17–29; b) Z. T. Li, J. L. Hou, C.
Li, H. P. Yi, Chem. Asian J. 2006, 1, 766–778.
[15] a) X. Li, D. Yang, Chem. Commun. 2006, 3367–3379; b) X. Li, Y.-D.
Wu, D. Yang, Acc. Chem. Res. 2008, 41, 1428–1438.
[16] D. Seebach, J. L. Matthews, Chem. Commun. 1997, 2015–2022.
[17] R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101,
1
3
73.9, 171.1, 170.4, 90.7, 83.5, 47.2, 38.1, 37.1, 30.9, 28.4, 27.1, 20.2, 18.8,
+
6.8 ppm; LRMS (EI, +20 eV): m/z (%): 403 (75) M , 118 (100); HRMS
+
(
EI): m/z (%) calcd for C18
H
33
N
3
O
7
: 404.2397 [M +H]; found: 404.2399.
2
D
0
1
Compound 3: ½aꢁ =+68.88 (c=0.65, CH
3
OH); H NMR (400 MHz,
3
219–3232.
3
CH OD): d=8.57 (t, J=5.8 Hz, 1H), 4.21 (dd, J=7.8, 3.9 Hz, 1H), 4.02
[
[
18] T. A. Martinek, F. Fꢂlçp, Eur. J. Biochem. 2003, 270, 3657–3666.
19] D. Seebach, A. K. Beck, D. J. Bierbaum, Chem. Biodiversity 2004, 1,
1111–1239.
(
d, J=4.9 Hz, 1H), 3.18–3.11 (m, 1H), 2.97–2.92 (m, 3H), 2.18–2.10 (m,
1
7
H), 1.93–1.54 (m, 7H), 1.16 (s, 9H), 1.04 (d, J=6.8 Hz, 3H), 0.96 (d, J=
1
.4 Hz, 3H), 0.92 ppm (d, J=6.8 Hz, 6H); H NMR (500 MHz, CD
3
OH,
[20] D. Seebach, D. F. Hook, A. Glꢃttli, Biopolymers 2006, 84, 23–37.
[21] W. S. Horne, S. H. Gellman, Acc. Chem. Res. 2008, 41, 1399–1408.
[22] D. H. Appella, J. J. Barchi, S. R. Durell, S. H. Gellman, J. Am.
Chem. Soc. 1999, 121, 2309–2310.
ꢀ
608C): d=12.49 (s, 1H), 11.65 (s, 1H), 9.04 (br, 1H), 7.93 (br, 3H),
4
2
0
1
3
.22 (br, 1H), 3.93 (d, J=5.8 Hz, 1H), 3.16–3.13 (br, 1H), 2.90 (br, 3H),
.17–2.11 (m, 1H), 1.78–1.55 (m, 7H), 1.14 (s, 9H), 0.99 (br, 3H),
.91 ppm (br, 9H); C NMR (100 MHz, CH
63.0–161.6 (br), 116.87 (q, J=274.6 Hz), 89.5, 85.7, 46.4, 39.2, 37.5, 30.9,
1
3
3
OD): d=178.7, 171.7, 170.1,
[
23] E. A. Porter, X. Wang, H.-S. Lee, B. Weisblum, S. H. Gellman,
Nature 2000, 404, 565.
1
3
0.6, 28.3, 26.7, 26.1, 21.7, 19.3, 17.7, 16.4 ppm; C NMR (150 MHz,
OH): d=178.9, 171.7, 170.2, 163.0–161.6 (br), 116.7 (q, J=283.8 Hz),
9.6, 85.8, 46.5, 39.4, 37.5, 30.8, 30.6, 28.2, 26.8, 26.1, 26.0, 21.6, 19.2, 17.6,
[
24] P. R. LePlae, J. D. Fisk, E. A. Porter, B. Weisblum, S. H. Gellman, J.
Am. Chem. Soc. 2002, 124, 6820–6821.
CD
8
1
3
3
1
[25] E. A. Porter, B. Weisblum, S. H. Gellman, J. Am. Chem. Soc. 2002,
124, 7324–7330.
[26] M. G. Woll, J. D. Fisk, P. R. LePlae, S. H. Gellman, J. Am. Chem.
Soc. 2002, 124, 12447–12452.
6.2 ppm;
F NMR (376.5 MHz, CD
3
OH): d=ꢀ76.8 ppm; LRMS
+
(
(
4
FAB): m/z (%): 417 (100) [M +HꢀCF
%) calcd for
417.3077 [M +HꢀCF
17.3076.
3
COOH]; HRMS (FAB): m/z
+
C
20
H
41
N
4
O
5
:
3
COOH]; found:
2
D
0
[27] T. L. Raguse, E. A. Porter, B. Weisblum, S. H. Gellman, J. Am.
Chem. Soc. 2002, 124, 12774–12785.
Compound 4: an oil; ½aꢁ =ꢀ11.78 (c=1.00, CHCl
3
); IR (CH
): d=7.36–7.31 (m,
2 2
Cl ): n˜ =
ꢀ
1
1
3
5
4
1
6
1
441, 3054, 1717 cm
;
H NMR (400 MHz, CDCl
3
[
[
[
28] T. L. Raguse, J. R. Lai, S. H. Gellman, J. Am. Chem. Soc. 2003, 125,
592–5593.
29] J. S. Park, H. S. Lee, J. R. Lai, B. M. Kim, S. H. Gellman, J. Am.
Chem. Soc. 2003, 125, 8539–8545.
30] A. Hayen, M. A. Schmitt, F. N. Ngassa, K. A. Thomasson, S. H.
Gellman, Angew. Chem. 2004, 116, 511–516; Angew. Chem. Int. Ed.
2004, 43, 505–510.
H), 6.08 (t, J=5.0 Hz, 1H), 5.15 (dd, J=6.9, 5.0 Hz, 1H), 5.09 (s, 2H),
.77 (br, 1H), 3.21–3.16 (m, 2H), 3.14–3.06 (m, 2H), 2.15 (s, 3H), 1.90–
.83 (m, 2H), 1.81–1.75 (m, 1H), 1.44–1.29 (m, 4H), 0.90 ppm (d, J=
.9 Hz, 6H); C NMR (100 MHz, CDCl
28.5 (2), 128.1, 74.0, 66.6, 46.5, 40.7, 31.4, 29.6, 28.5, 22.0, 20.9, 20.0 ppm;
5
1
3
3
): d=169.6, 169.5, 156.4 136.7,
+
LRMS (ESI): m/z (%): 401 (10) [M +Na], 379 (100); HRMS (MALDI/
DHB): m/z (%) calcd for C20
+
+
30 2 5
H N O Na : 401.2047 [M +Na]; found:
[
[
[
31] M. A. Schmitt, S. H. Choi, I. A. Guzei, S. H. Gellman, J. Am. Chem.
Soc. 2005, 127, 13130–13131.
32] M. A. Schmitt, S. H. Choi, I. A. Guzei, S. H. Gellman, J. Am. Chem.
Soc. 2006, 128, 4538–4539.
33] W. S. Horne, J. L. Price, J. L. Keck, S. H. Gellman, J. Am. Chem.
Soc. 2007, 129, 4178–4180.
4
01.2043.
Acknowledgements
[34] S. H. Choi, I. A. Guzei, S. H. Gellman, J. Am. Chem. Soc. 2007, 129,
3780–13781.
1
This work was supported by The University of Hong Kong, and Hong
Kong Research Grants Council (Project No. 7654/06M and HKU2/06C),
National Nature Science Foundation of China (Project No. 20202001),
and Fok Ying Tung Education Foundation (Project No. 94023). We thank
Prof. M.-J. Zhang and Prof. H.-Z. Sun for advice on NMR studies in
methanol.
[35] M. W. Giuliano, W. S. Horne, S. H. Gellman, J. Am. Chem. Soc.
2009, 131, 9860–9861.
[36] J. L. Matthews, K. Gademann, B. Jaun, D. Seebach, J. Chem. Soc.
Perkin Trans. 1 1998, 3331–3340.
[37] D. Seebach, A. Jacobi, M. Rueping, K. Gademann, M. Ernst, B.
Jaun, Helv. Chim. Acta 2000, 83, 2115–2140.
[
38] D. Seebach, T. Sifferlen, P. A. Mathieu, A. M. Hꢃne, C. M. Krell,
D. J. Bierbaum, S. Abele, Helv. Chim. Acta 2000, 83, 2849–2864.
[
1] W. F. DeGrado, C. M. Summa, V. Pavone, F. Nastri, A. Lombardi,
Annu. Rev. Biochem. 1999, 68, 779–819.
[39] T. Etezady-Esfarjani, C. Hilty, K. Wꢂthrich, M. Rueping, J. Schreib-
er, D. Seebach, Helv. Chim. Acta 2002, 85, 1197–1209.
[40] K. Gademann, A. Hꢃne, M. Rueping, B. Jaun, D. Seebach, Angew.
Chem. 2003, 115, 1573–1575; Angew. Chem. Int. Ed. 2003, 42, 1534–
1537.
[2] B. Imperiali, J. J. Ottesen, J. Pept. Res. 1999, 54, 177–184.
[3] N. C. Price, Biotechnol. Appl. Biochem. 2000, 31, 29–40.
[4] K. H. Lee, Curr. Med. Chem.: Anti-Infect. Agents 2002, 1, 305–318.
[5] J. D. A. Tyndall, B. Pfeiffer, G. Abbenante, D. P. Fairlie, Chem. Rev.
[41] M. Rueping, Y. R. Mahajan, B. Jaun, D. Seebach, Chem. Eur. J.
2004, 10, 1607–1615.
2
005, 105, 793–826.
[
[
6] M. Hong, Acc. Chem. Res. 2006, 39, 176–183.
7] T. L. Pukala, J. H. Bowie, V. M. Maselli, I. F. Musgrave, M. J. Tyler,
Nat. Prod. Rep. 2006, 23, 368–393.
[42] D. Seebach, R. I. Mathad, T. Kimmerlin, Y. R. Mahajan, P. Bind-
schꢃdler, M. Rueping, B. Jaun, C. Hilty, T. Etezady-Esfarjani, Helv.
Chim. Acta 2005, 88, 1969–1982.
1362
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 1356 – 1363

Conformational Studies on Peptides of a-Aminoxy Acids
[
[
[
[
[
[
[
[
43] G. Lelais, D. Seebach, B. Jaun, R. I. Mathad, O. Flçgel, F. Rossi, M.
Campo, A. Wortmann, Helv. Chim. Acta 2006, 89, 361–403.
44] B. W. Gung, D. Zou, A. M. Stalcup, C. E. Cottrell, J. Org. Chem.
[57] J. A. Kritzer, M. E. Hodsdon, A. Schepartz, J. Am. Chem. Soc. 2005,
127, 4118–4119.
[58] O. M. Stephens, S. Kim, B. D. Welch, M. E. Hodsdon, M. S. Kay, A.
Schepartz, J. Am. Chem. Soc. 2005, 127, 13126–13127.
[59] D. Yang, F.-F. Ng, Z.-J. Li, Y.-D. Wu, K. W. K. Chan, D.-P. Wang, J.
Am. Chem. Soc. 1996, 118, 9794–9795.
1
999, 64, 2176–2177.
45] R. P. Cheng, W. F. DeGrado, J. Am. Chem. Soc. 2001, 123, 5162–
163.
5
[
[
[
[
[
[
[
[
[
[
60] D. Yang, J. Qu, B. Li, F.-F. Ng, X.-C. Wang, K.-K. Cheung, D.-P.
Wang, Y.-D. Wu, J. Am. Chem. Soc. 1999, 121, 589–590.
61] D. Yang, B. Li, F.-F. Ng, Y.-L. Yan, J. Qu, Y.-D. Wu, J. Org. Chem.
46] S. A. Hart, A. B. F. Bahadoor, E. E. Matthews, X. Y. J. Qiu, A. Sche-
partz, J. Am. Chem. Soc. 2003, 125, 4022–4023.
47] J. A. Kritzer, J. Tirado-Rives, S. A. Hart, J. D. Lear, W. L. Jorgensen,
A. Schepartz, J. Am. Chem. Soc. 2005, 127, 167–178.
48] D. A. Guarracino, H. R. Chiang, T. N. Banks, J. D. Lear, M. E.
Hodsdon, A. Schepartz, Org. Lett. 2006, 8, 807–810.
49] J. X. Qiu, E. J. Petersson, E. E. Matthews, A. Schepartz, J. Am.
Chem. Soc. 2006, 128, 11338–11339.
2
001, 66, 7303–7312.
62] D. Yang, J. Qu, W. Li, Y.-H. Zhang, Y. Ren, D.-P. Wang, Y.-D. Wu,
J. Am. Chem. Soc. 2002, 124, 12410–12411.
63] D. Yang, J. Qu, W. Li, D.-P. Wang, Y. Ren, Y.-D. Wu, J. Am. Chem.
Soc. 2003, 125, 14452–14457.
64] D. Yang, W. Li, J. Qu, S.-W. Luo, Y.-D. Wu, J. Am. Chem. Soc. 2003,
50] O. Khakshoor, B. Demeler, J. S. Nowick, J. Am. Chem. Soc. 2007,
1
25, 13018–13019.
65] Y.-D. Wu, D.-P. Wang, K. W. K. Chan, D. Yang, J. Am. Chem. Soc.
999, 121, 11189–11196.
66] C. Peter, X. Daura, W. F. van Gunsteren, J. Am. Chem. Soc. 2000,
22, 7461–7466.
67] D. Yang, X. Li, Y.-F. Fan, D.-W. Zhang, J. Am. Chem. Soc. 2005,
27, 7996–7997.
68] D. Yang, X. Li, Y. Sha, Y.-D. Wu, Chem. Eur. J. 2005, 11, 3005–
009.
1
29, 5558–5569.
[
[
51] J. A. Patch, A. E. Barron, Curr. Opin. Chem. Biol. 2002, 6, 872–877.
52] P. I. Arvidsson, N. S. Ryder, H. M. Weiss, G. Gross, O. Kretz, R.
Woessner, D. Seebach, ChemBioChem 2003, 4, 1345–1347.
1
1
[
[
[
[
53] M. A. Schmitt, B. Weisblum, S. H. Gellman, J. Am. Chem. Soc. 2004,
1
26, 6848–6849.
54] T. B. Potocky, A. K. Menon, S. H. Gellman, J. Am. Chem. Soc. 2005,
27, 3686–3687.
55] B. Geueke, K. Namoto, I. Agarkova, J. C. Perriard, H. P. Kohler, D.
Seebach, ChemBioChem 2005, 6, 982–985.
56] A. Glꢃttli, X. Daura, P. Bindschꢃdler, B. Jaun, Y. R. Mahajan, R. I.
Mathad, M. Rueping, D. Seebach, W. F. van Gunsteren, Chem. Eur.
J. 2005, 11, 7276–7293.
1
1
3
69] G. V. M. Sharma, V. Manohar, S. K. Dutta, V. Subash, A. C.
Kunwar, J. Org. Chem. 2008, 73, 3689–3698.
Received: November 11, 2009
Published online: April 20, 2010
Chem. Asian J. 2010, 5, 1356 – 1363
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1363