β N-O turns and helices induced by β2-aminoxy peptides: Synthesis and conformational studies

Article abstract of DOI:10.1002/asia.201000933

Herein, we report an efficient route for the asymmetric synthesis of β²-aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of β²-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, β N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral β N-O turns leads to the formation of β N-O helical structures in solution, although both helical (composed of two β N-O turns of the same handedness) and reverse-turn (composed of two β N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of β²-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies.

Full text of DOI:10.1002/asia.201000933

DOI: 10.1002/asia.201000933
2
ꢀ
b N O Turns and Helices Induced by b -Aminoxy Peptides: Synthesis and
Conformational Studies
Zhi-Gang Jiao,[a] Xiao-Wei Chang,[a] Wei Ding,[a] Guo-Jun Liu,[a] Ke-Sheng Song,[b]
Nian-Yong Zhu,[b] Dan-Wei Zhang,*[a] and Dan Yang*[a, b]
On the occasion of the 150th anniversary of the Department of Chemistry, The University of Tokyo
ꢀ
ꢀ
Abstract: Herein, we report an effi-
cient route for the asymmetric synthe-
sis of b2-aminoxy acids as well as exper-
imental and theoretical studies of con-
formations of peptides composed of b2-
aminoxy acids. The nine-membered-
ring intramolecular hydrogen bonds,
consecutive homochiral b N O turns
verse-turn (composed of two b N O
ꢀ
leads to the formation of b N O heli-
turns with opposite handedness) struc-
tures are of similar stability, as suggest-
ed by theoretical studies. Nevertheless,
two slightly different conformations,
with the same handedness, of b2-amino-
xy monomers have been observed in
the solid state and in solution accord-
ing to our X-ray and 2D NOESY stud-
ies.
cal structures in solution, although
both helical (composed of two b N O
turns of the same handedness) and re-
ꢀ
Keywords: asymmetric synthesis ·
density functional calculations
hydrogen bonds · peptides · struc-
ꢀ
namely, b N O turns, are generated
·
between adjacent residues in those
peptides, in accordance with our com-
putational results. The presence of two
ture elucidation
Introduction
Aminoxy peptides, a family of peptidomimetic foldamers,
have been found to possess strong intramolecular hydrogen
bonds between adjacent residues and adopt predictable and
well-defined secondary structures.[6–9] For example, a-amino-
xy peptides, analogues of b peptides in which the b carbon is
Over the past decade, intensive research efforts have been
focused on developing new foldamers to obtain predictable,
specific, and stable conformations.[1] It is known that pepti-
domimetic foldamers, such as b,[2] g,[3] and d peptides,[4] have
the capability of adopting secondary, tertiary, and quaterna-
ry structures similar to those found in natural a peptides,
even within very short sequences. Moreover, many remark-
able biological activities have also been discovered through
the design and synthesis of peptidomimetic foldamers.[5]
ꢀ
replaced by an oxygen atom, adopt novel a N O turn struc-
tures involving eight-membered-ring intramolecular hydro-
gen bonds;[7] b-aminoxy peptides, analogues of g peptides,
can form nine-membered-ring intramolecular hydrogen
ꢀ
bonds (b N O turns) and six-membered-ring bifurcated in-
tramolecular hydrogen bonds;[8] g-aminoxy peptides can
ꢀ
induce g N O turns involving ten-membered-ring intramo-
lecular hydrogen bonds.[9] We also found that a small con-
necting loop could be created by disulfide-bridged dimers
when the oxygen atom of an aminoxy amide group was sub-
stituted by a sulfur atom.[10]
[a] Z.-G. Jiao, Dr. X.-W. Chang, W. Ding, Dr. G.-J. Liu,
Prof. Dr. D.-W. Zhang, Prof. Dr. D. Yang
Department of Chemistry
Fudan University
Shanghai 200433 (P.R. China)
Fax : (+8621) 65641740
Fax : (+852) 28571586
E-mail: zhangdw@fudan.edu.cn
yangdan@hku.hk
While oligomers consisting of consecutive a-, b-, or g-ami-
noxy acids can form helical structures (that is, N O helices),
ꢀ
reverse turns, sheets, and ribbon-like secondary structur-
es,[7c–f,8] the hybrid peptides containing alternating a-amino
acids and a-aminoxy acids can induce 7/8 helices, and some
peptides containing b-amino acids and a-aminoxy acids
induce 12/10 helices.[11]
[b] Dr. K.-S. Song, Dr. N.-Y. Zhu, Prof. Dr. D. Yang
Department of Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Previously, the synthesis and conformational studies of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000933.
several subclasses of b-aminoxy peptides, such as b3-, b2,2-,
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FULL PAPERS
and b2,3-aminoxy peptides, have been reported by our
group.[8] To enrich the category of b-aminoxy peptides,
herein we report the asymmetric synthesis of b2-aminoxy
peptides and detailed conformational analyses of these pep-
tides by using both experimental and theoretical ap-
proaches.
a mild esterification reagent, tert-butyl trichloroacetimidate,
to avoid racemization of the substrates 4a and 4b.[15,16] The
Mitsunobu reaction afforded the intermediates 11a and 11b
in moderate yields.
After selective protection of 11a at the C and N terminus,
respectively, we obtained compounds 7a and 12 (Scheme 3).
Then, dipeptide 13 was pre-
pared after a coupling reaction
between 7a and 12 in low yield
(27%), along with monomer 8a
(22% yield). As shown in
Scheme 4, monomer 8a was
likely to be produced by the re-
action of amine C, obtained
from N-terminal deprotection
of 7a, with (S)-4-methyl-2-piva-
loylisoxazolidin-3-one
(B),
which was produced from intra-
molecular cyclization of C-ter-
Results and Discussion
Synthesis of b2-Aminoxy
peptides
Scheme 1 gives the synthetic
route of monomers 8a and 8b.
First, we induced a chiral center
a to the carbonyl group by em-
ploying the Evans chiral auxili-
ary.[12] After removal of the
Evans auxiliary,[13] we construct-
ed the amide bond, deprotected
the benzyl ether, and intro-
duced the aminoxy group by
the Mitsunobu reaction[14] be-
tween 6a or 6b and N-hydrox-
yphthalimide. Finally, the de-
sired b2-aminoxy monomers 8a
and 8b were obtained in 32 and
51% overall yields from 6a and
6b, respectively.
Compounds 11a and 11b are
important intermediates for the
preparation of the dipeptides.
A general synthetic route for
the dipeptides is shown in
Scheme 2. We prepared tert-
butyl esters 9a and 9b by using
Scheme 1. Synthesis of b2-aminoxy monomers 8a and 8b. Reagents and conditions: a) NaH, propionyl chlo-
ride, THF, RT, overnight; or DCC, DMAP, 3-methylbutanoic acid, CH2Cl2, RT, overnight; b) TiCl4, DIPEA,
CH2Cl2, BnOCH2Cl, ꢀ58C, 6 h; c) LiOH·H2O, H2O2, THF, H2O, 0 8C, 3 h; d) isobutylamine, EDCI, HOBt,
CH2Cl2, RT, overnight; e) 10% Pd/C, H2, MeOH, RT, 2 h; f) N-hydroxyphthalimide, DEAD, PPh3, THF, 08C,
1 h, then RT, 4 h; g) NH2NH2·H2O, MeOH, RT, 3 h; h) PivCl, TEA, CH2Cl2, RT, 3 h. (Bn=benzyl, DCC=di-
cyclohexylcarbodiimide, DMAP=4-di(methylamino) pyridine, DIPEA=N,N-diisopropylethylamine, EDCI=
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methyl hydrochloride, HOBt=1-hydroxybenzotriazole,
DEAD=diethyl azodicarboxylate, PivCl=pivaloyl chloride, TEA=triethylamine, THF=tetrahydrofuran.)
minal-activated compound A because of the strong acidity
of its C-terminal aminoxy amide proton.
To avoid the generation of the monomer 8b, we employed
7b and N-terminal phthalimide-protected compound 11b as
precursors and found that the isolated yield of compound 14
was improved to 48%, and the desired product 15 was ob-
tained in 53% yield over two steps (Scheme 5).
Abstract in Chinese:
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Chem. Asian J. 2011, 6, 1791 – 1799

D.-W. Zhang, D. Yang et al.
tinely utilized to probe the for-
mation of intramolecular hy-
drogen bonds. There are dra-
matic chemical shift changes,
with respect to peptide concen-
tration and the amount of
[D6]DMSO added, for the sol-
vent-accessible NH protons, but
not for those solvent-inaccessi-
ble NH protons. We have used
these methods to study the con-
formations of the oligopeptides
of b2-aminoxy acids and the re-
sults are listed in Table 1. The
chemical shifts of the aminoxy
amide NHa protons of these
compounds at a concentration
of 1.56 mm were located consid-
Scheme 2. Synthesis of key intermediates 11a and 11b. Reagents and conditions: a) tert-butyl trichloroacetimi-
date, CH2Cl2, RT, overnight; b) 10% Pd/C, H2, MeOH, RT, 2 h; c) N-hydroxyphthalimide, DIAD, PPh3, THF,
08C, overnight. (DIAD=diisopropyl azodicarboxylate)
Scheme 3. Synthesis of b2-aminoxy dipeptide 13. Reagents and conditions: a) NH2NH2·H2O, MeOH, RT, 3 h;
b) PivCl, TEA, CH2Cl2, RT, 3 h, 53% in two steps; c) TFA, CH2Cl2, RT, 2 h; d) EDCI, HOAt, CH2Cl2, isobu-
tylamine, RT, overnight, 36% in two steps; e) EDCI, HOAt, TEA, CH2Cl2, RT, overnight; 27% yield for 13
and 22% yield for 8a over three steps. (HOAt=1-hydroxyazabenzotriazole, TFA=trifluoroacetic acid,
TEA=triethylamine.)
erably
upfield
(d=8.52–
8.63 ppm), with relatively large
chemical shift changes in both
1
the H NMR spectroscopic dilu-
tion
and
(Dddilut =0.76–1.80 ppm)
[D6]DMSO addition
(DdDMSO =1.59–2.16 ppm) stud-
ies, suggesting that these pro-
tons were not involved in intra-
molecular hydrogen bonds.
The chemical shifts of the
amide NHb protons of 8a and
8b and NHc protons of 13 and
15 were located downfield (d=
7.52, 6.91, and 7.96, 7.67 ppm,
respectively) and exhibited rel-
atively small changes in the
Scheme 4. Proposed mechanism for the generation of side product 8a during the preparation of dipeptide 13.
Table 1. Chemical shifts (dNH) and chemical shift changes (DdNH) of
1
amide protons in H NMR spectroscopic dilution (Dddilut) and [D6]DMSO
addition (DdDMSO) studies of peptides 8a, 8b, 13, and 15 at RT[a]
NHa [ppm]
NHb [ppm]
NHc [ppm]
d
Dddilut DdDMSO
d
Dddilut DdDMSO
d
Dddilut DdDMSO
8a 8.52 0.76
8b 8.61 0.84
13 8.57 1.79
15 8.63 1.80
1.78
1.59
2.16
2.07
7.52 0.36
6.91 0.45
11.52 0.43
11.08 0.48
0.64
0.84
0.29
0.31
7.96 0.21
7.67 0.26
0.07
0.13
[a] The d value refers to the chemical shift of the amide NH proton ob-
tained from the 1H NMR spectrum of the indicated compound at a con-
centration of 1.56 mm in CDCl3. The value of Dddilut in the dilution stud-
ies was calculated by using the equation Dddilute =dNH (200 mm)ꢀdNH
(1.56 mm). The value of DdDMSO in the [D6]DMSO addition studies was
calculated by using the equation DdDMSO =dNH (9% [D6]DMSO in 5 mm
in CDCl3)ꢀdNH (5 mm in CDCl3). The chemical shifts of aminoxy amide
NH protons are given in italics.
Scheme 5. Synthesis of b2-aminoxy dipeptide 15. Reagents and condi-
tions: a) TFA, CH2Cl2, RT, 2 h; b) EDCI, HOBt, isobutylamine, CH2Cl2,
08C, overnight, 75% in two steps; c) NH2NH2·H2O, MeOH, RT, 3 h;
d) EDCI, HOBt, CH2Cl2, RT, overnight, 48% over three steps; e) PivCl,
NaHCO3, CH2Cl2, H2O, RT, 3 h, 53% over two steps.
Conformational Studies of b2-Aminoxy Peptides
1H NMR spectroscopic dilution (Dddilut <0.5 ppm) and
[D6]DMSO addition (DdDMSO <0.9 ppm) studies. These facts
suggest that these amide protons contribute to the formation
of the nine-membered-ring intramolecular hydrogen bonds
1H NMR Spectroscopic Studies of b2-Aminoxy Peptides
The 1H NMR spectroscopic dilution[18] and [D6]DMSO
(DMSO=dimethylsulfoxide) addition[19] methods are rou-
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ꢀ
b N O Turns and Helices Induced by b -Aminoxy Peptides
FULL PAPERS
between C=Oi and NHi+2 groups, that is, forming b N O
turns. Moreover, the chemical shifts of the aminoxy amide
NHb protons of 13 (d=11.52 ppm) and 15 (d=11.08 ppm)
were located more downfield than those of NHa protons,
IR Spectroscopic Studies of b2-Aminoxy Peptides
ꢀ
ꢀ
The amide N H stretching region of peptides in IR spectra
provides valuable information on whether the amide proton
1
ꢀ
and the chemical shift changes in the H NMR spectroscopic
is involved in hydrogen bonding or not. The N H stretching
dilution and [D6]DMSO addition studies were less than 0.5
and 0.4 ppm, respectively. The results suggest that the ami-
noxy amide NHb protons in 13 and 15 are also involved in
strong intramolecular hydrogen bonds, which are likely to
be the nine-membered-ring intramolecular hydrogen bonds
regions of 8a, 8b, 13, and 15 in the FTIR spectra are illus-
trated in Figure 1. The spectra for these samples were re-
corded in dichloromethane at the diluted concentration of
2 mm, at which intermolecular hydrogen bonding was un-
likely to occur. For monomers 8a and 8b, two main sets of
signals were assigned, according to our previous studies,[7a,d]
ꢀ
between C=Oi and NHi+2 groups, namely, b N O turns. As
ꢀ
ꢀ
a result, there are two consecutive b N O turns in dipepti-
to the stretching frequencies of the free aminoxy amide N
des 13 and 15.
Ha (3416 (8a) and 3422 cmꢀ1
G
ꢀ1
ꢀ
Compared with the absolute chemical shift values of NHb
protons of 8a and 8b, and NHc protons of 13 and 15, we
found that the intramolecular hydrogen bond was enhanced
when the peptide was enlongated from the monomer to the
dipeptide, thereby indicating that the formation of consecu-
tive nine-membered-ring intramolecular hydrogen bonds
was a cooperative process.
regular amide N Hb (3320 (8a) and 3322 cm (8b)) bonds.
The presence of major hydrogen-bonded amide NHb bands
in 8a and 8b indicated that the conformations with nine-
membered-ring intramolecular hydrogen bonds were pre-
dominant. As for dipeptides 13 and 15, aside from the two
types of signals described above, there was a new signal at
3202 and 3208 cmꢀ1, respectively, assigned to the hydrogen-
ꢀ
bonded aminoxy amide N Hb stretch. These results of FTIR
spectroscopic studies were consistent with those from
ꢀ
Figure 1. N H stretching regions of the FTIR spectra of a) 8a, b) 8b, c) 13, and d) 15 (2 mm in CH2Cl2) at RT (after subtraction of the spectrum of pure
CH2Cl2).
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D.-W. Zhang, D. Yang et al.
1H NMR spectroscopic studies, that is, NHb and NHc pro-
tons formed strong intramolecular hydrogen bonds, whereas
NHa protons did not.
Table 2. Torsional angles of 16a–d optimized by using the B3LYP/6-31G
(d,p) level of theory.
Conformer
f [8]
q [8]
f [8]
y [8]
95.4
ꢀ78.2
ꢀ11.8
5.4
aOCbCaCMe [8]
16a
16b
16c
16d
111.7
ꢀ122.1
101.6
ꢀ99.1
ꢀ83.1
ꢀ68.5
61.0
71.6
ꢀ68.7
170.0
ꢀ70.7
ꢀ57.4
166.4
Theoretical Calculations
89.7
ꢀ170.5
171.3
To further understand the conformational features of the b2-
aminoxy peptides, theoretical calculations on the model
compounds 16–19 were performed by using the Gaussian 03
former 16a, and conformer 16c
had a similar stability to 16d.
Conformers 16e and 16 f
were left- and right-handed
turns, respectively, with seven-
membered-ring hydrogen bonds
(Figure 2a). The torsional angle
f was ꢀ56.1 and 76.48, respec-
ꢀ
software package.[20] All of the molecules were fully opti-
tively, indicating that, in both of them, the Ca CCO bond
ꢀ
mized by the B3LYP/6-311+G
N
was gauche to the Cb O bond. Both conformers 16e and
striction. Harmonic vibration frequency calculations were
also performed to ensure each structure was a minimum by
16 f were much less stable than conformer 16a. Conformer
16g was an extended conformation with torsional angles q=
176.38 (anti) and f=ꢀ172.88 (anti), and was also much less
stable than conformer 16a.
using the B3LYP/6-311+G
uated by MP2/6-311+G(d,p) calculations on B3LYP/6-
311+G(d,p) geometries. The solvent effect in dichlorome-
ACHTUNGTRNE(NUNG d,p) method. Energies were eval-
AHCTUNGTRENNUNG
N
These results revealed that the (R)-b2-methyl-substituted
aminoxy acid induced a nine-membered-ring intramolecular
hydrogen bond in the peptide backbone. The left- and right-
handed turns had similar stabilities. The left-handed turn in
structure 16a with torsional angle q=ꢀ83.18 (gauche) was
more stable than that of 16c, whereas the right-handed turn
in structure 16d with torsional angle q=171.38 (anti) was
more stable than that of 16b.
thane was evaluated by the polarizable continuum model
(PCM). The relative free energies of conformers were calcu-
lated based on the MP2/6-311+GACTHNUGTRNEUNG(d,p) energies with ther-
mal, entropic, and solvent energy corrections [Eq. (1)].
DG ¼ DE ðMP2Þþ½DE ðB3LYP, solventÞꢀDE ðB3LYP, gasÞꢁ
þenthalpy correctionsꢀTDS
Figure 2b displays the three most-stable nine-membered-
ring hydrogen-bonded turn structures of compound 17,
which was derived from those of compound 16 by replacing
the methyl side chain with an isopropyl group. Conformers
17a and 17b, which were derived from 16a and 16c, respec-
tively, exhibited a left-handed turn and 17b was less stable
than 17a. Conformer 17c, derived from 16d, showed a
right-handed turn and was much less stable than 17a and
17b due to repulsion between the bulky isopropyl side chain
and the carbonyl group of the backbone. The distance be-
tween the hydrogen atom of the isopropyl group and the
oxygen atom of the carbonyl group was 2.75, 2.65, and
2.46 ꢁ in 17a–c, respectively. One notable change was that
the calculated free energy difference between 17a and 17c
was about 2.7 kcalmolꢀ1 in dichloromethane, whereas the
corresponding energy difference between 16a and 16d was
negligible in dichloromethane. These results indicated that
the side chain had a dramatic influence on the conforma-
tional stability and the (R)-b2-isopropyl-substituted aminoxy
acid had a strong tendency to form a left-handed nine-mem-
bered-ring intramolecular hydrogen bond.
ð1Þ
The stable conformers and relative energies of (R)-b2-ami-
noxy peptide 16 are displayed in Figure 2a.[17] The nine-
membered-ring intramolecular hydrogen bonds were found
in conformers 16a–d, of which 16a was the most stable one
(hydrogen-bond length was 1.99 ꢁ, hydrogen-bond angle
was 168.58). The torsional angle, f, of conformers 16a and
16c were 111.7 and 101.68, respectively, thus indicating a
left-handed turn, whereas conformers 16b and 16d adopted
a right-handed turn (f=ꢀ122.1 and ꢀ99.18, respectively)
(Table 2). The torsional angles f in conformers 16a–d con-
ꢀ
ꢀ
firmed that the Cb O bond was gauche to the Ca
CCO. The
ꢀ
ꢀ
N O bond was gauche to the Cb Ca bond in conformers
ꢀ
16a and 16b. The methyl side chain was anti to Cb O bond
in conformer 16a, but gauche to the Cb O bond in confor-
mer 16b. For conformers 16c and 16d, the N O bond was
anti to the Cb Ca bond; the methyl side chain was gauche to
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
O
the Cb O bond in conformer 16c, but anti to the Cb
bond in conformer 16d. As a result, conformer 16b suffered
from severe steric interactions and it was the least-stable
conformation of the four conformers 16a–d. The torsional
angles q were ꢀ170.5 and 171.38 in conformer 16c and 16d,
respectively, indicating a longer hydrogen-bond length and
worse hydrogen-bond angle than those in conformer 16a.
Thus, conformers 16c and 16d were slightly stable than con-
Then, it is interesting to know whether homo- or hetero-
chiral b N O turns are preferred for dipeptides. The five
most-stable conformations of model dipeptide 18 are shown
in Figure 2c. Conformer 18a was the most stable one with
ꢀ
ꢀ
two most-stable contiguous left-handed b N O turn units
(two consecutive 16a-like units). Thus, conformer 18a
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ꢀ
b N O Turns and Helices Induced by b -Aminoxy Peptides
FULL PAPERS
monomer 8a. Conformers 18b and 18c also adopted helical
structures, although they were less stable than 18a because
ꢀ
of the presence of one less-stable b N O turn unit (16c-like
unit) at the C and N terminus, respectively. Similarly, con-
formers 18d (a 16a-like unit followed by a 16d-like unit)
and 18e (a 16d-like unit followed by a 16a-like unit) were
also less stable than 18a. Because 16a was a left-handed
turn, whereas 16d was right-handed turn, conformers 18d
and 18e were reverse-turn structures. These results showed
that the (R)-b2-methyl-substituted aminoxy dipeptide fa-
vored a helical structure with two left-handed nine-mem-
bered-ring turn units (two 16a-like units).
Figure 2d displays the five most-stable conformations of
model dipeptide 19 with the isopropyl side chain. Confor-
mer 19a was the most-stable one in vacuum with two con-
secutive most-stable left-handed units (two 17a-like units),
but conformer 19c was found to be the most-stable confor-
mation in CH2Cl2 with a less stable 17b-like unit followed
by a 17a-like unit. The length of the hydrogen bond of the
17b-like unit in dipeptide 19c was 2.04 ꢁ with hydrogen
bond angles of 155.88, which were better than those of 17b
due to stronger acidity of the hydrogen-bond-donor amino-
xy NH proton. Conformers 19a and 19c adopted a helical
ꢀ
structure, namely, a b N O helix. Again the results of the
calculation indicated that a cooperative process existed in
the dipeptide.
X-ray Analysis of b2-Aminoxy Peptides
Single crystals of 8a were employed for structural analy-
sis.[21] As shown in Figure 3, the X-ray structure of 8a indi-
ꢀ
cated that it adopted a right-handed b N O turn structure,
which was characterized by a nine-membered-ring hydrogen
bond between C=Oi and NHi+2, which was stabilized simul-
taneously by another six-membered-ring hydrogen bond be-
tween the NOi+1 and NHi+2 units. The hydrogen-bond
length between the C=Oi and NHi+2 units was 2.18 ꢁ, and
ꢀ
the hydrogen bond angle of aNHbO was 162.78. The N O
ꢀ
bond was anti to the Cb Ca bond with the dihedral angle
aNOCaCb of 171.28, and the existence of dihedral angles
aOCbCaCO of ꢀ68.48 and aOCbCaCMe of 59.68 indicated
ꢀ
that both the methyl side chain and Ca CCO bond were
ꢀ
gauche to the Cb O bond.
Figure 2. Calculated stable conformers of model compounds a) 16, b) 17,
c) 18, and d) 19. The calculated relative free energies [kcalmolꢀ1] in
ꢀ
CH2Cl2 and in the gas phase (in parentheses), N H···O hydrogen bond
lengths, and bond angles are shown.
ꢀ
adopted a helical structure, referred to as a b N O helix. It
was interesting that the lengths of the hydrogen bonds of
ꢀ
two N O turns of 18a were 1.92 and 1.95 ꢁ, with hydrogen-
bond angles of 164.8 and 170.78, respectively, which were
better than those of 16a. The results of the calculation sug-
gest that the formation of the two nine-membered-ring hy-
drogen bonds in 18 was a cooperative process, in good
agreement with the experimental observation that dipeptide
13 formed stronger intramolecular hydrogen bonds than
Figure 3. X-ray structure of 8a.
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D.-W. Zhang, D. Yang et al.
Table 3. The torsion angles of 8a in the X-ray structure.
f [8]
q [8]
f [8]
y [8]
aOCbCaCMe [8]
8a
89.3
171.2
ꢀ68.4
4.0
59.6
By comparison of the X-ray structure of 8a (Tables 3 and
4) with the calculated conformers of model compound 16
(Table 2), we found that 8a was similar to the calculated
stable conformer 16c.
Figure 4. Summary of the NOEs observed (s, strong NOE; m, medium
NOE; w, weak NOE) in the NOESY spectra of monomers 8a and 8b
(5 mm in CDCl3 at RT).
Table 4. The distances [ꢁ] of selected pairs of hydrogen atoms of 8a,
16a, 16b, 16c, and 16d.
8a
16a
16b
16c
16d
CbHi and NHi was stronger than that between CbHi and
(solid state)
NHi+1, and a strong NOE between CaHi and NH
also ex-
[a]
[a]
i+1
Ha···HS
3.05
2.75
4.72
3.22
2.26
3.43
2.79
3.65
3.75
2.25
4.10
3.77
3.57
2.74
4.83
3.62
3.59
3.93
3.35
3.03
5.05
3.47
2.35
3.61
3.04
3.37
4.32
3.28
3.58
2.30
ꢀ
isted. The results suggest that the N O bond was gauche to
Ha···HR
Ha···Ha
Hb···Ha
ꢀ
ꢀ
O
the Cb Ca bond and the side chain was anti to the Cb
bond. The NOE patterns of 13 and 15 in solution matched
well with the most-stable calculated conformers 18a and
19a, respectively; this indicates that both dipeptides 13 and
[a]
Hb···HS
Hb···HR
[a]
[a] HS indicates the pro-S configuration proton, whereas HR indicates the
pro-R configuration proton.
ꢀ
15 adopted a right-handed b N O helix structure in solu-
tion.
2D NOESY Studies of b2-
Aminoxy Peptides
The 2D NOESY spectroscopic
technique was employed to
study conformations of mono-
mers 8a and 8b, as well as di-
peptides 13 and 15 in solution.
All of the 2D NMR spectrosco-
py experiments were performed
by using 5 mm solutions in deu-
Figure 5. Summary of the NOEs observed (s, strong NOE; m, medium NOE; w, weak NOE) in the NOESY
spectra of dipeptides 13 and 15 (5 mm in CDCl3 at RT).
terated chloroform at room
temperature. The observed
NOEs of monomers 8a and 8b
Circular dichroism (CD) Studies of b2-Aminoxy Peptides
are summarized in Figure 4. Monomers 8a and 8b exhibited
the same NOE pattern: the NOE signal between NHa and
CbH was stronger than that between NHb and CbH, and the
NOE signal between NHb and CaH was the strongest. Thus,
monomers 8a and 8b adopted similar secondary structures
in deuterated chloroform. By comparison of the data in
Table 4, we found that the distances between CbH and NH
and that between CaH and NH in the X-ray structure of 8a
did not match with the NOE pattern observed in solution.
Instead, the distances between CbH and NH and that be-
tween CaH and NH in conformer 16a matched well with the
CD spectroscopy has been employed successfully to charac-
terize the secondary structures of natural peptides[1a,22] and
unnatural peptides, such as b peptides[1b,5f,p,23] and aminoxy
peptides.[7–9] We also applied CD spectroscopy to probe the
conformations of the homochiral oligomers of b2-aminoxy
peptides. In Figure 6 the CD spectra of 8a, 8b, 13, and 15
recorded in trifluoroethanol (TFE) at room temperature are
presented and these CD signals have been normalized for
ꢀ
the concentration and number of backbone b N O turns of
each compound. A unique absorption was observed with the
negative maximum at around 199 nm in the CD spectra of
monomers 8a and 8b as well as dipeptides 13 and 15 in
TFE. The similar shapes and intensities of 8a and 8b in
ꢀ
NOE pattern observed for 8a in solution. Therefore, the N
ꢀ
O bond was anti to the Cb Ca bond for 8a in the solid state,
but gauche in solution. This discrepancy indicated that the
molecule might adopt different conformations in solution
and in the solid state, possibly due to crystal packing. Never-
ꢀ
TFE indicated that they adopted a very similar b N O turn
structure. Dipeptide 13 also exhibited a similar shape and
intensity to that of 8a in TFE, thus it formed two consecu-
ꢀ
theless, both b N O turns adopted by 8a in solution as well
ꢀ
ꢀ
as in the solid state were right-handed.
tive b N O turns with similar intensity, that is, a b N O
helix. However, the CD intensity of dipeptide 15 was
weaker than the others, probably due to the presence of two
As shown in Figure 5, we also observed similar NOE pat-
terns for dipeptides 13 and 15. Each b2-aminoxy acid resi-
dues of 13 and 15 adopted a conformation similar to 16a
and 17a, respectively. The NOE signal between protons
ꢀ
different b N O turns, as suggested by the medium NOE
ꢀ
signal in the C-terminal b N O turn observed in the 2D
Chem. Asian J. 2011, 6, 1791 – 1799
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1797

2
ꢀ
b N O Turns and Helices Induced by b -Aminoxy Peptides
FULL PAPERS
Characterization of Compounds 8a, 8b, 13, and 15
Compound 8a: Oil; Rf =0.61 (EtOAc), ½aꢁ2D0 =ꢀ24.78 (c=1.0, CHCl3);
1H NMR (400 MHz, CDCl3): d=8.97 (brs, 1H), 7.66 (brm, 1H), 3.97 (t,
J=9.7 Hz, 1H), 3.85 (dd, J=10.1, 3.4 Hz, 1H), 3.17–3.07 (m, 2H), 2.67–
2.59 (m, 1H), 1.89–1.79 (m, 1H), 1.22 (s, 9H), 1.14 (d, J=7.2 Hz, 3H),
0.92 ppm (d, J=6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=177.2,
173.9, 78.4, 46.9, 39.5, 37.9, 28.3, 27.1, 20.1, 13.8 ppm; IR (CH2Cl2): n˜ =
3416, 3320, 1676, 1664 cmꢀ1; EIMS (20 eV): m/z (%): 142 (100), 186 (57),
258 (8) [M+]; HRMS (EI): m/z calcd for C13H26N2O3: 258.1943 [M+];
found: 258.1941.
Compound 8b: Oil; Rf =0.45 (EtOAc/hexane=1:1), ½aꢁ2D0 =ꢀ20.38 (c=
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.84 (s, 1H), 6.99 (brm,
1H), 4.10–4.01 (m, 2H), 3.19–3.08 (m, 2H), 2.23 (dt, J=7.6, 3.6 Hz, 1H),
2.12–2.07 (m, 1H), 1.86–1.80 (m, 1H), 1.21 (s, 9H), 0.97 (d, J=6.9 Hz,
3H), 0.95 (d, J=6.4 Hz, 3H), 0.92 ppm (d, J=6.9 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=176.8, 173.8, 75.4, 52.6, 47.1, 37.9, 28.5, 27.9, 27.2,
21.1, 20.3, 19.9 ppm; IR (CH2Cl2): n˜ =3422, 3322, 1671 cmꢀ1 (br); EIMS
(20 eV): m/z (%): 128 (96), 170 (100), 214 (65), 286 (14) [M+];
HRMS(EI): m/z calcd for C15H30N2O3: 286.2256 [M+]; found: 286.2248.
Figure 6. CD spectra of 0.4 mm solutions of 8a, 8b, 13, and 15 in 2,2,2-tri-
fluoroethanol (TFE) at RT.
Compound 13: Oil; Rf =0.60 (acetone/CH2Cl2 =1:1), ½aꢁ2D0 =ꢀ56.48 (c=
0.25, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=11.67 (s, 1H), 9.22 (brs,
1H), 8.03 (brs, 1H), 4.04 (t, J=10.2 Hz, 1H), 3.93 (t, J=10.0 Hz, 1H),
3.89–3.82 (m, 2H), 3.20–3.02 (m, 2H), 2.73–2.60 (m, 2H), 1.88–1.80 (m,
1H), 1.24 (s, 9H), 1.17 (d, J=7.2 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H),
0.91 ppm (d, J=6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=178.3,
174.7, 172.0, 78.2, 76.9, 47.1, 39.0, 37.7, 37.3, 28.4, 27.1, 20.2, 20.1, 13.6,
13.3; IR (CH2Cl2): n˜ =3401, 3306, 3202, 1665 cmꢀ1 (br); EIMS (20 eV):
m/z (%): 142 (100), 174 (73), 186 (31), 243 (19), 360 (7) [M++H]; HRMS
(EI): m/z calcd for C17H33N3O5: 359.2420 [M+]; found: 359.2417.
NOESY spectrum of 15. Moreover, the CD curves of 8a,
8b, 13, and 15 changed little when the concentration was in-
creased from 0.4 to 1 mm, which indicated that there was no
aggregation.[17]
Conclusion
Compound 15: Oil; Rf =0.55 (MeOH/CH2Cl2 =1:10), ½aꢁ2D0 =ꢀ67.48 (c=
0.5, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=11.24 (s, 1H), 9.23 (s, 1H),
7.74 (brs, 1H), 4.14 (t, J=10.2 Hz, 1H), 4.06–4.02 (m, 2H), 3.95 (dd, J=
9.8, 2.7 Hz, 1H), 3.14–3.11 (m, 2H), 2.35–2.30 (m, 1H), 2.28–2.17 (m,
2H), 2.15–2.07 (m, 1H), 1.89–1.81 (m, 1H), 1.24 (s, 9H), 1.00 (d, J=
6.5 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.6 Hz, 6H), 0.91 ppm
(d, J=6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=178.0, 173.9, 171.5,
75.6, 74.3, 52.1, 49.6, 47.1, 28.4, 27.5, 27.2, 21.1, 20.8, 20.3, 20.2, 19.9,
19.5 ppm; IR (CH2Cl2): n˜ =3393, 3310, 3205, 1665 cmꢀ1 (br) ; EIMS
We have presented the asymmetric synthesis and conforma-
tional studies of b2-aminoxy peptides; a new subclass of b-
aminoxy peptides. On the basis of experimental studies and
theoretical calculations for b2-aminoxy peptides, we found
that b2-aminoxy peptides possessed nine-membered-ring in-
tramolecular hydrogen bonds between adjacent residues,
2
ꢀ
that is, b N O turns. Moreover, b -aminoxy peptides dis-
(20 eV): m/z (%): 130 (63), 170 (100), 202 (88), 299 (19), 416 (14) [M+
+
played slightly different conformations in the solid state and
H]; HRMS (EI): m/z calcd for C21H41N3O5: 415.3046 [M+]; found:
ꢀ
in solution. In the solid state, the N O bond was anti to the
415.3027.
ꢀ
Cb Ca bond, and the methyl side chain was gauche to the
ꢀ
ꢀ
Cb O bond. In solution, the N O bond was gauche to the
Cb Ca bond and the methyl side chain was anti to the Cb
bond. The presence of two consecutive homochiral nine-
ꢀ
ꢀ
O
Acknowledgements
membered-ring intramolecular hydrogen bonds resulted in
This work was supported by Fudan University, the National Natural Sci-
ence Foundation of China (project no. 20202001), the Fok Ying Tung
Education Foundation (project no. 94023), the HKU-Fudan Joint Labo-
ratory on Molecular Design and Synthesis, and the Research Grants
Council of Hong Kong (project no. HKU 7654/06M). D.-W.Z. would like
to thank Fudan University for the conferment of the Century Star
Award.
ꢀ
the formation of a helical structure, that is, b N O helix.
These studies have provided better understanding of the
folding of peptides containing b2-aminoxy acids and also af-
forded a type of new scaffold for protein mimics.
Experimental Section
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General Methods
All reagents and solvents used for the reactions were of analytical grade
and were dried and distilled where necessary. Melting points were deter-
mined with a Shenguang WPS-2 microscope and the values were uncor-
rected. Optical rotations were measured with a Perkin–Elmer 341MC po-
larimeter. NMR spectra were recorded on Jeol ECA-400 or Bruker
Avance DPX 400 and 500 MHz Fourier-transform spectrometers. IR ab-
sorption spectra were recorded on a Bio-Rad FTS 165 Fourier-transform
spectrophotometer as thin films, unless otherwise noted. Mass spectra
were recorded with a Finnigan MAT 96 mass spectrometer for both low-
and high-resolution mass spectra. CD spectroscopic studies were carried
out with the use of a Jasco J-715 spectropolarimeter.
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Received: December 27, 2010
Published online: April 27, 2011
Chem. Asian J. 2011, 6, 1791 – 1799
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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