Di-oxanipecotic acids as more stable turn motifs than di-nipecotic acids

Article abstract of DOI:10.1016/S0040-4039(03)00677-4

The folded structures of peptidomimetics containing dimers of oxanipecotic acid (Oxa) in loop segments were characterized and compared with those of the corresponding nipecotic acid (Nip)-based ones. According to structural studies using FT-IR and NMR spectroscopies, di-oxanipecotic acid adopted more stable turn conformations than di-nipecotic acid, and for tetramers, L,(S)-Oxa,(S)-Oxa,L and L,(S)-Oxa,(R)-Oxa,L formed hairpin-like structures but only L,(R)-Nip,(S)-Nip,L promoted the stable folded conformations.

Full text of DOI:10.1016/S0040-4039(03)00677-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3447–3450
Di-oxanipecotic acids as more stable turn motifs than
di-nipecotic acids
Bong-hyeon Baek, Myung-ryul Lee, Kwang-Yon Kim, Ung-In Cho, Doo Wan Boo* and
Injae Shin*
Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
Received 23 February 2003; revised 8 March 2003; accepted 13 March 2003
Abstract—The folded structures of peptidomimetics containing dimers of oxanipecotic acid (Oxa) in loop segments were
characterized and compared with those of the corresponding nipecotic acid (Nip)-based ones. According to structural studies using
FT-IR and NMR spectroscopies, di-oxanipecotic acid adopted more stable turn conformations than di-nipecotic acid, and for
tetramers, L,(S)-Oxa,(S)-Oxa,L and L,(S)-Oxa,(R)-Oxa,L formed hairpin-like structures but only L,(R)-Nip,(S)-Nip,L promoted
the stable folded conformations. © 2003 Elsevier Science Ltd. All rights reserved.
Recently, a-aminooxy peptides have spurred consider-
able interests as novel pseudopeptides.1,2 Although
monomers of a-aminooxy peptides are slightly different
from those of b-peptides in that methylene groups in
the b positions of the latter are replaced by oxygen
atoms, their folded structures are remarkably altered.
The a-aminooxy peptides composed of acyclic a-
aminooxy acids adopt only g-turnlike conformations
(NꢀO turns) irrespective of the nature of monomers.1a
In contrast, b-peptides can form diverse seconadry
structures depending on monomeric residues.3
For structural comparison, we synthesized Oxa-based
dimers (1a, 2a) and tetramers (3–6) as well as Nip-based
dimers (1b, 2b) and tetramer 4b.5,6 Oxa-based pepti-
domimetics (1–6) were synthesized from BocOxa-OH
(7) as shown in Scheme 1.2a Monomer 7 was converted
to dimers 1a and 2a by coupling of 7 to methylamine
and subsequent condensation of Oxa-NHMe after Boc
deprotection and 7 in the presence of BOP (benzot-
riazole-1-yl-oxy-tris(dimethylamino)phosphonium hex-
afluorophosphate)-HOBt
(N-hydroxybenzotriazole)-
DIEA. To prepare Oxa-based tetramers (3–6),
monomer 7 was converted to 8 by esterification, Boc
deprotection and condensation of the resulting Oxa-
OMe and 7. After hydrolysis of methyl ester of 8, the
resulting acid was coupled to (L)-Phe-NHMe to pro-
duce trimers 9. Finally, tetramers 3–6 were obtained by
coupling of Boc-deprotected 9 to (L)-BocVal-OH. The
Nip-based compounds (1b, 2b, 4b) were synthesized by
modified known procedure.4
It was reported by Gellman and co-workers that di-
nipecotic acids (Nip-dimers; dimers of six-membered
b-amino acids) were able to form reverse turn struc-
tures.4 Previously we prepared oxanipecotic acid (six-
membered a-aminooxy acid) as
a nipecotic acid
analogue for structural studies.2a,f,g Although oxa-
nipecotic acid (Oxa) has structural similarity to
nipecotic acid (Nip), we postulated that peptidomimet-
ics containing two types of cyclic monomers might
adopt different folded structures because a-aminooxy
peptides formed quite different conformations from
b-peptides. Therefore, we characterized secondary
structures of peptidomimetics containing di-oxa-
nipecotic acids (Oxa-dimers) in loop segments and com-
pared with those of the corresponding Nip-based ones.
First, we characterized the folded structures of dimers 1
and 2 in chloroform by FT-IR and NMR spectro-
scopies at 1 mM concentrations, where aggregation was
found to be negligible.7 According to FT-IR spectra of
1 and 2 in Figure 1, two of hydrogen-bonded and
non-hydrogen-bonded NH stretching bands, whose
ratio reflects the position of the conformational equi-
librium, were observed.2f,4 The hydrogen-bonded and
non-hydrogen-bonded amide NH bands for 1 and 2
appeared at 3350–3370 and 3450–3460 cm−1, respec-
tively. Since the IR spectra for homochiral Oxa-S,S
(1a) exclusively displayed a hydrogen-bonded NH
Keywords: amino acids and derivatives; coupling reactions; hydrogen
bonding; peptide analogues/mimetics.
* Corresponding authors. Tel.: +82-2-2123-2631/2632; fax: +82-2-364-
7050; e-mail: dwboo@yonsei.ac.kr; injae@yonsei.ac.kr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00677-4

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B. Baek et al. / Tetrahedron Letters 44 (2003) 3447–3450
concentrations. The amide NH signal for Oxa-S,S (1a)
exhibited significantly downfield shift (7.79 ppm), sug-
gesting that the NH group was exclusively involved in
an internal hydrogen bond.4 Heterochiral dimers 2a
and 2b showed downfield shifts of amide NHs (7.11 and
7.13 ppm, respectively). This indicated that both NH
groups formed internal hydrogen bonds to a large
extent. However, the NH resonance for Nip-R,R (1b)
appeared relatively upfield (6.27 ppm), suggesting the
formation of a moderate internal hydrogen bond.
1
Taken together with IR and H NMR analyses, Oxa-
dimers favored the folded conformations, however,
only heterochiral Nip-R,S (2b) promoted the stable
turn structure.4c Overall, Oxa-S,S formed the most
stable folded structure among the four dimers tested.
Next, we carried out structural studies of Oxa-based
tetramers (3–6) composed of di-oxanipecotic acids in
loop segments and a-peptide strands, and compared
their structures with Nip-based tetramer 4b. Figure 2
shows FT-IR data of 3–6 in CHCl3 at 1 mM concentra-
tions. For 3 and 4a, two NH stretching bands were
observed at 3448 and 3309 cm−1; the former band with
weaker absorption is assigned to a non-hydrogen
bonded NH and the latter with stronger absorption to
an internal hydrogen-bonded NH. The tetramers 3 and
4a exhibited high ratio of hydrogen-bonded to non-
hydrogen-bonded NH bands, indicating that both tetra-
mers adopted the folded conformations. However, the
IR absorption bands of hydrogen-bonded NHs for 5
and 6 at 3307 and 3312 cm−1, respectively, appeared to
be very weak. In both cases, the shoulder peaks at 3424
and 3418 cm−1 for 5 and 6, respectively, were observed
Scheme 1. Synthesis of dimers and tetramers.
Figure 1. NH region of FT-IR spectra for dimers in CHCl3 at
room temperature (1 mM concentrations): (1a) maximum at
3370 cm−1; (2a) maxima at 3455 and 3354 cm−1; (1b) maxima
at 3462 and 3354 cm−1; (2b) maxima at 3462 and 3369 cm−1
.
band, it was deduced that 1a predominantly adopted
the folded conformation. Given the higher ratio of
hydrogen-bonded to non-hydrogen-bonded NH bands,
the homochiral Oxa-S,S (1a) formed more stable b-
turnlike structure than heterochiral Oxa-S,R (2a). Inter-
estingly, these structural features are quite different
from Nip-dimers whose preference is reversed as shown
in Figure 1. For Nip-dimers, heterochiral dimer
adopted the more stable folded conformation.4c
Figure 2. NH region of FT-IR spectra for tetramers in CHCl3
at room temperature (1 mM concentrations): (3) maxima at
3448 and 3309 cm−1; (4a) maxima at 3448 and 3309 cm−1; (5)
maxima at 3447, 3424 (shoulder) and 3307 cm−1; (6) maxima
at 3450, 3418 (shoulder) and 3312 cm−1; (4b) maxima at 3449
1
The H NMR chemical shift of amide NH has been
used to ascertain which amide NH forms an internal
hydrogen bond. We determined chemical shifts for
major conformers of dimers 1 and 2 in CDCl3 at 1 mM
and 3318 cm−1
.

B. Baek et al. / Tetrahedron Letters 44 (2003) 3447–3450
3449
and assigned to C5 interactions.4,8 The IR data also
revealed that NHs of 3 and 4a formed the comparable
hydrogen-bonding interactions to Nip-based tetramer
4b.
We assigned the chemical shifts of amide NHs for
tetramers 3–6 that participated in an internal hydrogen
bond(s). Table 1 summarizes chemical shifts for major
conformers of 3–6. The downfield resonance of Phe NH
(> 8.0 ppm) for 3, 4a and 4b relative to
AcNH6 PheNHMe (6.09 ppm) as a reference implied that
Figure 3. Summary of partial ROEs observed for tetramers 3
and 4 in CDCl3 at room temperature (1 mM concentrations).
Phe NH predominantly formed a strong internal hydro-
gen bond. However, the upfield signal of Phe NH
(ꢀ6.6 ppm) for 5 and 6 suggested that both tetramers
had large population of non-hydrogen-bonded Phe
NH. The N-terminal Val NH for 3 and 4a was involved
in an internal hydrogen bond based on significant
downfield shift (6.93 and 6.81 ppm, respectively) rela-
Nip-R,S was somewhat longer (Fig. 4). However, Nip-
R,R (1b) exhibited hydrogen-bonded and non-hydro-
gen-bonded conformers with similar energies. As a
consequence, the Nip-R,R equilibrated between hydro-
gen-bonded and non-hydrogen-bonded conformers and
thus might adopt poorly folded structures. The distinct
structural feature between two types of dimers is that
the oxyamide group connecting the two rings of Oxa-
dimers shows pyramidal conformation at the amide
nitrogen atom, in contrast, the Nip-dimers exhibit
nearly planar conformation at the corresponding amide
group (Fig. 4). Another structural difference is the
presence of steric hindrance between two b-CH2 in the
rings of Nip-dimers. Overall, these structural differ-
ences might dictate the tendency of the examined Oxa-
and Nip-based peptidomimetics to form the folded
structures.
tive to 5.29 ppm of BocNH6 ValNMe2 as a reference. In
contrast, Val NH resonance for 5 and 6 exhibited
remarkably upfield shift (5.24 and 5.01 ppm, respec-
tively), demonstrating that Val NH groups were not
involved in internal hydrogen bonds. For Nip-based
tetramer 4b, Val NH signal appeared at 6.15 ppm,
indicating that the amide NH group equilibrates
between hydrogen-bonded and non-hydrogen-bonded
states. The C-terminal amide NH signals for all the
tetramers appeared upfield in the narrow range (5.6–6.1
ppm).9
The 2D ROESY NMR spectra of tetramers further
supported the formation of hairpin-like conformations.
As anticipated, tetramers 3, 4a and 4b exhibited strong
ROEs between tBu and NH-CH3 as well as Val Cb-H
and Phe Cb-H on a-peptide strands (Fig. 3).7 However,
tetramers 5 and 6, which were found to lack the stable
folded conformations, did not show the corresponding
ROEs between a-strand residues. Taken together with
IR and NMR analyses, it was concluded that 3 and 4a
adopted the stable hairpin-like conformations, whereas
only L,(R)-Nip,(S)-Nip,L (4b) formed the folded
structure.
In conclusion, we demonstrated that Oxa-dimers
adopted more stable turn conformations than the corre-
sponding Nip-dimers. In addition, we also revealed that
for tetramers, L,(S)-Oxa,(S)-Oxa,L and L,(S)-Oxa,(R)-
Finally, we investigated the molecular basis of confor-
mational differences between Oxa- and Nip-based pep-
tidomimetics
by
comparing
the
ab
initio
energy-minimized structures of dimers 1 and 2 gener-
ated at RHF/6-31G(d,p) level.10 According to the
energy-minimized structures, the Oxa-dimers (1a, 2a)
and Nip-R,S (2b) predominantly adopted the folded
conformations, albeit the hydrogen bond distance of
Table 1. Chemical shifts of amide protons for the major
conformers of 3–6 in CDCl3 at 1 mM concentrations
3
4a
4b
5
6
Phe NH
Val NH
Me NH
8.59
6.93
6.12
8.33
6.81
5.81
8.01
6.15
5.96
6.68
5.24
5.79
6.64
5.01
5.64
Figure 4. Energy-minimized structures of dimers generated at
RHF/6-31G(d,p) level. Distances are shown in angstroms
(black: C, gray: N, patterned: O, white: H).
Percent major conformer of 3, 4a, 4b, 5 and 6 is 87, 83, 82, 61 and
90%, respectively.

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B. Baek et al. / Tetrahedron Letters 44 (2003) 3447–3450
Oxa,L formed folded structures, however, only L,(R)-
Nip,(S)-Nip,L promoted the stable folded conforma-
tions.
5. Since N-acetylated peptidomimetics possessing di-oxa-
nipecotic acids were sparingly soluble in nonpolar sol-
vents such as methylene chloride and chloroform, which
are ideal for examining hydrogen bond formations by
FT-IR and NMR, Boc-protected compounds were pre-
pared for structural studies.
Acknowledgements
6. According to FT-IR and NMR studies of four Boc-pro-
tected Nip-tetramers [L,(R)-Nip,(S)-Nip,L, L,(R)-
Nip,(R)-Nip,L, L,(S)-Nip,(S)-Nip,L, L,(S)-Nip,(R)-
Nip,L], only L,(R)-Nip,(S)-Nip,L (4b) exhibited folded
conformations. Accordingly, we selected 4b for these
studies. In fact, this result is a little different from previ-
ous results that heterochiral acetylated Nip-tetramers
(L,(R)-Nip,(S)-Nip,L and L,(S)-Nip,(R)-Nip,L) promote
turn formations.4c We assumed that carbonyl of Boc
group is a worse hydrogen bond acceptor to C-terminal
NH than that of acetyl group and thus only L,(R)-
Nip,(S)-Nip,L forms the folded conformation.
This work was supported by a grant of the Center for
Integrated Molecular Systems (KOSEF). We thank Dr.
Yong Jun Chung for several helpful discussions con-
cerning IR studies.
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