Solid-state conformation of diastereomeric -Pro-Pro-(Aib)4 sequences

Article abstract of DOI:10.1016/j.tet.2010.02.003

The crystal structures of two diastereomeric -Pro-Pro-(Aib)₄- sequences, Cbz-l-Pro-l-Pro-(Aib)₄-OMe (1) and Cbz-d-Pro-l-Pro-(Aib)₄-OMe (2), have been determined by X-ray crystallographic analysis. The crystals of the two compounds were characterized by the following parameters: (1) monoclinic, P2₁, a=10.543 ?, b=8.103 ?, c=22.642 ?, β=97.679, Z=2, R₁=0.104, and R_w=0.327; (2) orthorhombic, P2₁2₁2₁, a=10.470 ?, b=10.953 ?, c=32.405 ?, Z=4, R₁=0.040, and R_w=0.046. In the asymmetric unit of 1, the homochiral l-Pro¹-l-Pro² adopts a polyproline II structure, which induces a left-handed (M) 3₁₀-helical structure in the following -(Aib)₄- sequence. The preferred conformation of diastereomeric 2, which contains heterochiral d-Pro¹-l-Pro² segments, was similar to that of 1 with differences at the N-terminal d-Pro residue.

Full text of DOI:10.1016/j.tet.2010.02.003

Tetrahedron 66 (2010) 2293–2296
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solid-state conformation of diastereomeric -Pro-Pro-(Aib)4 sequences
,
b
b
c
d
Makoto Oba a, Yosuke Demizu b , Nanako Yamagata , Yukiko Sato , Mitsunobu Doi , Masakazu Tanaka ,
*
Hiroshi Suemune a, Haruhiro Okuda b, Masaaki Kurihara b
,
*
a Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
b Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan
c Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
d Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The crystal structures of two diastereomeric -Pro-Pro-(Aib)4- sequences, Cbz-L-Pro-L-Pro-(Aib)4-OMe (1)
Received 28 December 2009
Received in revised form 1 February 2010
Accepted 1 February 2010
and Cbz-
crystals of the two compounds were characterized by the following parameters: (1) monoclinic, P21,
a¼10.543 Å, b¼8.103 Å, c¼22.642 Å, ¼97.679, Z¼2, R1¼0.104, and Rw¼0.327; (2) orthorhombic, P212121,
a¼10.470 Å, b¼10.953 Å, c¼32.405 Å, Z¼4, R1¼0.040, and Rw¼0.046. In the asymmetric unit of 1, the
homochiral
-Pro1- -Pro2 adopts a polyproline II structure, which induces a left-handed (M) 310-helical
D-Pro-L-Pro-(Aib)4-OMe (2), have been determined by X-ray crystallographic analysis. The
b
Available online 4 February 2010
L
L
Keywords:
Peptide
Helix
X-ray crystallographic analysis
Conformation
Secondary structure
structure in the following -(Aib)4- sequence. The preferred conformation of diastereomeric 2, which
contains heterochiral
-Pro residue.
D
-Pro1-
L
-Pro2 segments, was similar to that of 1 with differences at the N-terminal
D
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
helical-screw handedness bias because of its achiral amino acid.6
We have designed and synthesized two hexapeptides, Cbz-
L-Pro-
The development of a template for controlling the secondary
structure of peptides is important for creating a variety of artificial
peptides, proteins, and macromolecules.1 To date, we have studied
L
-Pro-(Aib)4-OMe (1) and Cbz- -Pro- -Pro-(Aib)4-OMe (2), and
D
L
studied their preferred conformations in the crystalline state.
2. Results and discussion
the conformation of peptides composed of various
a,a-disubstituted
a
-amino acids.2
L
-Proline ( -Pro), one of the 20 naturally occurring
L
amino acids, has a propensity to induce a turn structure in peptide
sequences because of the constraint of its pyrrolidine ring skeleton,
2.1. Synthesis of two diastereomeric peptides 1 and 2
and
derivatives) have been synthesized to control peptide secondary
structures.3 Furthermore, homochiral diproline (
-Pro- -Pro) seg-
ments have been used as templates for the induction and stabili-
zation of helical structures,4 and heterochiral
-Pro- -Pro segments
have been used as templates for
-hairpin structures.5 As part of our
L-Pro and its derivatives (including some specially designed
The synthesis of peptides 1 and 2 was performed by the cou-
pling of Cbz-(Pro)2-OH and H-(Aib)4-OMe using 1-(3-dimethyla-
minopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and
1-hydroxybenzotriazole hydrate (HOBt) as coupling reagents by
the solution-phase method (Scheme 1). The spectroscopic data of
1 and 2 supported the structures in Scheme 1.
L
L
D
L
b
ongoing research, we wish herein to report the conformation of two
diastereomeric hybrid peptides containing diproline segments and
2.2. Conformation of peptides 1 and 2
an
-Pro-
isobutyric acid (Aib) was used as an
a
,
a
L
-disubstituted
-Pro were used as diproline segments, and 2-amino-
-disubstituted -amino acid.
a-amino acid. That is to say, L-Pro-L-Pro and
D
Single crystals of peptides 1 and 2 were grown from MeOH/H2O
and EtOH, respectively. Data collection was performed using
Bruker Smart 1000 imaging plate diffractometers and graphite-
a,
a
a
Aib is widely used to construct helical structures and does not show
monochromated Mo K
a radiation. All crystals remained stable
during the X-ray-data collection. The structures were solved using
the SHELEX-977 and SIR-978 direct methods and expanded by the
Fourier technique.9 All non-H-atoms were given anisotropic ther-
mal parameters, some H-atoms were refined isotropically, and the
* Corresponding authors.
E-mail addresses: demizu@nihs.go.jp (Y. Demizu), masaaki@nihs.go.jp
(M. Kurihara).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.003

2294
M. Oba et al. / Tetrahedron 66 (2010) 2293–2296
O
O
H
N
H
N
CO2Me
N
H
O
N
H
ref . 12
a
N
O
O
H2N
CO2H
H
N
H
OMe
O
4
Cbz
N
Aib
H-(Aib)4-OMe
Cbz-L-Pro-L-Pro-(Aib)4-OMe (1)
Cbz-
D-Pro-L-Pro-(Aib)4-OMe (2)
Scheme 1. Reagents and conditions: (a) EDC, HOBt, Cbz-L-Pro-L-Pro-OH, or Cbz-D-Pro-L-Pro-OH, MeCN.
Table 3
remaining H-atoms were given at the calculated positions. The final
cycle of full-matrix least-squares refinement of 1 gave an R1 factor
Intra- and intermolecular H-bond parameters for 1 and 2a
Donor
D-H
Acceptor
A
Distance [Å]
D/A
Angle [ꢁ]
D-H/A
Symmetry
operations
of 0.104 based on 4908 (I>2
0.327 for all data. The R1 factor of 2 was 0.040 based on 2951
(I>2 (I)) reflections and an Rw factor of 0.046 for all data. All data
s(I)) reflections and an Rw factor of
Cbz-
L-Pro-
L-Pro-(Aib)4-OMe (1)
s
N4–H
N5–H
N6–H
O1
O2
O3
O1
3.31b
3.08
2.91
2.79
2.81
3.04
2.84
138.3
153.0
141.9
174.3
168.5
160.6
171.3
x, y, z
x, y, z
x, y, z
x, y, z
for peptides 1 and 2 have been deposited in the Cambridge Crys-
tallographic Data Centre (CCDC) as a supplementary publication,
and their CCDC reference numbers are CCDC-757487 and -757488,
respectively.10 The crystal and diffraction parameters of 1 and 2 are
summarized in Table 1. The relevant backbone torsion angles and
the intra- and intermolecular hydrogen-bond parameters are listed
in Tables 2 and 3.
Owa–Hc
Owb–H
N3–H
Owa
x, y, z
0
O5
xꢀ1, y, z
0
Owb–H
O4
xꢀ1, y, z
Cbz-
D
-Pro-
L-Pro-(Aib)4-OMe (2)
N4–H
N5–H
N6–H
Ow–H
Ow–H
N3–H
O1
Ow
O3
O0
O1
3.12
2.90
2.95
2.78
2.74
2.99
162.3
160.8
150.5
172.2
163.4
171.0
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
x, yꢀ1, z
c
Table 1
Crystal and diffraction parameters of 1 and 2
0
O5
1
2
a
The number of amino acid residues begins from the N-terminus of the peptide
Empirical formula
Mr
C35H52O9N6, 2H2O
736.85
C35H52O9N6, H2O
718.85
chain.
b
The D/A distance is somewhat long for a hydrogen bond.
Ow: Water.
Crystal dimensions [mm]
Crystal system
0.30ꢂ0.20ꢂ0.10
0.35ꢂ0.25ꢂ0.25
c
Monoclinic
Orthorhombic
Lattice parameters:
In the asymmetric unit of 1, only one conformer of the peptide
a, b, c [Å]
10.543, 8.103, 22.642
90, 97.679, 90
1917.0
P21
2
10.470, 10.953, 32.405
molecule was found together with two water molecules, and the -
Pro1- -Pro2 adopted a polyproline type II (PII) structure, which in-
duced a left-handed (M) 310-helical structure in the following
L-
a
,
b
,
g
[ꢁ]
90, 90, 90
3716.3
P212121
4
1.285
0.94
2951 (I>2s(I))
462
0.040, 0.046
EtOH
L
V [Å3]
Space group
Z value
-(Aib)4- sequence (Fig. 1). The
f and 4 torsion angles of L
-Pro1 were
Dcalcd [g/cm3]
1.270
0.95
ꢀ60.3ꢁ and þ159.8ꢁ, and those of
L
-Pro2 were ꢀ57.9ꢁ and þ145.2ꢁ,
m
(Mo Ka) [cmꢀ1
]
which are close to those of the PII structure (ꢀ78ꢁ and þ149ꢁ). The
No. of observations
No. of variables
R1, Rw
4908 (I>2
s(I))
mean values of the
f and 4
torsion angles of the Aib residues (Aib3 to
469
0.104, 0.327
MeOH/H2O
Aib5) were þ52.5ꢁ and þ37.1ꢁ, which are close to those for an ideal
left-handed (M) 310-helical structure (þ57ꢁ and þ30ꢁ). Flipping of
the torsion angles at the C-terminus occurred, that is, the values of
Solvent
the
f
and
4
torsion angles (ꢀ47.4ꢁ, and ꢀ46.2ꢁ) of the Aib6 residue
were negative while those of the preceding residues, Aib3, Aib4, and
Aib5, were positive.
Table 2
Selected torsion angles
lographic analysis
u, f, and 4
[ꢁ] for 1 and 2 as determined by X-ray crystal-
Torsion angles
1
2
u0
f1
41
u1
f2
42
u2
f3
43
u3
f4
44
u4
f5
45
u5
f6
46
u6
ꢀ0.6
176.9
62.8
ꢀ60.3
159.8
176.4
ꢀ57.9
145.2
173.8
51.1
ꢀ136.8
ꢀ163.6
ꢀ59.0
125.2
174.7
63.8
19.7
156.1
51.7
35.3
172.2
53.7
34.4
178.8
52.8
49.3
172.2
66.6
Figure 1. X-ray diffraction structure of 1.
41.6
17.4
Two intramolecular hydrogen bonds, in which each hydrogen
bond formed a 10-membered (atoms) pseudo ring of the i)iþ3
type, were present in the 310-helical molecule of 1. That is, they
were present between the H–N(5) and C(2)]O(2) [N(5)/
172.2
ꢀ47.4
ꢀ46.2
ꢀ172.2
179.7
ꢀ51.0
ꢀ41.2
ꢀ179.5

M. Oba et al. / Tetrahedron 66 (2010) 2293–2296
2295
Figure 2. Packing of 1 in the crystalline state. Intramolecular (red) and intermolecular (blue) hydrogen bonds are indicated as dashed lines.
O(2)¼3.08 Å] and between the H–N(6) and C(3)]O(3) [N(6)/
O(3)¼2.91 Å]. Furthermore, one weak intramolecular hydrogen
bond was observed between the H–N(4) and C(1)]O(1) [N(6)/
O(1)¼3.31 Å]. Two water molecules (a, b) formed intermolecular
hydrogen bonds between the H–Ow(a) of the water (a) donor and
the C(1)]O(1) [Ow(a)/O(1)¼2.79 Å] and between the H–Ow(b) of
the water (b) donor and the Ow(a) of the water (a) acceptor
[Ow(b)/Ow(a)¼2.81 Å]. In the packing mode, two intermolecular
hydrogen bonds were observed between the H–N(3) peptide donor
and the C(50)]O(50) acceptor [N(3)/O(50)¼3.04 Å] of a symmetry-
related molecule (xꢀ1, y, z) and between the H–Ow(b) of the water
(b) donor and the C(40)]O(40) acceptor [Ow(b)/O (40)¼2.84 Å] of
a symmetry-related molecule (xꢀ1, y, z), as shown in Figure 2.
In the asymmetric unit of 2, only one conformer of the peptide
molecule was present together with one water molecule (Fig. 3).
those of
L
-Pro2 were ꢀ59.0ꢁ and þ125.2ꢁ. Thus, the
D
-Pro1-
L
-Pro2
segment did not form a type-II0 -turn conformation11 because of
b
the presence of the water molecule. The mean values of the
f and 4
torsion angles of the Aib residues (Aib3 to Aib5) were þ60.7ꢁ and
þ28.8ꢁ, which are close to those of an ideal left-handed (M) 310
-
helical structure. The flipping of the torsion angles occurred at the
C-terminus, and the
f
and
4
torsion angles (ꢀ51.0ꢁ and ꢀ41.2ꢁ,
respectively) of the Aib6 residue were negative while those of the
Aib3, Aib4, and Aib5 residues were positive.
Two intramolecular hydrogen bonds, in which each hydrogen
bond formed a 10-membered (atoms) pseudo ring of the i)iþ3
type, were present in the 310-helical molecule of 2. These bonds
were found between the H–N(4) and C(1)]O(1) [N(4)/
O(1)¼3.12 Å] and the H–N(6) and C(3)]O(3) [N(6)/O(3)¼2.95 Å].
The water molecule was fixed by three hydrogen bonds between
H–N(5) and Ow [N(5)/Ow¼2.90 Å], H–Ow and C(0)]O(0) [Ow/
O(0)¼2.78 Å], and between H–Ow and C(1)]O(1) [Ow/
O(1)¼2.74 Å]. In the packing mode, one intermolecular hydrogen
bond was observed between the H–N(3) peptide donor and the
C(50)]O(50) acceptor [N(3)/O(50)¼2.99 Å] of a symmetry-related
molecule (x, yꢀ1, z), as shown in Figure 4.
The
f
and
4
torsion angles of
D
-Pro1 were þ62.8ꢁ and ꢀ136.8ꢁ, and
Figure 5. Overlay of the structures of peptides 1 (blue) and 2 (green).
Figure 3. X-ray diffraction structure of 2.
Figure 4. Packing of 2 in the crystalline state. Intramolecular (red) and intermolecular (blue) hydrogen bonds are indicated as dashed lines.

2296
M. Oba et al. / Tetrahedron 66 (2010) 2293–2296
The structure of 2 is well matched with that of 1 except for the
(0.5 mmol scale). 137 mg, 39% yield; colorless crystals; mp 175–
24
N-terminal
Figure 5.
D-Pro residue, as shown by their superimposition in
177 ꢁC (recryst from EtOH); [
a
]
D
ꢀ20.1 (c1.1, CHCl3). IR (in CDCl3
solution) 3327, 1740, 1666 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 7.45
(br s, 1H), 7.29–7.39 (m, 5H), 7.25 (br s, 1H), 7.24 (br s, 1H), 7.09 (br s,
1H), 5.19 (d, J¼13.0 Hz,1H), 4.99 (d, J¼13.0 Hz,1H), 4.46 (t, J¼6.7 Hz,
1H), 4.41 (t, J¼6.2 Hz, 1H), 3.97 (m, 1H), 3.68 (s, 3H), 3.55–3.64 (m,
3H), 1.91–2.27 (m, 8H), 1.52 (s, 3H), 1.50 (s, 6H), 1.48 (s, 3H), 1.44 (s,
3H), 1.43 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
3. Conclusion
Two diastereomeric diproline (L-Pro-L-Pro and D-Pro-L-Pro)
segments were attached on the N-terminus of H-(Aib)4-OMe seg-
ment. X-ray crystallographic analysis revealed the preferred con-
formations of hexapeptides 1 and 2 in the crystalline state. In the
d
175.5,174.6,173.4,172.7,171.4,155.1,135.9,128.6,128.2,127.3, 67.2,
61.5, 58.2, 56.8, 56.6, 56.5, 55.6, 51.9, 47.5, 47.0, 29.7, 29.2, 28.4, 26.3,
25.8, 25.7, 25.2, 25.0, 24.9, 24.5, 24.4, 24.3, 24.0, 19.3; FAB(þ)-MS:
701 (MþH).
crystal state of 1, the homochiral L L
-Pro1- -Pro2 segment adopted
a polyproline type II structure, which induced a left-handed (M)
310-helical structure in the following -(Aib)4- sequence. On the
other hand, in the crystal state of 2, the heterochiral
segment did not form a type-II0
-turn conformation because of the
presence of a fixed water molecule. Thus, the
-Pro2-Aib3 segment
bestowed a left-handed (M) screw sense3c on the following Aib
sequence. That is to say, the two diastereomeric Cbz-Pro- -Pro-
(Aib)4-OMe peptides formed similar structures with different
N-terminal Pro residues. These results will be valuable for re-
searchers investigating the control of secondary structures and may
be also relevant for the de novo design of peptides/proteins.
D L
-Pro1- -Pro2
Acknowledgements
b
L
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) (21790018) and by a Grant-in-Aid for Scientific Re-
search on Priority Areas (No. 20037054, ‘Chemistry of Concerto
Catalysis’) from the Ministry of Education, Science, Sports, and
Culture of Japan.
L
References and notes
4. Experimental
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2. (a) Oba, M.; Tanaka, M.; Kurihara, M.; Suemune, H. Helv. Chim. Acta 2002, 85,
3197–3218; (b) Tanaka, M.; Nishimura, S.; Oba, M.; Demizu, Y.; Kurihara, M.;
Doi, M.; Suemune, H. Chem.dEur. J. 2003, 9, 3082–3090; (c) Tanaka, M.;
Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H. Angew. Chem., Int. Ed. 2004, 43,
5360–5363; (d) Tanaka, M.; Anan, K.; Demizu, Y.; Kurihara, M.; Doi, M.; Sue-
mune, H. J. Am. Chem. Soc. 2005, 127, 11570–11571; (e) Tanaka, M. Chem. Pharm.
Bull. 2007, 55, 349–358; (f) Demizu, Y.; Tanaka, M.; Nagano, M.; Kurihara, M.;
Doi, M.; Maruyama, T.; Suemune, H. Chem. Pharm. Bull. 2007, 55, 840–842; (g)
Nagano, M.; Tanaka, M.; Doi, M.; Demizu, Y.; Kurihara, M.; Suemune, H. Org.
Lett. 2009, 11, 1135–1137.
3. (a) Chou, P. Y.; Fasman, G. D. J. Mol. Biol. 1977, 115 435–175; (b) Wilmot, C. M.;
Thornton, J. M. J. Mol. Biol. 1988, 203, 221–232; (c) Inai, Y.; Oshikawa, T.;
Yamashita, M.; Hirabayashi, T.; Ashitaka, S. J. Chem. Soc. Perkin 2 2001, 892–897.
4. (a) Kemp, D. S.; Curran, T. P.; Boyd, J. G.; Allen, T. J. J. Org. Chem. 1991, 56, 6683–
6697; (b) Kemp, D. S.; Boyd, J. G.; Muendel, C. C. Nature 1991, 352, 451–454; (c)
Rai, R.; Aravinda, S.; Kanagarajadurai, K.; Raghothamana, S.; Shamala, N.;
Balaram, P. J. Am. Chem. Soc. 2006, 128, 7916–7928; (d) Chatterjee, B.; Saha, I.;
Raghothama, S.; Aravinda, S.; Rai, R.; Shamala, N.; Balaram, P. Chem.dEur. J.
2008, 14, 6192–6204.
5. (a) Robinson, J. A. Synlett 2000, 429–441; (b) Hanessian, S.; Angiolini, M.
Chem.dEur. J. 2002, 8, 111–117; (c) Haines, L. A.; Rajagopal, K.; Ozbas, B.; Salick,
D. A.; Pochan, D. J.; Schneider, J. P. J. Am. Chem. Soc. 2005, 127, 17025–17029; (d)
Rai, R.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc. 2006, 128, 2675–2681.
6. (a) Karle, I. L.; Balaram, P. Biochemistry 1990, 29, 6747–6756; (b) Heimgartner, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 238–264; (c) Wysong, C. L.; Yokum, T. S.;
McLaughlin, M. L.; Hammer, R. P. Chemtech 1997, 27, 26–33; (d) Toniolo, C.;
Crisma, M.; Formaggio, F.; Peggion, C.; Broxterman, Q.; Kaptein, B. J. Incl. Phenom.
Macro. Chem. 2005, 51, 121–136.
7. Sheldrick, G. M. SHELXL 97. Program for Crystal Structure Refinement; University
of Go¨ttingen: Go¨ttingen, 1997.
8. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Gua-
gliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999,
32, 115–119.
9. Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de Gelder, R.; Israel,
R.; Smits, J. M. M. The DIRDIF-99 Program System, Technical Report of the Crys-
tallography Laboratory; University of Nijmegen: The Netherlands, 1994.
10. CCDC-757487 and -757488 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336 033; or deposit@ccdc.
cam.ac.uk).
4.1. General methods
Optical rotations [a] were measured with a Jasco DIP-316 po-
D
larimeter using a 0.5 or 1.0 dm cell. 1H NMR and 13C spectra were
recorded on a Varian AS 400 spectrometer, and measurements were
carried out in CDCl3 with tetramethylsilane used as an internal
standard. FTIR spectra were recorded on a JASCO FT/IR-4100 spec-
trometer at 1 cmꢀ1 resolution, with a mean of 32 scans used for the
solution (CDCl3) method and a 0.1 mm path length adopted for
NaCl cells. FABMS spectra were measured on a JEOL JMS-SX 102
spectrometer. Elemental analysis was performed at the Analytical
Center of the Faculty of Sciences at Kyushu University.
4.1.1. Cbz-L-Pro-L-Pro-(Aib)4-OMe (1). A mixture of Cbz-L-Pro-L-Pro-
OH (173 mg, 0.5 mmol), H-(Aib)4-OMe (186 mg, 0.5 mmol),12 EDC
(115 mg, 0.6 mmol), and HOBt (81 mg, 0.6 mmol) in MeCN was
stirred at room temperature for 48 h. The solution was then evapo-
rated; diluted with AcOEt (30 mL); washed with 3% aqueous HCl, 5%
NaHCO3, and brine; and dried over anhydrous MgSO4. Evaporation of
the solvent gave a white solid, which was purified by column chro-
matography on silica gel (n-hexane/AcOEt¼1:9) to give 1 (164 mg,
47%) as colorless crystals. Mp 193–194 ꢁC (recryst from MeOH/H2O);
24
[a]
ꢀ51.2 (c1.7, CHCl3); IR (in CDCl3 solution) 3317, 1741, 1698,
D
1645 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.41 (br s,1H), 7.30–7.36 (m,
5H), 7.21 (br s, 1H), 7.19 (br s, 1H), 6.76 (br s, 1H), 5.14 (ABX,
JAX¼13.0 Hz, JBX¼13.0 Hz, JAB¼37.0 Hz, 2H), 4.50 (t, J¼7.5 Hz, 1H),
4.25 (t, J¼7.5 Hz, 1H), 3.62–3.73 (m, 2H), 3.68 (s, 3H), 3.44 (m, 1H),
3.34 (m, 1H), 2.19–2.37 (m, 2H), 1.79–2.04 (m, 6H), 1.44–1.52 (m,
24H); 13C NMR (100 MHz, CDCl3)
d 175.5, 174.6, 174.2, 173.6, 172.0,
171.3,154.9,136.4,128.5,128.2,128.0, 67.2, 61.8, 59.8, 56.9, 56.8, 56.5,
55.7, 52.0, 47.2, 46.7, 29.0, 28.8, 25.8, 25.6, 25.5, 25.2, 25.0, 24.9, 24.7,
24.5, 23.9; FAB(þ)-MS: 701 (MþH); Anal. Calcd for C35H52N6O9: C,
59.98; H, 7.48; N, 11.99. Found: C, 59.73; H, 7.40; N, 11.91.
11. Ideal backbone torsion angles of type-II0
b
-turn:
f
¼60ꢁ,
4
¼ꢀ120ꢁ. (a) Nair, C.
M.; Vijayan, M.; Venkatachalapathi, Y. V.; Balaram, P. J. Chem. Soc., Chem.
Commun. 1979, 1183–1184; (b) Nair, C. M.; Vijayan, M. J. Chem. Soc. Perkin 2 1980,
1800–1804; (c) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992,
114, 5328–5334.
4.1.2. Cbz-D-Pro-L-Pro-(Aib)4-OMe (2). Peptide 2 was prepared us-
ing a similar method to that described for the preparation of 1
12. Karle, I. L.; Ranganathan, D.; Lakshmi, C. Biopolymers 2001, 59, 301–304.