β-Turn mimic in tripeptide with Phe(1)-Aib(2) as corner residues and β-strand structure in an isomeric tripeptide: An X-ray diffraction study

Article abstract of DOI:10.1039/b415455j

A single crystal X-ray diffraction study of the tripeptide Boc-Phe-Aib-Leu-OMe (Aib = α-aminoisobutyric acid) reveals that it forms structurally one of the best type II β-turns so far reported in tripeptides, stabilized by 10 atom intramolecular hydrogen

Full text of DOI:10.1039/b415455j

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A R T I C L E
b-Turn mimic in tripeptide with Phe(1)-Aib(2) as corner residues
and b-strand structure in an isomeric tripeptide: an X-ray
diffraction study
a
b
a
Anita Dutt, Roland Fr o¨ hlich and Animesh Pramanik*
a
Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata, 700 009, India.
E-mail: animesh_in2001@yahoo.co.in
Organisch-Chemisches Institut, Universit a¨ t M u¨ nster, Corrensstraße 40, D-48149, M u¨ nster,
Germany
b
Received 6th October 2004, Accepted 29th November 2004
First published as an Advance Article on the web 21st January 2005
A single crystal X-ray diffraction study of the tripeptide Boc-Phe-Aib-Leu-OMe (Aib = a-aminoisobutyric acid)
reveals that it forms structurally one of the best type II b-turns so far reported in tripeptides, stabilized by 10 atom
intramolecular hydrogen bonding. In contrast, the isomeric tripeptide Boc-Phe-Leu-Aib-OMe adopts a b-strand like
conformation. Interestingly, a previously reported structure of another isomeric tripeptide, Boc-Leu-Aib-Phe-OMe,
shows a double bend conformation without any intramolecular hydrogen bonding. These results demonstrate an
example of the creation of structural diversities in the backbone of small peptides depending upon the co-operative
steric interactions amongst the amino acid residues.
Introduction
considerable interest in designing b-turns and b-turn mimetics,
as well as in the creation of b-strand like structures which
promote b-sheet assemblage.
b-Turns were first recognized in the late 1960s by
Venkatachalam. To date, more than 10 different types of b-
turns have been identified and classified. They are now known
to be common structural motifs comprising up to 25% of all
residues in folded proteins and peptides. b-Turns also appear to
1
Creation of b-turns in small synthetic peptides with non-coded
amino acids is an emergingaspect inthe fieldof peptidomimetics.
A list of various tripeptides with adopted type II b-turns and
bend structures are presented in Table 1 (Fig. 1). Balaram
et al. have established that the peptides Boc-Ala(1)-Dpg(2)-
Ala(3)-OMe and Boc-Ala(1)-Dbg(2)-Ala(3)-OMe (where Dpg =
a,a-di-n-propylglycine and Dbg = a,a-di-n-butylglycine) adopt
distorted type II b-turn with Ala(1) and Dpg/Dbg(2) as the
2
,3
4
play important roles in stabilizing tertiary structures, initiating
4a
folding and facilitating intermolecular recognition. Recently, it
has been shown that b-turn and extended b-strand like structures
are subunits for supramolecular b-sheet assembles and amyloid-
like fibrils in short model peptides. The formation of amyloid-
like fibrils is a causative factor in many neurodegenerative
diseases including Alzheimer’s disease, Huntington’s disease
5
–8
10
corner residues (Fig. 1). In both peptides however, the observed
(N---O) distances between the Boc CO and Ala(3) NH groups
˚
are far too long (3.44 and 3.63 A) for an intramolecular 4→1
9
and prion-related encephalopathies. The therapeutic challenge
hydrogen bond (Table 1, Entry a, b). The same group have
in all forms of these fatal neurodegenerative diseases is to
prevent amyloid fibril formation, a goal that requires a detailed
understanding of the pathways of b-sheet aggregation as well as
fibrillation. Because of their critical importance there has been
also demonstrated that peptides Boc-Ala-Ac
Boc-Ala-Ac c-Ala-OMe (where Ac
c = 1-aminocyclohexane-1-
carboxylic acid and Ac
6
c-Ala-OMe and
7
6
7
c = 1-aminocycloheptane-1-carboxylic
11
acid) form b-turns in solution phase (Table 1, Entry c, d).
◦
Table 1 List of type II b-turns in tripeptides (Entry a–i, m) with torsion angles ( ) of the residues at turn, intra-molecular hydrogen bond (HB)
◦
distance H---O=C ( A˚ ) and N–H---O angles ( )
Entry
Peptides
φ
1
w
1
φ
2
w
2
H---O=C
N–H---O
Ref.
Idealized type II b-turn
Boc-Ala-Dpg-Ala-OMe
Boc-Ala-Dbg-Ala-OMe
−60
120
139.9
143.3
80
66.2
66.5
0
19.3
21.1
1
a
a
a.
b.
c.
d.
e.
f.
g.
h.
i.
−56.1
−61.5
b-Turn without HB
b-Turn without HB
b-Turn in solution phase
b-Turn in solution phase
10
10
11
11
5
5
7
5
6
6
a
Boc-Ala-Ac
Boc-Ala-Ac
Boc-Ala-Aib-Val-OMe
Boc-Ala-Aib-Ile-OMe
6
c-Ala-OMe
a
7
c-Ala-OMe
a
−58.1
−54.6
−58.0
−55.6
−57.1
146.7
147.1
134.6
139.6
128.3
126.5
60.1
60.0
63.0
72.7
66.0
70.7
30.8
30.0
23.0
19.1
18.1
13.1
2.89
2.77
2.48
2.56
2.24
2.17
142.0
141.0
138.5
143.0
148.4
153.2
Boc-Ala-Aib-b-Ala-OMe
Boc-Ala-Gly-Val-OMe
Boc-Leu-Aib-b-Ala-OMe
b
(
Mol. A and B)
−57.9
c
j.
k.
l.
m.
n.
Z-Aib-2Dpy-Aib-OMe
Type III b-turn
Double bend structure
Double bend structure
14
12
13
Boc-Leu-Aib-Leu-OMe
Boc-Leu-Aib-Phe-OMe
−78.2
−62.8
−62.0
−98.8
−117.5
−27.6
−41.5
127.5
117.7
128.1
134.7
49.5
58.6
61.5
−63.7
−86.7
−80.7
49.5
46.2
26.6
130.1
131.7
130.5
Boc-Phe-Aib-Leu-OMe (I)
2.35
158.0
Boc-Phe-Leu-Aib-OMe (II)
b-Strand structure
b-Strand structure
b-Strand structure
(
Mol. A, B and C)
−
125.2
a
Dpg = a,a-di-n-propylglycine and Dbg = a,a-di-n-butylglycine, Ac
6
c = 1-aminocyclo-hexane-1-carboxylic acid and Ac
7
c = 1-aminocycloheptane-
b
c
1
-carboxylic acid, Aib = a-aminoisobutyric acid. Two molecules in the asymmetric unit. 2Dpy = a,a-di(2-pyridyl) glycine.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 1 – 6 6 5
6 6 1

View Article Online
Results and discussion
The crystal structure of the tripeptide Boc-Phe(1)-Aib(2)-
Leu(3)-OMe I (Fig. 2) reveals that it adopts a folded confor-
mation corresponding to a slightly distorted type II b-turn
structure with Phe(1) and Aib(2) occupying the i + 1 and
i + 2 positions respectively. In ideal type II b-turns, torsion
◦
◦
◦
◦
angles of φ
i
+1 = −60 , w
i
+1 = 120 , φ
i
+2 = 80 , w
◦
i
+2 = 0
1
have been observed. As a consequence of the deviation of
w +1 (127.5 ), φ +2 (61.5 ) and w +2 (26.6 ) from these values
i i i
◦
◦
(
Table 2), a weak 4→1 hydrogen bond between Boc-CO and
˚
Leu (3)-NH with an N25---O7 distance of 3.15A (Table 3)
Fig. 1 b-Turn conformation in a tripeptide.
resulted. The observed hydrogen bond (H---O=C)) distance
◦
˚
=
2
.35 A is well complimented by the N–H---C O angle of 158 .
Recently, Banerjee and co-workers have shown that the frag-
ments such as Ala(1)-Aib(2), Ala(1)-Gly(2) can also induce b-
turns stabilised by 10 atom intramolecular hydrogen bonding
The formation of a longer hydrogen bond is a characteristic of
slightly distorted type II b-turns, as it has been exemplified by
the structures of short synthetic peptides with non-coded amino
acids. Nevertheless, peptide I produces one of the best type
II b-turn structures so far reported in the literature (Table 1).
There are two intermolecular hydrogen bonds (N8–H8---O32,
N19–H19---O24) that are responsible for connecting individual
peptide molecules to stabilize the supra-molecular assembly in
5,7
in tripeptides (Table 1, Entry e–h) (Fig. 1). They have also
demonstrated that the sequence Boc-Leu(1)-Aib(2)-bAla(3)-
OMe, where Ala(1) has been replaced by Leu(1), can also
preferentially adopt a b-turn conformation by intramolecular
6
hydrogen bonding (Table 1, Entry i). From these results it is
evident that in tripeptides, a fragment of chiral amino acid (1)
followed by an achiral amino acid (2) is necessary to nucleate a b-
turn structure. However, this theory does not hold good owing
to the observation that sequences such as Boc-Leu(1)-Aib(2)-
Leu(3)-OMe and Boc-Leu(1)-Aib(2)-Phe(3)-OMe (Table 1,
Entry k, l) adopt a double bend structure instead of a b-
turn conformation, emphasising the role of third residue in b-
˚
crystals. In the first, the O---H separation of 2.35 A and the
˚
N---O separation of 3.12 A indicate a weak hydrogen bond when
compared to the second, where the corresponding geometrical
˚
˚
parameters are 2.15 A and 2.99 A, respectively. Fig. 3 shows the
network of hydrogen bonds creating the self-assembly of peptide
I in the b-turn conformation.
12,13
turn formation.
Interestingly another tripeptide Z-Aib(1)-
2
Dpy(2)-Aib(3)-OMe (Z = benzyloxycarbonyl, 2Dpy = a,a-
di(2-pyridyl)glycine), where all the three amino acids are achiral,
has been reported to fold in a type III b-turn structure
1
4
(
Table 1, Entry j). Therefore, it is apparent that various factors
15
contributing to b-turn formation are not yet fully understood.
To gain further insight regarding the role of various residues
in the formation of b-turn and b-strand like structures in small
peptides we have prepared two peptides, Boc-Phe(1)-Aib(2)-
Leu(3)-OMe (I) and Boc-Phe(1)-Leu(2)-Aib(3)-OMe (II)
(
Table 1, Entry m, n) with the same amino acids as that of peptide
Boc-Leu(1)-Aib(2)-Phe(3)-OMe, but at different positions in
the sequence. In peptide I the incorporation of the fragment
Phe(1)-Aib(2) is unprecedented. Moreover, the positioning of
the sterically demanding Leu residue at the end of the peptide I
may influence the adopted configuration. In addition to this, it
is interesting to see whether peptide II prefers a double bend or
extended b-strand like structure. Importantly this investigation
will provide more information about the creation of structural
diversities in the backbone of small peptides depending upon
the co-operative steric interactions among the residues. Peptides
I and II were prepared by conventional solution phase synthesis
and their single crystal X-ray diffraction studies are described
below.
Fig. 2 The SCHAKAL diagram of peptide I showing the atomic
numbering scheme. The weak intramolecular hydrogen bond is shown
as a dotted line.
Interestingly, the crystal structure of peptide II reveals that
the asymmetric unit contains three independent molecules
(mol. A, B, and C). The SCHAKAL diagram with the atom
numbering scheme for one of the molecules of the peptide
II is illustrated in Fig. 4. The backbone torsions are mostly
◦
Table 2 Selected torsion angles ( ) for peptides I and II
Peptide I
C9–N8–C6–O5
−177.4
−62.0
127.5
176.0
61.5
x
0
N19–C20–C23–N25
C20–C23–N25–C26
C23–N25–C26–C31
N25–C26–C31–O33
26.6
179.0
w
x
2
C6–N8–C9–C17
φ
1
2
N8–C9–C17–N19
C9–C17–N19–C20
C17–N19–C20–C23
Peptide II (mol. A, B, C)
C9–N8–C6–O5
w
x
1
−129.0
φ
3
1
15.2
w
3
φ
2
−178.4
−98.8
117.7
−177.6
−117.5
128.1
−165.8
−125.2
134.7
x
φ
w
x
φ
w
x
φ
0
C6–N8–C9–C17
1
N8–C9–C17–N19
C9–C17–N19–C20
C17–N19–C20–C25
N19–C20–C25–N27
C20–C25–N27–C28
C25–N27–C28–C31
N27–C28–C31–O33
1
177.4
179.8
169.0
1
−63.7
−86.7
−80.7
2
130.1
131.7
178.4
130.5
2
−179.1
−49.9
−43.2
−170.9
−54.1
−43.7
2
−52.0
3
−40.7
w
3
6
6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 1 – 6 6 5

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Fig. 3 Hydrogen bonding scheme of peptide I (hydrogen atoms bonded to carbon atoms are omitted for clarity).
Table 3 Intra- and intermolecular hydrogen bonding parameters of
peptides I and II
◦
D–H---A
H---A/A˚
D---A/A˚
D–H---A/
Peptide I
N25–H25---O7
2.35
2.35
2.15
3.15
3.12
2.99
158
162
170
a
N8–H8---O32
N19–H19---O24
b
Peptide II
N8A–H8A---O26B
N19A–H19A---O18C
N27A–H27A---O7B
2.39
1.95
2.15
2.20
1.82
2.42
2.02
1.98
2.05
2.21
3.02
2.75
3.22
3.03
2.74
3.09
2.84
2.86
2.84
2.83
169
165
179
158
167
173
177
159
152
131
c
N8B–H8B---O26C
N19B–H19B---O18A
N8C–H8C---O26A
N19C–H19C---O18B
N27B–H27B---O101
N27C–H27C---O201
O201–H201---O7A
d
a
b
Symmetry equivalent x + 1, y, z. Symmetry equivalent −x, y + 1/2,
c
d
−
z. Symmetry equivalent x, y + 1, z. Symmetry equivalent x, y − 1,
z.
Fig. 4 The SCHAKAL diagram of peptide II including the atom
numbering scheme.
in the extended conformations (Table 2); a prerequisite for
individual b-strand formation. The torsion angles at Phe
◦
◦
(
φ
1
= −98.8/−117.5/−125.2 , w
1
◦
= 111.7/128.1/134.7 ) and
◦
Leu (φ
2
= −63.7/−86.7/−80.7 , w
2
= 130.1/131.7/130.5 )
indicate a fully extended conformation. The variations from
extended values of torsions occur near the terminal posi-
tion, which is occupied by the conformationally restricted a-
◦
aminoisobutyric acid (Aib) residue (φ
3
= −49.9/52.0/−54.1 ,
◦
w
3
= −43.2/−40.7/−43.7 ). In case of peptide II, the hydrogen
bonding scheme (Fig. 5) is more complex than in peptide I due to
the three independent molecules in the asymmetric unit and the
presence of solvent molecules (for details see Table 3). Seven of
the nine possible hydrogen donors form hydrogen bonds between
the different peptide molecules. The O---H separation varies
˚
between 1.82 and 2.42 A and the N---O separation between
.74 and 3.22 A, showing a wide range of possible hydrogen
˚
2
bonds in the self-assembly. The remaining two hydrogen donors
from the peptide molecules form hydrogen bonds with solvent
molecules. In addition, there is a relatively weak hydrogen bond
O–H---O7A where the water molecule acts as hydrogen donor.
It is also interesting to note that another previously reported
isomeric tripeptide Boc-Leu(1)-Aib(2)-Phe(3)-OMe adopts a
double bend structure without any intramolecular hydrogen
Fig. 5 Hydrogen bonding scheme of peptide II (hydrogen atoms
bonded to carbon atoms and solvent molecules are omitted for clarity).
13
bonding (Table 1). Therefore, three isomeric tripeptides show
totally different conformational preferences depending only
upon the position of the constituent amino acids in the
backbone.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 1 – 6 6 5
6 6 3

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Conclusions
Boc-Phe-Leu-Aib-OMe (II)
The peptide I adopts a remarkable type II b-turn structure
in solid state, stabilized by 10 atom intra-molecular hydrogen
bonding. These results demonstrate that the fragment Phe(1)-
Aib(2) is equally effective in inducing b-turn like structures in
tripeptides such as that of Ala(1)-Aib(2) and Leu(1)-Aib(2).
Interestingly, peptide II where the position of the last two
residues (Aib and Leu) of peptide I are interchanged, takes on
a fully extended b-strand like structure. These two peptides may
serve as subunits in the formation of supra-molecular b-sheet
Peptide II was synthesised following a similar procedure to that
for peptide I. Single crystals were grown from a methanol–
water mixture by slow evaporation and were stable at room
◦
25
◦
temperature. Mp = 148–150 C; [a]578 = −26 (c = 0.10 g per
100 ml; CH OH), (found: C, 62.97; H, 8.29; N, 8.88. C25
requires: C, 62.87; H, 8.23; N, 8.80%); IR (KBr): 3312, 3069,
3
H
39
N
3
O
6
−
1
1
2958, 1746, 1650, 1536 cm ; H NMR 500 MHz (CDCl ,
3
d
d ppm): 0.91 (C H of Leu, 6H, d), 1.41 (Boc-CH s, 9H, s), 1.51
(C H of Aib, 6H, s), 1.60–1.62 (C H and C H of Leu, 2H, m),
3.11 (C H of Phe, 2H, m), 3.70 (OCH
H, m), 4.36 (C H of Phe, 1H, m), 4.89 (Phe NH, 1H, d), 6.30
3
b
b
c
5–8
b
a
assemblage and amyloid-like fibrils.
3
, 3H, s), 4.26 (C H of Leu,
a
1
(
Leu NH, 1H, d), 6.69 (Aib NH, 1H, s), 7.19–7.31 (phenyl ring
Experimental
protons).
Synthesis of peptides
Crystal data
Peptide I.
The peptides were synthesised by conventional solution phase
procedures. The t-butyloxycarbonyl and methyl ester group were
used for amino and carboxyl protections and dicyclohexylcar-
bodiimide (DCC) or DCC 1-hydroxybenzotriazole (HOBT) as
coupling agents. Methyl ester hydrochlorides of Aib and Leu
were prepared by the thionyl chloride–methanol procedure. All
the intermediates obtained were checked for purity by thin layer
chromatography (TLC) on silica gel and used without further
purification. All of the final peptides were purified by column
chromatography using silica gel (100–200 mesh) as the stationary
phase and an ethyl acetate and petroleum ether mixture as the
eluent.
C
25
H
39
N
3
O
6
, M = 477.59, monoclinic, space
group P2
1
(No. 4), a = 8.889(1), b = 11.196(1), c = 13.856(1)
◦
3
−3
˚
˚
A, b = 92.09(1) , V = 1378.0(2) A , D
c
= 1.151 g cm , l =
−
1
˚
0
.82 cm , Z = 2, k = 0.71073 A, T = 198 K, 11 001 reflections
−1
˚
collected (± h, ± k, ± l), [(sinh)/k] = 0.66 A , 6281 independent
(
R
int = 0.032) and 4504 observed reflections [I ≥ 2r(I)], 324
2
refined parameters, R = 0.060, wR = 0.109.
Peptide II. (C H N O ) ·CH OH·H O, M = 1482.84,
2
5
39
3
6
3
3
2
monoclinic, space group C2 (No. 5), a = 47.011(1), b =
◦
3
13.325(1), c = 14.106(1) A˚ , b = 95.26(1) , V = 8799.1(9) A˚ ,
−
3
−1
˚
D
c
= 1.119 g cm , l = 0.81 cm , Z = 4, k = 0.71073 A, T =
1
98 K, 35 335 reflections collected (± h, ± k, ± l), [(sinh)/k] =
−1
Boc-Phe-Aib-Leu-OMe (I)
˚
0.65 A , 18 476 independent (Rint = 0.045) and 12 183 observed
Boc-Phe-Aib-OMe (1). Boc-Phe-OH (1.33 g, 5 mmol) was
dissolved in dimethylformamide (DMF, 3 mL). Aib-OMe
2
reflections [I ≥ 2r(I)], 976 refined parameters, R = 0.067, wR =
0.155.†
(
0.59 g, 5 mmol) obtained from its hydrochloride was added,
followed by DCC (1.0 g, 5 mmol). The reaction mixture
was stirred at room temperature for 3 days. The precipitated
dicyclohexylurea (DCU) was filtered and diluted with ethyl
acetate (80 mL). The organic layer was washed with an excess
Acknowledgements
A. D. is grateful to the UGC, New Delhi for offering her a Junior
research Fellowship. We are thankful to UGC, New Delhi and
the University of Calcutta for providing financial support.
of water, 1 N HCl (3 × 30 mL), 1 M Na
0 mL) and again with water. The solvent was then dried over
anhydrous Na SO and evaporated in vacuo, giving a light yellow
2
CO
3
solution (3 ×
3
2
4
gum. Yield: 1.46 g (80.0%).
References
1
2
C. M. Venkatachalam, Biopolymers, 1968, 6, 1425.
(a) J. S. Richardson, Adv. Protein Chem., 1981, 34, 167; (b) P. N.
Lewis, F. A. Momany and H. A. Scheraga, Biochim. Biophys. Acta.,
1973, 303, 211.
Boc-Phe-Aib-OH (2). Peptide 1 (0.84 g, 2.3 mmol) was
dissolved in methanol (10 mL) and 4 N NaOH (3 mL) was
added. The reaction mixture was stirred at room temperature for
2b
ꢀ
ꢀ
2
days. The progress of the reaction was monitered by TLC. After
3 Lewis et al. classified b-turns into 10 distinct types (I, I , II, II , III,
2a
ꢀ
completion of the reaction the methanol was evaporated. The
residue obtained was diluted with water and washed with
diethylether. The aqueous layer was cooled on ice, neutralised
using 2 N HCl and extracted with ethyl acetate. The solvent was
evaporated in vacuo to give a yellow gum. Yield: 0.63 g (78.0%).
III , IV, V, VI and VII), while Richardson later reclassified b-turns
ꢀ
ꢀ
into 6 distinct types (I, I , II, II , VIa and VIb) and a random category
IV).
(a) C. Mattos, G. A. Petsko and M. Karplus, J. Mol. Biol., 1994, 238,
(
4
5
7
2
33; (b) C. M. Wilmont and J. M. Thornton, J. Mol. Biol., 1988, 203,
21; (c) W. Kabsch and C. Sander, Biopolymers, 1983, 22, 2577.
S. K. Maji, D. Haldar, M. G. B. Drew, A. Banerjee, A. K. Das and
Boc-Phe-Aib-Leu-OMe (I). Peptide 2 (0.35 g, 1 mmol)
was dissolved in DMF (4 mL). Leu-OMe obtained from its
hydrochloride (0.26 g, 2 mmol) was added, followed by DCC
A. Banerjee, Tetrahedron, 2004, 60, 3251.
6 A. Banerjee, S. K. Maji, M. G. B. Drew, D. Haldar and A. Banerjee,
Tetrahedron Lett., 2003, 44, 335.
7
8
S. K. Maji, S. Malik Michael, G. B. Drew, A. K. Nandi and A.
Banerjee, Tetrahedron Lett., 2003, 44, 4103.
(
0.2 g, 1 mmol) and HOBT (0.14 g). The reaction mixture was
stirred at room temperature for 5 days. The work up of the
reaction was carried out as in the case of 1. Yield: 0.36 g (76.0%).
Single crystals were grown from a methanol–water mixture by
slow evaporation and were stable at room temperature. Mp =
(a) S. K. Maji, M. G. B. Drew and A. Banerjee, Chem. Commun.,
2
001, 1946; (b) S. K. Kundu, P. A. Mazumdar, A. K. Das, V. Bertolasi
and A. Pramanik, J. Chem. Soc., Perkin Trans. 2, 2002, 1602; (c) S. K.
Maji, D. Haldar, A. Banerjee and A. Banerjee, Tetrahedron, 2002, 58,
8695.
◦
25
◦
1
(
16–118 C; [a] = −21 (c = 0.10 g per 100 ml; CH
3
OH),
requires: C, 62.87;
H, 8.23; N, 8.80%); IR (KBr): 3376, 3315, 2957, 1697, 1660,
5
78
9
(a) S. B. Prusiner, Science, 1997, 278, 245; (b) S. B. L. Ng and
A. J. Doig, Chem. Soc. Rev., 1997, 26, 425; (c) G. Tubes, Science,
found: C, 62.95; H, 8.28; N, 8.85. C25
H
39
N
3
O
6
1
996, 271, 1493; (d) R. Baumeister and S. Eimer, Angew. Chem., Int.
−
1
1
d
1
531 cm ; H NMR 500 MHz (CDCl
3
, d ppm): 0.94 (C H of
Leu, 6H, m), 1.40 (C H of Aib, 6H, s), 1.43 (Boc-CH s, 9H, s),
.58 (C H and C H of Leu, 2H, m), 3.07 (C H of Phe, 2H, d),
Ed., 1998, 37, 2978; (e) T. S. Burkoth, T. L. S. Benzinger, V. Urban,
b
3
b
c
b
1
3
(
a
.70 (−OCH
3
, 3H, s), 4.15–4.19 (C H of Leu, 1H, m), 4.53–4.57
†
CCDC reference numbers 252275 and 255975. See http://www.
rsc.org/suppdata/ob/b4/b415455j/ for crystallographic data in .cif or
other electronic format.
a
C H of Phe, 1H, q), 5.01 (Phe NH, 1H, d), 6.14 (Aib NH, 1H, s),
6
.93 (Leu NH, 1H, d), 7.21–7.30 (phenyl ring protons).
6
6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 6 1 – 6 6 5

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