C O M M U N I C A T I O N S
‚
‚‚C(M)‚‚‚D(P)‚‚‚C(M)‚‚‚D(P)‚‚‚ are formed along the c direction
in the crystal state.
Molecular-mechanics calculation of 11 with Macromodel (AM-
BER*) produced a (P) 310-helix as a global minimum-energy
conformation (0 kcal/mol), and an (M) 310-helix as a local
minimum-energy conformation (+1.60 kcal/mol). The (P) 310-helix
8
and (M) 310-helix are similar to those in the crystal state.
In summary, we synthesized a hydrophobic bicyclic dAA having
chiral centers at the side-chain fused-ring junctions and described
1
its modifications. The IR, H NMR, CD spectra, and the X-ray
analysis revealed that the (R,R)-Ab5,6)c hexapeptide 11 having
1
Figure 1. (a) Plots of NH chemical shifts in the H NMR spectra of 12
1.0 mM) as a function of increasing percentage of DMSO (v/v) added to
twelve chiral centers forms both diastereomeric (P) and (M) 310
-
(
helices,13 which is in contrast with the left-handed (S,S)-Ac cdOM
5
the CDCl3 solution. (b) Plots of bandwidth of the NH protons of 12 (1.0
mM) as a function of increasing percentage of TEMPO (w/v) added to the
CDCl3 solution.
2a
homopeptides controlled by side-chain chiral centers. These results
indicate that the side-chain chiral environments (bulkiness or
flexibility) might be important for control of the helical-screw sense
of peptides.2
Acknowledgment. This work was partly supported by a Grant-
in-Aid for Scientific Research (B), and Young Scientists (B) from
the Japan Society for the Promotion of Science, and also by the
Sasakawa Scientific Research Grant from the Japan Science Society.
Supporting Information Available: Experimental section, spec-
troscopic data of 1-13, crystallographic details (CIF), IR, CD, ROESY
1
H NMR (PDF), and molecular mechanics calculation (PDB). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(
1) (a) Branden, C.; Tooze, J. Introduction to Protein Structure; Garland:
New York, 1991; pp 1-31. (b) Seebach, D.; Matthews, J. L. Chem.
Commun. 1997, 2015-2022. (c) Seebach, D.; Beck, A. K.; Bierbaum, D.
J. Chem. BiodiVersity 2004, 1, 1111-1239. (d) Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173-180.
(
2) (a) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H. Angew.
Chem., Int. Ed. 2004, 43, 5360-5363. (b) Royo, S.; Borggraeve, W. M.
D.; Peggion, C.; Formaggio, F.; Crisma, M.; Jimenez, A. I.; Cativiela,
C.; Toniolo, C. J. Am. Chem. Soc. 2005, 127, 2036-2037.
Figure 2. Four crystallographically independent molecules (A-D) of 11,
determined by X-ray crystallographic analysis.
(3) Abbreviation: Ac(n)c: 1-aminocycloalkanecarboxylic acid (n ) ring size);
(
R,R)-Ab5,6c: (1R,6R)-8-aminobicyclo[4.3.0]nonane-8-carboxylic acid;
HBTU:O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophos-
8
the right-handed (P) and the left-handed (M) helices exist. The
phate; TEMPO: 2,2,6,6-tetramethyl-1-piperidinoxyl, free radical; TFE:
2
,2,2-trifluoroethanol.
CD spectrum of nonapeptide 12 shows weak negative maxima at
(
4) For peptides composed of dAA with axial chirality, see: (a) Mazaleyrat,
J. P.; Wright, K.; Gaucher, A.; Wakselman, M.; Oancea, S.; Formaggio,
F.; Toniolo, C.; Setnicka, V.; Kapitan, J.; Keiderling, T. A. Tetrahedron:
Asymmetry 2003, 14, 1879-1893. (b) Mazaleyrat, J.-P.; Wright, K.;
Gaucher, A.; Toulemonde, N.; Wakselman, M.; Oancea, S.; Peggion, C.;
Formaggio, F.; Sentnicka, V.; Keiderling, T. A.; Toniolo, C. J. Am. Chem.
Soc. 2004, 126, 12874-12879.
208 and 222 nm and a weak positive maximum at 192 nm,
suggesting both the (P) and (M) helices, but the (P) helix would
be slightly predominant. Interestingly, the conversion of 11 into
the saturated 13 by hydrogenation changes the shape of the CD
spectrum, which suggests the dominant conformation may slightly
be changed.8
(5) See chiral peptoids: Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch,
J. A.; Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. J. Am.
Chem. Soc. 2003, 125, 13525-13530.
The crystal structure of hexapeptide 11 was solved in the P1
(
6) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahedron:
Asymmetry 1999, 10, 3403-3407.
7) (a) Cativiela, C.; de Villegas, M. D. Tetrahedron: Asymmetry 2000, 11,
1
0
space group by a direct method using SHELXS-97, by X-ray
crystallographic analysis (Figure 2).11 In the crystal state, four
crystallographically independent molecules (A, B, C and D) along
with two ethanol molecules, exist in the asymmetric unit, meaning
(
6
45-732. (b) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J.
Org. Chem. 2001, 787-792.
(
8) See Supporting Information.
(
9) Santini, A.; Barone, V.; Bavoso, A.; Benedetti, E.; Di Blasio, B.; Fraternali,
F.; Lelj, F.; Pavone, V.; Pedone, C.; Crisma, M.; Bonora, G. M.; Toniolo,
C. Int. J. Biol. Macromol. 1988, 10, 292-299 and 300-304.
the empirical molecular weight is 4594.0 [4(C67
H
92
N
6
O
9 2 6
)‚2(C H O)].
Two molecules A and D are right-handed (P) 310-helices (mean
value: A φ ) -59.3°, ψ ) -23.9°; D φ ) -59.2°, ψ ) -25.5°)
and two molecules B and C are left-handed (M) 310-helices (mean
value: B φ ) 58.2°, ψ ) 25.8°; C φ ) 57.6°, ψ ) 24.8°).8 These
two molecules, respectively, are very similar in the conformation
of the peptide backbone, but small differences in the conformation,
especially at the side-chain cyclohexene and at the C- and
N-terminus, are observed.
Four intramolecular hydrogen bonds are found in each molecule.
In the packing mode, the molecules A and B are connected by two
intermolecular hydrogen bonds, and the molecules C and D are
connected by one or two intermolecular hydrogen bonds. Thus,
head-to-tail aligned chains of ‚‚‚A(P)‚‚‚B(M)‚‚‚A(P)‚‚‚B(M)‚‚‚ and
(
10) Sheldrick, G. M. SHELXS-97. Program for the solution of crystal structures
from diffraction data, University of G o¨ ttingen: G o¨ ttingen, Germany, 1997.
(
92 6 9 2 6
11) Crystal data for 11: 4(C67H N O )‚2(C H O), M ) 4594.0, space group
P1, a ) 15.765 Å, b ) 16.535 Å, c ) 26.90 Å, R ) 74.22°, â ) 82.32°,
,12
3
-1
γ ) 75.39°, V ) 6514 Å , Z ) 4, T ) 123 K, µ (Mo KR) ) 0.78 cm
,
2
9 059 reflections measured, 14 531 unique reflections (Rint ) 0.0530)
1 2
R (I > 2σ) ) 0.0589, wR (I > 2σ) ) 0.1373, GOF ) 0.885.
(
12) The signs of φ, ψ torsion angles at the C-terminus are opposite to those
of the preceding residues. Thus, the mean values refer to those of the
amino acid residues 1-5, respectively.
(
13) Concomitant occurrences of two diastereomeric (P) and (M) 310-helices
of peptides having the main-chain asymmetric centers have already been
reported. See: (a) Valle, G.; Crisma, M.; Toniolo, C.; Besswenger, R.;
Rieker, A.; Jung, G. J. Am. Chem. Soc. 1989, 111, 6828-6833. (b) Jaun,
B.; Tanaka, M.; Seiler, P.; K u¨ hnle, F. N. M.; Braun, C.; Seebach, D.
Liebigs Ann. Recueil 1997, 1697-1710.
JA053842C
J. AM. CHEM. SOC.
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