Sh eet Str u ctu r e of a n L,D-Dip ep tid e Aggr ega te: In clu sion
Com p ou n d s of (S)-P h en ylglycyl-(R)-p h en ylglycin e w ith Am id es
Motohiro Akazome, Kyoko Senda, and Katsuyuki Ogura*
Department of Materials Technology, Faculty of Engineering, Chiba University,
1-33 Yayoicho, Inageku, Chiba 263-8522, J apan
katsu@galaxy.tc.chiba-u.ac.jp
Received J uly 2, 2002
A simple dipeptide, (S)-phenylglycyl-(R)-phenylglycine (S,R-1), formed inclusion compounds with
a small amide such as formamide, acetamide, N,N-dimethylformamide (DMF), or N,N-dimethy-
lacetamide. By single-crystal X-ray analysis, the inclusion compounds were shown to have a wavy
layer structure. The molecules of S,R-1 are arranged in parallel via ionic pairing of the carboxyl
and amino groups to construct the wavy layers. The guest molecules were accommodated in a
channel cavity between the layers by means of hydrogen bonding with +NH3 of S,R-1. The cavity
is surrounded by the phenyl groups of S,R-1 that conformationally rotate so as to make the cavity
size fit the guest amide.
In tr od u ction
with the observation that homoconfigurational dipeptides
favor an extended conformation in solution.6 Since the
L,D-dipeptides are shown to adopt a more compact,
intramolecularly hydrogen-bonded structure in water,6
we were interested to see whether a diastereomer of R,R-
1, namely (S)-phenylglycyl-(R)-phenylglycine (S,R-1), can
form an inclusion compound with an appropriate guest
and, if so, what conformation S,R-1 adopts in the inclu-
sion crystals. Molecular orbital calculation with a PM3
method suggested that the most stable conformation of
S,R-1 is an extended one (A in Figure 1b).7 In this
conformation, two phenyl groups face one another. When
a zwitterion form is considered for S,R-1, a cyclic form
(B) is more stable than an expanded form (C). Here, we
wish to report that S,R-1 forms an inclusion compound
with an appropriate amide that is accommodated in the
cavity between the layers of S,R-1.
In recent years, peptides, oligopeptides, and polypep-
tides with a regular sequence of enantiomeric residues
(L and D) along the chain have received considerable
attention because their conformational behavior somehow
differs from that of homoconfigurational peptides or
polypeptides. Most interestingly, they form intriguing
structures1 such as double-stranded helices2 and nano-
tubes.3 The structures of these peptides seem to come
from the favorable conformation of the D,L-dipeptide unit
that is different from that of L,L-dipeptides.
Hitherto we have reported that simple homoconfigu-
rational D,D-dipeptide, (R)-phenylglycyl-(R)-phenylglycine
[R,R-1], and its naphthyl analogue construct a layered
structure, and guest molecules are included between the
layers as illustratively depicted in Figure 1a.4,5 In all of
the crystals investigated, the dipeptide backbone adopts
a linear extended conformation. This is in accordance
Resu lts a n d Discu ssion
(1) Recent reviews on peptide helices and tubes: (a) Bong, D. T.;
Clark, T. D.; Granja, J . R.; Ghadiri, M. R. Angew. Chem., Int. Ed. 2001,
40, 988. (b) Karle, I. L. Acc. Chem. Res. 1999, 32, 693.
(2) (a) Di Blasio, B.; Benedetti, E.; Pavone, V.; Pedone, C.; Spiniello,
O.; Lorenzi, G. P. Biopolymers 1989, 28, 193-201. (b) Di Blasio, B.;
Benedetti, E.: Pavone, V.; Pedone, C.; Gerber, C.; Lorenzi, G. P.
Biopolymers 1989, 28, 203. (c) Benedetti, E.; Di Blasio, B.; Pedone, C.;
Spiniello, O.; Lorenzi, G. P.; Tomasic, L.; Gramlich, V. A. Nature 1979,
282, 630.
(3) (a) Hartgerink, J . D.; Granja, J . R.; Milligan, R. A.; Ghadiri, M.
R. J . Am. Chem. Soc. 1996, 118, 43. (b) Ghadiri, M. R.; Granja, J . R.;
Milligan, R. A.; McRee, D. E.; Khazanovich, N. Nature 1993, 366, 324.
(c) Pavone, V.; Benedetti, E.; Di Blasio, B.; Lombardi, A.; Pedone, C.;
Tomasic, L.; Lorenzi, G. P Biopolymers 1989, 28, 215.
(4) (a) Akazome, M.; Ueno, Y.; Ooiso, H.; Ogura, K. J . Org. Chem.
2000, 65, 68. (b) Akazome, M.; Noguchi, M.; Tanaka, O.; Sumikawa,
A.; Uchida, T. Ogura, K. Tetrahedron 1997, 53, 8315. (c) Ogura, K.;
Uchida, T.; Noguchi, M.; Murata, A.; Fujita, M.; Ogata, K. Tetrahedron
Lett. 1990, 31, 3331.
In clu sion of Am id es. Quite different from R,R-1,
which easily forms crystals, S,R-1 is poor in crystallinity.
Actually, S,R-1 is more soluble in methanol (up to 23.4
mM) than R,R-1 (4.6 mM). This seems to result from
their conformational difference based on the stereochem-
istry of the dipeptides. During our examination of the
solubility of S,R-1 in various solvents, it was found that,
when S,R-1 was dissolved in DMF, an inclusion com-
pound of DMF was formed. This finding encouraged us
to investigate the formation of inclusion compounds of
S,R-1 with amides.
First, we recrystallized S,R-1 from methanol involving
various amides. Formamide, N,N-dimethylformamide,
(5) (a) Akazome, M.; Takahashi, T.; Sonobe, R.; Ogura, K. Supramol.
Chem. 2001, 13, 109. (b) Akazome, M.; Takahashi, T.; Ogura, K. J .
Org. Chem. 1999, 64, 2293. (c) Akazome, M.; Yanagita, Y.; Sonobe, R.;
Ogura, K. Bull. Chem. Soc. J pn. 1997, 70, 2823. (d) Akazome, M.;
Sumikawa, A.; Sonobe, R.; Ogure, K. Chem. Lett. 1996, 995.
(6) Barrett, G. C. In Comprehensive Organic Chemistry; Barton, S.
D., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 5, p 367.
(7) With MOPAC (Ver. 6): Stewart, J . J . P. QCPE Bull. 1989, 10,
209-220 and 221-264.
10.1021/jo0204451 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/09/2002
J . Org. Chem. 2002, 67, 8885-8889
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