Helical-screw directions of diastereoisomeric cyclic α-amino acid oligomers

Article abstract of DOI:10.1021/ol802963a

Two series of homooligomers composed of diastereoisomeric cyclic α-amino acids having two chiral centers at the α-carbon and the side chain were synthesized, and their preferred secondary structures were studied in solution and in the crystal state. The o

Full text of DOI:10.1021/ol802963a

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1135-1137
Helical-Screw Directions of
Diastereoisomeric Cyclic r-Amino Acid
Oligomers
Masanobu Nagano,† Masakazu Tanaka,*,†,‡ Mitsunobu Doi,§ Yosuke Demizu,|
Masaaki Kurihara,| and Hiroshi Suemune*,†
Graduate School of Pharmaceutical Sciences, Kyushu UniVersity, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan, Graduate School of Biomedical Sciences,
Nagasaki UniVersity, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, Osaka
UniVersity of Pharmaceutical Sciences, Osaka 569-1094, Japan, and DiVision of
Organic Chemistry, National Institute of Health Sciences, Tokyo 158-8501, Japan
matanaka@nagasaki-u.ac.jp
Received December 24, 2008
ABSTRACT
Two series of homooligomers composed of diastereoisomeric cyclic r-amino acids having two chiral centers at the r-carbon and the side
chain were synthesized, and their preferred secondary structures were studied in solution and in the crystal state. The oligomers are a new
class of helical-foldamers possessing two kinds of chiral centers on the helical backbone and at the lateral surface of the helix.
Right-handed R-helical-screw structures in proteins are
believed to result from the L-(S)-chiral R-carbon atoms on
the peptide backbone.1 Recently, Toniolo’s group and we
independently reported that the helical-screw sense of
peptide-oligomers can be controlled without a chiral center
on the peptide backbone, but by chiral centers at the side
chain.2 However, so far, little attention has been paid to how
both chiral centers on the peptide backbone and at the side
chain influence the secondary structures of their oligomers.3
Herein, we designed two diastereoisomeric cyclic amino
(2) (a) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
Angew. Chem., Int. Ed. 2004, 43, 5360–5363. (b) Tanaka, M.; Anan, K.;
Demizu, Y.; Kurihara, M.; Doi, M.; Suemune, H. J. Am. Chem. Soc. 2005,
127, 11570–11571. (c) Royo, S.; Borggraeve, W. M. D.; Peggion, C.;
Formaggio, F.; Crisma, M.; Jime´nez, A. I.; Cativiela, C.; Toniolo, C. J. Am.
Chem. Soc. 2005, 127, 2036–2037.
(3) (a) Jime´nez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J. Am.
Chem. Soc. 1998, 120, 9452–9459. (b) Sharma, G.; Reddy, K. R.; Krishna,
P. R.; Sankar, A. R.; Jayaprakash, P.; Jagannadh, B.; Kunwar, A. C. Angew.
Chem., Int. Ed. 2004, 43, 3961–3965. (c) Andreetto, E.; Peggion, C.; Crisma,
M.; Toniolo, C. Biopolymers (Peptide Sci.) 2006, 84, 490–501. (d) Ku¨min,
M.; Sonntag, L.-S.; Wennemers, H. J. Am. Chem. Soc. 2007, 129, 466–
467.
† Kyushu University.
‡ Nagasaki University.
§ Osaka University of Pharmaceutical Sciences.
| National Institute of Health Sciences.
(1) Branden, C.; Tooze, J. Introduction to Protein Structure; Garland:
New York, 1991; pp 1-31.
10.1021/ol802963a CCC: $40.75
Published on Web 02/03/2009
2009 American Chemical Society

acids,4 (1S,3S)- and (1R,3S)-1-amino-3-(methoxy)cyclopen-
tanecarboxylic acids (Ac5cOM), constructed their homooli-
gomers having chiral centers both on the peptide-backbone
and at the side chain, and revealed their unique helical
structures with high resolution analyses.
Two cyclic amino acids (1S,3S)-Ac5cOM and (1R,3S)-
Ac5cOM were synthesized starting from L-(-)-malic acid 1
(Scheme 1). After esterification of 1, the secondary alcohol
groups] and strong bands at 3320-3380 cm-1 (intramolecu-
larly H-bonded peptide NH groups). The latter bands
observed at 3380 cm-1 in 5a and at 3376 cm-1 in 5b shift
to lower wavenumbers (3320 cm-1 in 10a and 3320 cm-1
in 10b), respectively, and the relative intensities increase with
elongation of the peptide length. These IR spectra are very
similar to those of helical Ac(n)c oligomers.7
In the ROESY 1H NMR spectra, the hexamers 8a and 8b
showed a complete series of sequential dNN cross-peaks of
NOEs from the N-terminal NH(1) to the C-terminal NH(6),
respectively.6 These correlations are characteristic for the
helical structure, albeit that those of longer oligomers only
gave a partial series of sequential dNN cross-peaks. Addition
of DMSO or the free-radical TEMPO in the 1H NMR
spectroscopy indicated that the two NH signals [NH(1) and
NH(2)] at the N-terminus of (1R,3S)-oligomers 8b and 9b
are sensitive (solvent-exposed NH group), respectively,
suggesting that the two NH groups are not intramolecularly
H-bonded, and formation of a helical structure.2,6,7 The
experiments of (1S,3S)-oligomers 8a and 9a did not give
clear results because the relevant NH peaks overlapped.6
The CD spectra of tetramers 7 and hexamers 8 in 2,2,2-
trifluoroethanol (TFE) solution, both (1S,3S)- and (1R,3S)-
Ac5cOM, did not show characteristic maxima (208 and 222
nm) for the helical structure. These spectra may suggest the
presence of both right-handed (P) and left-handed (M) helices
or disordered structures. Elongation of oligomer length
changed the shapes of CD spectra, and positive maxima at
208 and 222 nm were observed in the (1S,3S)-octamer 9a
and decamer 10a while negative maxima were seen in the
(1R,3S)-9b and 10b. These CD spectra suggest that the
dominant conformation of (1S,3S)-9a and 10a is a left-handed
(M) helix and that of (1R,3S)-9b and 10b is a right-handed
(P) helix. The CD spectra of (1S,3S)- and (1R,3S)-oligomers
showed a pseudosymmetric shape, strongly indicating that
the CD curves are the result of approximately enantiomeric
global chain helicity (Figure 1).
Scheme 1.
Synthesis of (1S,3S)- and (1R,3S)-Ac5cOM
was converted to a methyl ether. Then, reduction of diester
followed by iodination of alcohol gave a diiodide 2.
Dialkylation of dimethyl malonate with 2 afforded a cyclo-
pentane diester 3. Monohydrolysis of 3 with an alkaline
solution, followed by Curtius rearrangement with diphe-
nylphosphoryl azide (DPPA), produced two separable dias-
tereoisomers (1S,3S)-Ac5cOM (4a) and (1R,3S)-Ac5cOM (4b)
in a ratio of 3:1 in 85% yield.5 Meanwhile, hydrolysis of 3
with pig liver esterase (PLE) followed by Curtius rearrange-
ment could change the diastereoselectiviy (4a:4b ) 1:2; 84%
yield). The stereochemistry of products was unambiguously
assigned by the X-ray crystallographic analyses of their
oligomers.6
Oligomers Cbz-{(1S,3S)-Ac5cOM}m-OMe {m ) 2 (5a), 4
(7a), 6 (8a), 8 (9a), 10 (10a)} and Cbz-{(1R,3S)-Ac5cOM}n-
OMe {n ) 2 (5b), 3 (6b), 4 (7b), 6 (8b), 8 (9b), 10 (10b)}
were generally prepared by the coupling between N-terminal-
free oligomers and N-protected dipeptide acid via solution-
phase methods. It should be noted that elongation of
N-terminal-free (1R,3S)-Ac5cOM dimer to a tetramer 7b did
not work well because diketopiperazine was formed as a
byproduct. Thus, the (1R,3S)-tetramer was prepared via a
trimer 6b, which was derived from an N-terminal-free amino
acid and the dipeptide acid.6
The FT-IR absorption spectra of both (1S,3S)- and (1R,3S)-
Ac5cOM oligomers in CDCl3 solution showed weak bands in
the region 3420-3430 cm-1 [free (solvated) peptide NH
Figure 1. CD spectra of (1S,3S)- and (1R,3S)-oligomers in TFE
solution (100 µM). (a) 7-10a: Cbz-{(1S,3S)-Ac5cOM}m-OMe (m
) 4, 6, 8, 10). (b) 7-10b: Cbz-{(1R,3S)-Ac5cOM}n-OMe (n ) 4,
6, 8, 10). Tetramer 7 (green), hexamer 8 (yellow), octamer 9 (blue),
and decamer 10 (red).
(4) (a) Cativiela, C.; D.-de-Villegas, M. D. Tetrahedron: Asymmetry
2000, 11, 645–732. (b) Kotha, S. Acc. Chem. Res. 2003, 36, 342–351.
(5) Nagano, M.; Demizu, Y.; Tanaka, M.; Kurihara, M.; Doi, M.;
Suemune, H. Peptide Science 2005; The Japanese Peptide Society: Osaka,
Japan, 2006; pp 345-346.
The X-ray analysis of (1S,3S)-Ac5cOM hexamer 8a having
12 chiral centers showed both diastereomeric right-handed
(6) See the Supporting Information.
1136
Org. Lett., Vol. 11, No. 5, 2009

(P) and left-handed (M) 310-helices (Figure 2). In contrast,
(1S,3S)-octamer 9a crystallized exclusively to left-handed
Figure 3.
X-ray crystallographic analysis of Cbz-{(1R,3S)-Ac5cOM}n-
OMe [(a) 8b: n ) 6, (b) 9b: m ) 8].
Ac5cOM possess a unique chiral structure; i.e., transfer of the
MeO-substituent on the γ-positions of cyclopentane in
(1S,3S)-4a results in formation of enantiomer (1R,3R) or
diastereomer (1R,3S) because the chirality of the R-carbon
(C1) is changed (Figure 4). Thus, the helical-screw structures
Figure 2.
X-ray crystallographic analysis of Cbz-{(1S,3S)-Ac5cOM}m-
OMe {(a) 8a: m ) 6, (b) 9a: m ) 8}. Red: left-handedness (M),
blue: right-handedness (P).
(M) 310-helices, while in the asymmetric unit there were two
crystallographically independent (M) 310-helical conformers.
The diastereomeric (1R,3S)-Ac5cOM hexamer 8b showed two
crystallographically independent right-handed (P) 310-helices.
The (1R,3S)-octamer 9b also showed two conformers, both
(P) 310-helices but in the one conformer the signs of φ, ψ
torsion angles at the C-terminal residue were opposite. There,
six consecutive intramolecular H-bonds of the iri+3 type
(i ) 0∼5) were found, respectively.6,8
In the crystal state, the (1S,3S)-hexamer 8a having 12
chiral centers at the R-carbon and the side chain assumed
both (P) and (M) 310-helices,2b while the (1R,3S)-hexamer
8b formed only (P) helices, probably influenced by the
crystal packing force. By the elongation of peptide length,
i.e., by the increase of chiral centers, both (1S,3S)- and
(1R,3S)-oligomers were controlled to form one-handed
helical-screw structures in solution and in the crystal state;
i.e., the (1S,3S)-octamer 9a formed (M) helices and the
(1R,3S)-octamer 9b formed (P) helices. Molecular mechan-
ics/ab initio (RHF/3-21G*) calculations of (1S,3S)-9a pro-
duced a (M) 310-helix as a global minimum-energy (GME)
conformation, and those of (1R,3S)-9b gave a (P) 310-helix
as a GME conformation.6
Figure 4.
Unique chiral structure of Ac5cOM and helical-screw
direction of their oligomers.
might be controlled by the whole chiral cyclopentane amino
acid structure.
In summary, we synthesized two series of the diastereo-
meric Ac5cOM oligomers that are a new class of helical-
foldamers possessing two kinds of chiral centers on the
helical backbone and at the lateral surface of the helix9 and
revealed their preferred helical conformations in solution and
in the crystal state. These results might be useful for design
of foldamer catalysts and lead compounds, which are
currently under investigation in our group.
At first, we considered each effect of the R-carbon and
the side-chain chiral centers or match/mismatch of chiral
centers on one-handed helical-screw direction. However, the
(7) (a) 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. (b) Crisma,
M.; Bonora, G. M.; Toniolo, C.; Benedetti, E.; Bavoso, A.; Di Blasio, B.;
Pavone, V.; Pedone, C. Int. J. Biol. Macromol. 1988, 10, 300–304.
(8) In some oligomers, inversions of signs or distortions of φ, ψ torsion
angles at the C-terminal residue are observed. See the Supporting Informa-
tion.
(9) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (b) Seebach,
D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111–1239.
(c) 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. (d) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion,
C.; Broxterman, Q. B.; Kaptein, B. Biopolymers (Peptide Sci.) 2004, 76,
162–176. (e) Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxterman, Q. B.
Synlett 2006, 1295–1310. (f) Tanaka, M. Chem. Pharm. Bull. 2007, 55,
349–358. (g) Maity, P.; Ko¨nig, B. Biopolymers (Peptide Sci.) 2008, 90,
8–27.
Acknowledgment. This work was in part supported by
Grant-in-Aid (B) from JSPS, by a Grant-in Aid for Scientific
Research on Priority Areas (No. 20037054, “Chemistry of
Concerto Catalysis”) from MEXT, and also by a Grant-in-
Aid from the ASAHI GLASS Foundation. M.N. thanks the
JSPS for Research Fellowships.
Supporting Information Available: Experimental sec-
tion, spectroscopic data of new compounds, crystallographic
details (CIF), and molecular calculations. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL802963A
Org. Lett., Vol. 11, No. 5, 2009
1137