ChemComm
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peptides with no significant preference for a helical conforma-
tion is a noteworthy finding.
We thank the Department of Science and Technology (DST
and DST-FIST) and CSIR, New Delhi, for the financial support.
We thank Prof. Narayanan Kurur (IITD) for discussions regard-
ing NMR experiments. We also thank Prof. Venugopalan Paloth,
Punjab University, for the help in X-ray structure analysis.
Notes and references
1 (a) D. Seebach, D. F. Hook and A. Glattli, Biopolymers, 2006, 84, 23–37;
(b) M. Davis, L. K. Tsou and A. D. Hamilton, Chem. Soc. Rev., 2007, 36,
326–334; (c) V. Haridas, Eur. J. Org. Chem., 2009, 5112–5128.
2 (a) N. H. Shepherd, H. N. Hoang, G. Abbenante and D. P. Fairlie,
J. Am. Chem. Soc., 2005, 127, 2974–2983; (b) M. T. Ma, H. N. Hoang,
C. C. G. Scully, T. G. Appleton and D. P. Fairlie, J. Am. Chem. Soc.,
2009, 131, 4505–4512.
3 (a) A. Patgiri, A. L. Jochim and P. S. Arora, Acc. Chem. Res., 2008, 41,
1289–1300; (b) A. Patgiri, S. T. Joy and P. S. Arora, J. Am. Chem. Soc.,
2012, 134, 11495–11502.
4 J. Becerril and A. D. Hamilton, Angew. Chem., Int. Ed., 2007, 46,
4471–4473.
5 (a) W. S. Horne, J. L. Price, J. L. Keck and S. H. Gellman, J. Am. Chem.
Soc., 2007, 129, 4178–4180; (b) M. W. Giuliano, W. S. Horne and
S. H. Gellman, J. Am. Chem. Soc., 2009, 131, 9860–9861; (c) L. Guo,
W. Zhang, I. A. Guzei, L. C. Spencer and S. H. Gellman, Org. Lett.,
2012, 14, 2582–2585.
6 (a) W. S. Horne and S. H. Gellman, Acc. Chem. Res., 2008, 41,
1399–1408; (b) G. A. Lengal, R. C. Frank and W. S. Horne, J. Am.
Chem. Soc., 2011, 133, 4246–4249.
Fig. 4 X-ray crystal structure of B3: (a) capped stick representation, (b) back-
bone of B3 showing a right handed helical conformation. The peptide backbone
is coloured yellow. (c) Intermolecularly H-bonded assembly in the solid state
showing H-bonds between Val NHs and Phe COs.
7 (a) K. A. Dill, S. Bromberg, K. Yue, K. M. Fiebig, D. P. Yee,
P. D. Thomas and H. S. Chan, Protein Sci., 1995, 4, 561–602;
(b) S. V. Krivov and M. Karplus, Proc. Natl. Acad. Sci. U. S. A., 2004,
101, 14766–14770.
8 (a) D. S. Kemp, Trends Biotechnol., 1990, 8, 249; (b) A. Grauer and
B. Konig, Eur. J. Org. Chem., 2009, 5099–5111.
9 (a) E. L. McCallister, E. Alm and D. Baker, Nat. Struct. Biol., 2000, 7,
669–673; (b) A. M. C. Marcelino and L. M. Gierasch, Biopolymers,
2008, 89, 380–391.
10 (a) J. S. Park, H.-S. Lee, J. R. Lai, B. M. Kim and S. H. Gellman, J. Am.
Chem. Soc., 2003, 125, 8539–8545; (b) T. A. Martinek, I. M. Mandity,
L. Fulop, G. B. Toth, E. Vass, M. Hollosi, E. Forro and F. Fulop, J. Am.
Chem. Soc., 2006, 128, 13539–13544.
The protonation of the tertiary nitrogen in bispidine was
expected to result in a conformational change (Fig. S13, ESI†).
The CD spectrum of B3 changed from a helical conformation to
the one similar to a polyproline type I (PPI) conformation with
the addition of trifluoromethane sulfonic acid or methane
sulfonic acid (Fig. S13, ESI†). The CD spectrum displayed a
maximum at 225 nm, indicative of a PPI conformation.20 The
CD, NMR and FT-IR studies on B6 and B7 also showed helical
conformation (Fig. S14–19, ESI†).
Compound B3 was crystallized from acetonitrile and
dimethylformamide (Table S3, ESI†). The X-ray crystal structure
of B3 showed topological similarity to a right-handed helical
conformation (Fig. 4) with torsional angles (Table S5, ESI†)
different from a typical a-helix. The two piperidine rings of
bispidine adopted chair conformations, resulting in a chair–chair
(CC) conformation.21 The distance between the two nitrogens in
the bispidine unit is 2.93 Å. The intramolecular hydrogen bonds
were observed between Leu-CO with Ala NH (2.338 Å), Ala CO with
Leu NH (2.072 Å) and Phe NH with Val CO (2.398 Å) (Fig. S20, ESI†).
These hydrogen bonds resulted in 10, 11, and 12-membered rings
(Fig. S20, ESI†). The crystal structure further showed that free Val
NH present in B3 is involved in an intermolecular H-bond with the
Phe CO of another molecule to form a linear chain of helical
molecules (Fig. 4c).
11 J.-I. Cho, M. Tanaka, S. Sato, K. Kinbara and T. Aida, J. Am. Chem.
Soc., 2010, 132, 13176–13178.
12 P. G. Vasudev, K. Ananda, S. Chatterjee, S. Aravinda, N. Shamala and
P. Balaram, J. Am. Chem. Soc., 2007, 129, 4039–4048.
13 (a) D. E. Hibbs, M. B. Hursthouse, I. G. Jones, W. Jones and K. M. A.
Malik, J. Org. Chem., 1998, 63, 1496–1504; (b) D. Ranganathan,
V. Haridas, S. Kurur, A. Thomas, K. P. Madhusudanan, R. Nagaraj,
A. C. Kunwar, A. V. S. Sarma and I. L. Karle, J. Am. Chem. Soc., 1998,
120, 8448–8460; (c) W. Han, J. C. Pelletier, L. J. Mersinger,
C. A. Kettner and C. N. Hodge, Org. lett., 1999, 1, 1875–1877.
14 M. Favre, K. Moehle, L. Jiang, B. Bfeiffer and J. A. Robinson, J. Am.
Chem. Soc., 1999, 121, 2679–2685.
15 V. Haridas, S. Sadanandan, Y. K. Sharma, S. Chinthalapalli and
A. Shandilya, Tetrahedron Lett., 2012, 53, 623–626.
16 O. Huttenloch, J. Spieler and H. Waldmann, Chem.–Eur. J., 2001, 7,
671–675.
17 H. Kessler, Angew. Chem., Int. Ed. Engl., 1982, 21, 512–523.
18 D. F. Kennedy, M. Crisma, C. Toniolo and D. Chapman, Biochemistry,
1991, 30, 6541–6548.
19 (a) D. H. Chin, R. W. Woody, C. A. Rohl and R. L. Baldwin, Proc. Natl.
Acad. Sci. U. S. A., 2002, 99, 15416–15421; (b) W. H. Driver,
H. N. Hoang, G. Abbenante and D. P. Fairlie, Org. Lett., 2009, 11,
3092–3095.
In conclusion, we have identified bispidine as a moiety that
can induce a helical conformation. The NMR, IR, CD and X-ray
structure supported the right handed helical conformation in 20 J.-C. Horng and R. T. Raines, Protein Sci., 2006, 15, 74–83.
21 (a) P. H. McCabe, N. J. Milne and G. A. Sim, J. Chem. Soc., Chem.
solution and in the solid state. The conformational transition
from a helix to PPI-type conformation is an additional observa-
Commun., 1985, 625–626; (b) L. Toom, A. Kutt, I. Kaljurand, I. Leito,
H. Ottoson, H. Grennberg and A. Gogoll, J. Org. Chem., 2006, 71,
tion. The effectiveness of bispidine in facilitating the folding of
7155–7164.
c
This journal is The Royal Society of Chemistry 2013
10982 Chem. Commun., 2013, 49, 10980--10982