Design of peptides with α,β-dehydro residues: A dipeptide with a branched β-carbon dehydro residue at the (i+1) position, methyl N-(benzyloxycarbonyl)-α, β-didehydrovalyl-l-tryptophanate

Article abstract of DOI:10.1107/S010827010100840X

The structure of the title peptide, C₂₅H₂₇N₃O₅, has been determined and its conformation analysed. Values of the standard peptide torsion angles are Φ₁ = -44.2 (3)°, Ψ₁ = 135.9 (2)°, Φ

Full text of DOI:10.1107/S010827010100840X

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
dehydroisoleucine (ÁIle), the structure of a dipeptide with
ÁVal, (II), has been determined.
The structure (Fig. 1) shows that the C1AÐC1B distance of
Ê
ISSN 0108-2701
1.339 (3) A in ÁVal corresponds to a standard C C double-
Ê
bond distance of 1.32 A (Rose et al., 1985). Due to unfa-
vourable interactions between the atoms of the backbone and
those of the side chain, the N1ÐC1AÐC1P angle closes to
Design of peptides with a,b-dehydro
residues: a dipeptide with a branched
b-carbon dehydro residue at the (i+1)
position, methyl N-(benzyloxycar-
bonyl)-a,b-didehydrovalyl-L-trypto-
phanate
Rangachari Vijayaraghavan, Pravindra Kumar, Sharmistha
Dey and Tej P. Singh*
Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi 110 029, India
Correspondence e-mail: tps@aiims.aiims.ac.in
Received 15 February 2001
Accepted 7 August 2001
The structure of the title peptide, C25H27N3O5, has been
determined and its conformation analysed. Values of the
standard peptide torsion angles are '1 = 44.2 (3)ꢁ, =
1
T
2
135.9 (2)ꢁ, '2 = 141.6 (2)ꢁ and = 168.0 (2)ꢁ. The crystal
structure is stabilized by an intermolecular hydrogen bond,
Figure 1
The molecular structure of the title peptide shown with the atom-
numbering scheme and 30% probability displacement ellipsoids.
Ê
with an NÁ Á ÁO distance of 2.919 (3) A, which is formed
between screw-axis-related NH and CO groups of dehydro-
valine residues.
114.2 (2)ꢁ. The other two angles, N1ÐC1AÐC1B and C1PÐ
C1AÐC1B, are 121.3 (2) and 123.5 (2)ꢁ, respectively.
The peptide adopts a conformation characterized by the
Comment
torsion angles '1 (CPÐN1ÐC1AÐC1P) = 44.2 (3)ꢁ,
ꢀ,ꢁ-Dehydroamino acids are strong inducers of folded
conformations in peptides. A set of design rules have been
developed with dehydrophenylalanine (ÁPhe), dehydro-
leucine (ÁLeu), dehydro-ꢀ-aminobutyric acid (ÁAbu) and
dehydroalanine (ÁAla) (Singh & Kaur, 1996). However, the
branched ꢁ-carbon residues, such as valine and isoleucine,
1
(N1ÐC1AÐC1PÐN2) = 135.9 (2)ꢁ, '2 (C1PÐN2ÐC2AÐ
T
C2P) = 141.6 (2)ꢁ and (N2ÐC2AÐC2PÐO3T) =
2
168.0 (2)ꢁ. It may be noted that the values of the torsion angles
of ÁVal correspond to the ', values of an (i+1)th residue in a
ꢁ-turn II conformation. This indicates that the ÁVal residue at
the (i+1) position may promote a ꢁ-turn II conformation. The
values of the torsion angles ꢂ11,1 (N1ÐC1AÐC1BÐC1G1)
and ꢂ11,2 (N1ÐC1AÐC1BÐC1G2) of dehydrovaline are
6.6 (4) and 170.1 (3)ꢁ, respectively, and indicate that the
ÁVal side chain is essentially planar.
The crystal packing is stabilized by a hydrophobic region
formed by the aromatic rings of tryptophans and the benzene
rings of benzyloxycarbonyl (Cbz) groups. The packing is
further stabilized by an intermolecular hydrogen bond formed
between the screw-axis-related NH and CO groups of the
have not been used so far as dehydro residues, although the
conformational preferences of valine and isoleucine are
known to be different from those of other residues. In order to
develop new design rules with dehydrovaline (ÁVal) and
ÁVal residue [N1ÐH1Á Á ÁO1Pi: N1Á Á ÁOPi = 2.919 (3) A,
Ê
i
i
ꢁ
Ê
H1Á Á ÁO1P = 2.16 A and N1ÐH1Á Á ÁO1P = 147 ; symmetry
1
2
code: (i) x, y
,
z + 12].
ꢀ
1220 # 2001 International Union of Crystallography
Printed in Great Britain ± all rights reserved
Acta Cryst. (2001). C57, 1220±1221

organic compounds
Re®nement
Experimental
Re®nement on F2
R[F2 > 2ꢅ(F2)] = 0.046
wR(F2) = 0.146
S = 1.04
2576 re¯ections
w = 1/[ꢅ2(Fo2) + (0.1137P)2
+ 0.5403P]
The synthesis of Cbz±ÁVal±OH, (I), was carried out by condensation
of 3-methyl-2-oxo-butanoic acid (1 g, 7.2 mmol) with benzyl
carbamate (1.98 g, 10.8 mmol) and p-toluenesulfonic acid (0.47 g,
2.1 mmol) in dry benzene. The reaction mixture was re¯uxed at 373 K
for 8 h using a Dean±Stark water remover. The solution was then
extracted with saturated sodium bicarbonate. The extracts were
neutralized by adding concentrated HCl dropwise to yield a white
solid, which was ®ltered off and recrystallized from benzene. The
solid product of Cbz±ÁVal±OH was obtained in 67% yield. For the
synthesis of Cbz±ÁVal±l-Trp±OCH3 (Trp is l-tryptophan), (II),
N-methylmorpholine (0.29 ml, 2.69 mmol) was added to a chilled
(263 K) solution of (I) (0.67 g, 2.69 mmol) in tetrahydrofuran. This
was followed by the addition of isobutyl chloroformate (0.36 ml,
2.69 mmol) and the resulting solution was stirred for 20 min. A
precooled solution of l-Trp±OCH3ÁHCl (0.82 g, 3.2 mmol) was added
to the reaction mixture. The resulting solution was stirred for 2 h at
273 K and then overnight at room temperature. After completion of
the reaction (monitored by thin-layer chromatography), the solvent
was removed under vacuum; the resulting residual material was
dissolved in ethyl acetate and washed successively with water, 10%
sodium bicarbonate, 5% citric acid and water. The organic layer was
dried over anhydrous sodium sulfate and then evaporated to yield
72% of (II) (m.p. 438 K). The peptide was recrystallized from a
solution in acetone±water (4:1) by slow evaporation.
where P = (Fo2 + 2Fc2)/3
(Á/ꢅ)max < 0.001
3
Ê
Áꢆmax = 0.24 e A
Áꢆmin
3
Ê
0.25 e A
302 parameters
H-atom parameters constrained
=
Extinction correction: SHELXL97
Extinction coef®cient: 0.0018 (4)
All H atoms were visible in difference maps and were allowed for
Ê
as riding atoms (with CÐH distances of 0.93±0.98 A and an NÐH
Ê
distance of 0.86 A). In this light-atom structure, it was not possible to
establish the absolute con®guration from the Flack (1983) parameter
[0.1 (3)]; the con®guration chosen and shown in both the Scheme and
Fig. 1 was determined by the con®guration of the starting material in
the synthesis (l-tryptophan).
Data collection: SDP (Enraf±Nonius, 1979); cell re®nement: SDP;
data reduction: SDP; program(s) used to solve structure: SHELXS97
(Sheldrick, 1997); program(s) used to re®ne structure: SHELXL97
(Sheldrick, 1997); molecular graphics: PLATON (Spek, 2001); soft-
ware used to prepare material for publication: SHELXL97.
The authors thank the Council of Scienti®c and Industrial
Research, New Delhi, for ®nancial support.
Crystal data
3
C25H27N3O5
Mr = 449.50
Monoclinic, A2
a = 17.1524 (9) A
Ê
b = 6.1439 (9) A
c = 22.6183 (11) A
ꢁ = 107.791 (12)ꢁ
Ê
V = 2269.6 (4) A
Z = 4
Dx = 1.315 Mg m
Cu Kꢀ radiation
Cell parameters from 25
re¯ections
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: VJ1138). Services for accessing these data are
described at the back of the journal.
Ê
ꢃ = 0±25ꢁ
ꢄ = 0.76 mm
T = 293 (2) K
1
Ê
3
Prism, colourless
0.3 Â 0.2 Â 0.1 mm
References
Enraf±Nonius (1979). Structure Determination Package. Enraf±Nonius, Delft,
The Netherlands.
Flack, H. D. (1983). Acta Cryst. A39, 876±881.
Rose, G. D., Gierasch, L. M. & Smith, J. A. (1985). Advances in Protein
Chemistry, edited by C. B. An®nsen Jr, J. T. Edsal & F. M. Richards, p. 37.
New York: Academic Press.
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of GoÈtt-
ingen, Germany.
Singh, T. P. & Kaur, P. (1996). Prog. Biophys. Mol. Biol. 66, 141±165.
Spek, A. L. (2001). PLATON. University of Utrecht, The Netherlands.
Data collection
Enraf±Nonius CAD-4
diffractometer
!±2ꢃ scans
Absorption correction: empirical
(SDP; Enraf±Nonius, 1979)
Tmin = 0.835, Tmax = 0.928
2576 measured re¯ections
2576 independent re¯ections
2434 re¯ections with I > 2ꢅ(I)
ꢃ
max = 75.6ꢁ
h = 0 ! 21
k = 0 ! 7
l = 28 ! 26
3 standard re¯ections
frequency: 60 min
intensity decay: none
ꢀ
Acta Cryst. (2001). C57, 1220±1221
Rangachari Vijayaraghavan et al. C25H27N3O5 1221