Oxazol-5(4H)-one from benzyloxycarbonyl-(Aib)4-OH

Article abstract of DOI:10.1107/S0108270100003413

Benzyl N-[8-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)-2,5,5,8- tetramethyl-3,6-dioxo-4,7-diazanon-2-yl]carbamate, C₂₄H₃₄N₄O₆, an oxazol-5(4H)-one from N-α-benzyloxycarbonyl-(Aib)₄-OH (Aib = α-aminoisobutyryl) represents the longest peptide oxazolone so far characterized by X-ray diffraction. The overall geometry of the oxazolone ring compares well with literature data. The Aib(1) and Aib(2) residues are folded into a type III β-bend, while the conformation adopted by Aib(3), preceding the oxazolone moiety, is semi-extended. The disposition of the oxazolone ring relative to the preceding residue is stabilized by C-H···N and C-H···O intramolecular interactions.

Full text of DOI:10.1107/S0108270100003413

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
the C3 N4 bond and the widening of both the C3AÐC3ÐN4
and the C4AÐC4ÐO4 exocyclic bond angles compared with
the C3AÐC3ÐO3 and O3ÐC4ÐO4 bond angles, respec-
tively, are con®rmed.
ISSN 0108-2701
The oxazolone ring is nearly planar. The largest displace-
ments from the mean plane are observed for atoms C4A and
Ê
N4 [ 0.023 (2) and 0.017 (2) A, respectively]. For the ring
substituents, atoms C3A and O4 are displaced out of the plane
An oxazol-5(4H)-one1 from
benzyloxycarbonyl-(Aib)4-OH
Ê
by 0.017 (3) and 0.055 (2) A, respectively.
The urethane and peptide bonds are trans. However, a
signi®cant deviation from the trans planarity is observed for
the C2AÐC2ÐN3ÐC3A torsion angle [ 164.78 (16)ꢀ]. The
disposition of the benzyloxycarbonylamino moiety is
described by the values of the torsion angles C07ÐOUÐC0Ð
N1 [ 175.88 (16)ꢀ], C01ÐC07ÐOUÐC0 [99.2 (2)ꢀ] and
C02ÐC01ÐC07ÐOU [99.8 (2)ꢀ].
Marco Crisma,* Fernando Formaggio and Claudio Toniolo
Biopolymer Research Centre, CNR, Department of Organic Chemistry, University of
Padova, Via Marzolo 1, 35131 Padova, Italy
Correspondence e-mail: biop02@chor.unipd.it
Received 27 January 2000
Accepted 3 March 2000
An intramolecular hydrogen bond is observed between the
N3-H group and the O0 carbonyl O atom of the Z-protecting
group, giving rise to an intramolecularly hydrogen-bonded
ten-membered ring structure (ꢁ-bend). The sets of the ',
backbone torsion angles in the peptide chain are 60.5 (2)
and 25.5 (2)ꢀ, and 59.4 (2) and 28.7 (2)ꢀ, for the Aib(1)
and Aib(2) residues, respectively. These values are close to
those of an ideal type III ꢁ-bend (Venkatachalam, 1968).
The values of the ' (C2ÐN3ÐC3AÐC3) and (N3Ð
C3AÐC3ÐN4) torsion angles for the Aib(3) residue are
48.4 (2) and 140.36 (18)ꢀ, respectively. The sign of this '
angle is opposite to those of the preceding residues, thus
reversing the screw sense of the peptide chain. The confor-
mation of this residue, although unusual for an Aib, falling in
the semi-extended F region of the conformational map
(Zimmerman et al., 1977), has been found previously in the
structures of other oxazolones containing Aib as the penulti-
mate residue (Toniolo et al., 1996). It must be noted that such a
conformation leads to a cisoid arrangement of the atoms C3B1
and N4, the value of the C3B1ÐC3AÐC3ÐN4 torsion angle
Benzyl N-[8-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)-2,5,-
5,8-tetramethyl-3,6-dioxo-4,7-diazanon-2-yl]carbamate,
C24H34N4O6, an oxazol-5(4H)-one from N-ꢀ-benzyloxycar-
bonyl-(Aib)4-OH (Aib = ꢀ-aminoisobutyryl) represents the
longest peptide oxazolone so far characterized by X-ray
diffraction. The overall geometry of the oxazolone ring
compares well with literature data. The Aib(1) and Aib(2)
residues are folded into a type III ꢁ-bend, while the
conformation adopted by Aib(3), preceding the oxazolone
moiety, is semi-extended. The disposition of the oxazolone
ring relative to the preceding residue is stabilized by
CÐHÁ Á ÁN and CÐHÁ Á ÁO intramolecular interactions.
Comment
Intramolecular dehydration of peptides or N-acylamino acid
derivatives carrying a free carboxy terminus leads to 2-
substituted oxazol-5(4H)-ones. Such activated compounds are
of use for peptide synthesis involving Cꢀ-tetrasubstituted ꢀ-
amino acids. All peptide oxazolones so far characterized by
X-ray diffraction derive from di- or tripeptides (Toniolo et al.,
1996; Crisma et al., 1997, 1998). Therefore, their peptide chain
is not long enough to allow the onset of a regular secondary
structure. We herewith report the X-ray structure of the title
peptide oxazolone, (I), derived from the tetrapeptide Z-
(Aib)4-OH (Z is benzyloxycarbonyl and Aib is ꢀ-amino-
isobutyric acid).
The bond distances and angles of the oxazolone ring in (I)
compare well with those averaged from the published X-ray
structures of 2-alkyl-oxazol-5(4H)-ones (Toniolo et al., 1996;
Crisma et al., 1997). In particular, the double bond character of
Figure 1
A view of (I) with the atom-numbering scheme. The intramolecular
hydrogen bond is represented as a dashed line. Displacement ellipsoids
are drawn at the 30% probability level and H atoms are shown as spheres
of arbitrary radii.
1 Alternative name: 4,4-dimethyl-2-[1-(phenylmethoxycarbonyl-2-methyl-
alanyl-2-methylalanylamino)-1-methylethyl]oxazol-5(4H)-one.
ꢁ
Acta Cryst. (2000). C56, 695±696
# 2000 International Union of Crystallography
Printed in Great Britain ± all rights reserved 695

organic compounds
being 17.4 (3)ꢀ. As a consequence, the intramolecular
Ê
distance between C3B1 and N4 is 2.871 (3) A. Among the
Table 2
Hydrogen-bonding geometry (A, ).
ꢀ
Ê
geometrically calculated H atoms linked to C3B1, the H3B2
Ê
H3B2Á Á ÁN4 angle is 93ꢀ. On the other hand, the C3B2 atom is
in a gauche disposition relative to the O3 atom [the torsion
angle C3B2ÐC3AÐC3ÐO3 is 73.31 (18)ꢀ], leading to a
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
atom is located 2.66 A from N4, and the value of the C3B1Ð
N3ÐH3Á Á ÁO0
0.86
0.86
2.21
2.11
3.052 (2)
2.9627 (18)
167
169
N1ÐH1Á Á ÁO1i
Symmetry code: (i) x; 12 y; z
.
1
2
Ê
C3B2Á Á ÁO3 distance of 3.041 (3) A, an H3B4Á Á ÁO3 distance of
ꢀ
Ê
2.70 A and a C3B2ÐH3B4Á Á ÁO3 angle of 102 . The CÐHÁ Á ÁN
and CÐHÁ Á ÁO angles reported above are quite acute.
However, they are consistent with the observation that both
interactions give rise to a ®ve-membered ring. Both CÐHÁ Á ÁN
and CÐHÁ Á ÁO interactions described above, although weak,
might contribute to the stabilization of the disposition of the
oxazolone ring relative to the preceding residue.
Data collection
Philips PW1100 diffractometer
ꢂ±2ꢂ scans
h = 10 ! 10
k = 0 ! 29
4649 measured re¯ections
4427 independent re¯ections
3058 re¯ections with I > 2ꢄ(I)
Rint = 0.020
l = 0 ! 13
3 standard re¯ections
every 50 re¯ections
intensity decay: negligible
ꢂmax = 24.71ꢀ
The angle between the normals to the average planes of the
oxazolone ring and the benzyloxycarbonyl phenyl ring is
26.7 (1)ꢀ. The folded conformation of the peptide chain forces
the oxazolone and phenyl rings to approach each other, the
shortest separation being observed between atoms C05 and
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.043
wR(F2) = 0.132
S = 1.003
4427 re¯ections
315 parameters
H-atom parameters constrained
w = 1/[ꢄ2(Fo2) + (0.0835P)2]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max = 0.021
Ê
O3 [3.668 (3) A].
In the packing mode of (I) an intermolecular hydrogen
3
Ê
Áꢅmax = 0.15 e A
3
Ê
0.22 e A
Áꢅmin
=
bond is observed between the N1ÐH group and O1(x, 12 y,
z
12). As a result, chains of molecules are formed running
parallel to the c direction. The N2-H group does not partici-
pate in any hydrogen bonding.
Data collection was performed up to sinꢂ/ꢆ = 0.5882 A 1; the
crystal did not signi®cantly diffract at higher resolution. A planarity
restraint was applied to the phenyl ring. The H atoms were included
in calculated positions and re®ned as riding, with Uiso values 1.2 (or
1.5 for the methyl groups) times the Ueq of the parent atoms.
Geometrical calculations were performed with the program PARST
(Nardelli, 1995).
Ê
Experimental
Data collection: FEBO (Belletti, 1993); cell re®nement: FEBO;
data reduction: FEBO; program(s) used to solve structure:
SHELXS97 (Sheldrick, 1997); program(s) used to re®ne structure:
SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek,
1998); software used to prepare material for publication:
SHELXL97.
Compound (I) was prepared from Z-(Aib)4-OH and acetic anhydride
according to the procedure described by Jones et al. (1965). Crys-
tallization was carried out from a solution in ethyl acetate±petroleum
ether by vapour diffusion (m.p. 430 K).
Crystal data
3
C24H34N4O6
Mr = 474.55
Monoclinic, P21=c
Ê
a = 9.324 (2) A
Dx = 1.203 Mg m
Mo Kꢀ radiation
Cell parameters from 48
re¯ections
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: LN1097). Services for accessing these data are
described at the back of the journal.
ꢂ = 7±12ꢀ
ꢃ = 0.087 mm
T = 293 (2) K
Ê
b = 25.149 (3) A
1
Ê
c = 11.753 (2) A
ꢁ = 108.00 (5)ꢀ
V = 2621.1 (8) A
Z = 4
3
Ê
Prism, colourless
0.6 Â 0.4 Â 0.4 mm
References
Belletti, D. (1993). FEBO. Internal Report 1/93. Centro di Studio per la
Strutturistica Diffractometrica del CNR, Parma, Italy.
Crisma, M., Valle, G., Formaggio, F. & Toniolo, C. (1998). Z. Kristallogr. New
Cryst. Struct. 213, 315±316.
Table 1
Selected geometric parameters (A, ).
ꢀ
Ê
Crisma, M., Valle, G., Formaggio, F., Toniolo, C. & Bagno, A. (1997). J. Am.
Chem. Soc. 119, 4136±4142.
Jones, D. S., Kenner, G. W., Preston, J. & Sheppard, R. C. (1965). J. Chem. Soc.
pp. 6227±6239.
Nardelli, M. (1995). J. Appl. Cryst. 28, 659.
C3AÐC3
C3ÐN4
C3ÐO3
N4ÐC4A
C4AÐC4
1.510 (3)
1.259 (2)
1.397 (2)
1.468 (2)
1.516 (3)
C4AÐC4B2
C4AÐC4B1
C4ÐO4
1.518 (3)
1.539 (3)
1.196 (2)
1.374 (2)
C4ÐO3
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of
È
Gottingen, Germany.
N4ÐC3ÐO3
N4ÐC3ÐC3A
O3ÐC3ÐC3A
C3ÐN4ÐC4A
N4ÐC4AÐC4
117.23 (15)
128.92 (16)
113.79 (14)
106.66 (15)
103.53 (16)
O4ÐC4ÐO3
O4ÐC4ÐC4A
O3ÐC4ÐC4A
C4ÐO3ÐC3
121.66 (19)
131.2 (2)
107.14 (17)
105.28 (14)
Spek, A. L. (1998). PLATON. University of Utrecht, The Netherlands.
Toniolo, C., Crisma, M. & Formaggio, F. (1996). Biopolymers, 40, 627±651.
Venkatachalam, C. M. (1968). Biopolymers, 6, 1425±1436.
Â
Zimmerman, S. S., Pottle, M. S., Nemethy, G. & Scheraga, H. A. (1977).
Macromolecules, 10, 1±9.
ꢁ
696 Marco Crisma et al. C24H34N4O6
Acta Cryst. (2000). C56, 695±696