N-(tert-Butoxycarbonyl)-α-aminoisobutyryl-α-aminoisobutyric acid methyl ester: Two polymorphic forms in the space group P21/n

Article abstract of DOI:10.1107/S0108270111024322

The title compound (systematic name: methyl 2-{2-[(tertbutoxycarbonyl) amino]-2-methylpropanamido}-2-methylpropanoate), C₁₄H ₂₆N₂O₅, (I), crystallizes in the monoclinic space group P21/n in two polymorphic forms, each with one molecule in the asymmetric unit. The mol-ecular conformation is essentially the same in both polymorphs, with the α-amino-isobutyric acid (Aib) residues adopting φ and ψ values characteristic of α-helical and mixed 3_10- and α-helical conformations. The helical handedness of the C-terminal residue (Aib2) is opposite to that of the N-terminal residue (Aib1). In contrast to (I), the closely related peptide Boc-Aib-Aib-OBn (Boc is tert-butoxycarbonyl and Bn is benzyl) adopts an α_L-P_II backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen-bonded para-llel β-sheet-like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen-bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one ,-disubstituted residue.

Full text of DOI:10.1107/S0108270111024322

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
the Aib residue is almost invariably restricted to ’ and
ꢂ
values corresponding to the right- (’ = ꢀ60ꢁ20 and
=
ꢂ
ꢂ
ꢂ
ꢀ
30ꢁ20 ) or left-handed (’= 60ꢁ20 and = 30ꢁ20 ) 3 - or
1
0
ISSN 0108-2701
ꢀ-helical regions of the Ramachandran plot (Venkatraman et
al., 2001). It has been known for a long time that Aib can
increase the conformational stability of peptide helices
N-(tert-Butoxycarbonyl)-a-aminoiso-
butyryl-a-aminoisobutyric acid methyl
ester: two polymorphic forms in the
(
Burgess & Leach, 1973; Karle & Balaram, 1990) with both ꢀ-
and 3 -helical hydrogen-bonding patterns (Marshall et al.,
10
1990). The introduction of Aib residues into polypeptide
chains limits the range of conformations accessible to the
ꢀ
peptide because of the extra methyl group at the C atom,
space group P2 /n
1
forcing the peptide chain into a left- or right-handed helical
conformation or nucleating a ꢁ-turn (Aravinda et al., 2003).
Numerous X-ray diffraction studies of short Aib-based model
peptides have demonstrated their preference for 3 -helical
a,b
c
Hadgu Girmay Gebreslasie, Øyvind Jacobsen and
a
Carl Henrik G o¨ rbitz *
1
0
a
structures (Karle & Balaram, 1990; Toniolo & Benedetti, 1991;
Toniolo et al., 2001). A review of crystal structures of synthetic
tri-, tetra- and pentapeptides containing at least one Aib
residue showed that almost all form incipient 3 -helices
Department of Chemistry, University of Oslo, PO Box 1033 Blindern, N-0315 Oslo,
b
Norway, Department of Medicine-Medical Biochemistry, College of Health
c
Sciences, Mekelle University, PO Box 1871, Mekelle-Tigray, Ethiopia, and School
of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
Correspondence e-mail: c.h.gorbitz@kjemi.uio.no
1
0
(
Toniolo et al., 1983). However, while shorter Aib peptides
0
preferentially adopt type III/III ꢁ-turn and 3 -helical
Received 6 June 2011
Accepted 21 June 2011
Online 5 July 2011
10
conformations, longer Aib peptides are able to form ꢀ-helical
structures (Butters et al., 1981; Schmitt et al., 1982; Pavone et
al., 1990).
The title compound (systematic name: methyl 2-{2-[(tert-
butoxycarbonyl)amino]-2-methylpropanamido}-2-methylpro-
panoate), C H N O , (I), crystallizes in the monoclinic
Although 3 - and ꢀ-helical conformations are statistically
10
by far the most prevalent conformations observed for Aib in
crystal structures of Aib-containing peptides, a number of Aib
residues have also been found to adopt polyproline II
conformations, in particular in structures of protected di- and
tripeptides (Aravinda et al., 2008). Other nonhelical confor-
mations are, however, very rare. Notably, because of the
severe steric clash between the carbonyl group of the
preceding residue and one of the methyl groups, ꢁ-strand
conformations are energetically very unfavourable (Aravinda
et al., 2008), making Aib one of the best ꢁ-sheet-breaking
amino acids (Moretto et al., 1989; Toniolo et al., 2001).
1
4
26
2
5
space group P2 /n in two polymorphic forms, each with one
1
molecule in the asymmetric unit. The molecular conformation
is essentially the same in both polymorphs, with the ꢀ-amino-
isobutyric acid (Aib) residues adopting ’ and
values
characteristic of ꢀ-helical and mixed 3 - and ꢀ-helical
10
conformations. The helical handedness of the C-terminal
residue (Aib2) is opposite to that of the N-terminal residue
(Aib1). In contrast to (I), the closely related peptide Boc-Aib-
Aib-OBn (Boc is tert-butoxycarbonyl and Bn is benzyl) adopts
an ꢀ -P backbone conformation (or the mirror image
L
II
Aib residues at the C-terminus of a helix have a tendency to
adopt a different conformation from the rest of the molecule.
In a recent investigation of 143 crystal structures of Aib-
containing helical peptides with more than three residues,
conformation). Compound (I) forms hydrogen-bonded para-
llel ꢁ-sheet-like tapes, with the carbonyl groups of Aib1 and
Aib2 acting as hydrogen-bond acceptors. This seems to
represent an unusual packing for a protected dipeptide
containing at least one ꢀ,ꢀ-disubstituted residue.
6
6.2% of the C-terminal Aib residues were found to adopt
helical conformations corresponding to a different helical
handedness than the body of the peptide, and 20.3% to adopt
polyproline II conformations (Aravinda et al., 2008).
Comment
The title compound, (I), was synthesized as part of an
ongoing effort to develop a generic methodology for the
conformational stabilization of synthetic analogues of 3 -
ꢀ
-Aminoisobutyric acid (Aib) is an achiral nonproteinogenic
amino acid found in peptaibiotics, a group of fungal peptides
with antibiotic activity (Degenkolb & Br u¨ ckner, 2008; Toniolo
1
0
helical protein segments (Jacobsen et al., 2009, 2011).
&
(
Br u¨ ckner, 2009). Peptaibiotics, exemplified by alamethicin
Pandey et al., 1977), are believed to exert their biological
effect by folding into amphipathic helices that oligomerize,
forming voltage-gated transmembrane ion channels (Mueller
&
1
(
Rudin, 1968; Nagaraj & Balaram, 1981; Fox & Richards,
982). Key to the biological activity of peptaibiotics is the
conformational) preference of Aib for helical conformations.
As was first recognized by Ramachandran & Chandrasekaran
1972) and, independently, by Marshall & Bosshard (1972),
Many biologically important protein–protein interactions
are mediated by helical protein segments and could therefore,
in principle, be modulated by synthetic peptides with similar
(
Acta Cryst. (2011). C67, o283–o287
doi:10.1107/S0108270111024322
# 2011 International Union of Crystallography o283

organic compounds
Figure 2
a) The hydrogen-bonded tape parallel to the shortest crystallographic
axis (about 6.1 A) occurring in both polymorphs of (I) (the drawing is for
form A). (b) The hydrogen-bonded tape in the structure of Boc-Aib-l-
Ile-OMe (CSD refcode AJOLEQ; Nilofarnissa et al., 2000).
Figure 1
(
The molecular structure of (I) in polymorph A at 105 K (top) and in
polymorph B at 293 K (bottom). The atomic numbering scheme is the
same for both polymorphs. Displacement ellipsoids are drawn at the 50%
probability level.
˚
primary structures and conformations. Because the entropy
reduction associated with ligand–receptor binding is likely to
be smaller for a prestructured or conformationally restricted
peptide than for a related random coil peptide, the ability of
Aib to induce or stabilize helical conformations makes Aib-
containing peptides mimicking protein segments potentially
valuable in drug discovery. Improved proteolytic stability is
another beneficial effect of a higher degree of helicity in
solution (Banerjee et al., 2002), which derives from the fact
that proteases recognize their substrates in a ꢁ-strand
conformation (Tyndall et al., 2005).
a single isolated residue to be ꢀ-helical if a hypothetical
oligopeptide with the same torsion angles as the said residue
would be ꢀ-helical, i.e. would form consecutive i ! i + 4
intramolecular hydrogen bonds. Notably, the helical handed-
ness of the C-terminal residue Aib2 is opposite to that of the
N-terminal residue Aib1 in both polymorphs, which helps to
avoid unfavourable intramolecular contacts (Van Roey et al.,
1983) [as (I) is achiral and crystallizes in a centrosymmetric
space group, it is not meaningful to designate the conforma-
tions of Aib1 and Aib2 as left- or right-handed]. Interestingly,
Aib2 in the closely related protected dipeptide Boc-Aib-Aib-
OBn [Cambridge Structural Database (CSD; Version 5.32 of
November 2010; Allen, 2002) refcode BAJROT10 (Van Roey
et al., 1983); Table 1] adopts a polyproline II conformation (or
Diffraction data were collected for two needle-shaped
crystals, which proved to represent two different polymorphs
of (I), hereafter denoted A and B, which both belong to the
monoclinic space group P2 /n (see Experimental). The mol-
1
its mirror image conformation) instead of a 3 - or ꢀ-helical
10
ecular structure of (I) is depicted in Fig. 1. The conformation is
virtually the same in both polymorphic forms, as reflected by
conformation.
Pairs of strong hydrogen bonds (Tables 2 and 3) link the
peptide molecules of (I) into tapes, as shown in Fig. 2(a). In
form A, these are supported by two reasonably linear C—
the torsion angles listed in Table 1 and the r.m.s. deviation of
˚
0.157 A for the best fit between heavy atoms. The ’and
˚
values are characteristic of ꢀ-helical and mixed 3 - and ꢀ-
Hꢃ ꢃ ꢃO C contacts with Hꢃ ꢃ ꢃO < 2.60 A; these are essentially
1
0
helical conformations. An ꢀ-helix is defined by the presence of
two or more consecutive i ! i + 4 intramolecular hydrogen
bonds and thus involves at least six residues. Similarly, two or
more consecutive i ! i + 3 intramolecular hydrogen bonds
constitute the defining feature of a 3 -helix. It is difficult to
missing in form B as the pertinent Hꢃ ꢃ ꢃO distances are
˚
>2.85 A. A similar tape motif has previously only been found
for Boc-ꢀ-methyl-l-Phe-l-Val-OBn (CSD refcode CAPZIC;
Van Roey et al., 1981). Other protected Aib*-Xaa dipeptides
in the CSD, where Aib* is either Aib or another ꢀ,ꢀ-disub-
stituted amino acid and Xaa is a chiral amino acid, form a
second type of tape motif that in a sense constitutes a ‘frame
shift’ compared with (I), as the pair of carbonyl acceptors is
10
label the conformation of a single isolated residue as 3 - or
10
ꢀ-helical exclusively based on its torsion angles. For the
purpose of this study, we define the backbone conformation of
ꢄ
o284 Gebreslasie et al.
26 2
Two polymorphs of C14H N O
5
Acta Cryst. (2011). C67, o283–o287

organic compounds
of stabilization energy (Hinderaker & Raines, 2003). The
˚
observed O to C distances are 2.916 (2) and 2.663 (2) A for
i
i+1
Aib1 and Aib2, respectively, in polymorph A, while the
corresponding values for polymorph B are 2.861 (3) and
˚
.730 (3) A. The crystal structures of (I) thus provide good
2
examples of n!ꢂ* C O !C
O stabilizing interactions
i
i+1
in a short peptide. A helical or polyproline II conformation
allows the lone pair on the carbonyl O atom to interact with
the antibonding Ci+1 O orbital along an angle of attack very
ꢂ
close to the B u¨ rgi–Dunitz angle (107 ), the preferred angle of
attack of a nucleophile at a carbonyl group (B u¨ rgi et al., 1973).
Significantly, the O —C Oi+1 angles for both polymorphic
i
forms of (I) are very close to the B u¨ rgi–Dunitz angle, with
ꢂ
values of 108.80 (11) and 103.01 (11) for Aib1 and Aib2,
respectively, in polymorph A, and 107.42 (16) and
ꢂ
1
04.08 (18) , respectively, in polymorph B.
The overall crystal packing arrangements of the two poly-
morphs, illustrated in Fig. 3, are quite different, despite the
occurrence of hydrogen-bonded tapes in both forms, as shown
in Fig. 2. The B form is more clearly divided into layers.
Experimental
ꢀ
-Aminoisobutyric acid methyl ester hydrochloride was obtained by
treating aminoisobutyric acid with thionyl chloride in methanol
solution (Jacobsen et al., 2011). Compound (I) was synthesized by
standard solution-phase peptide coupling of ꢀ-aminoisobutyric acid
methyl ester, which was generated in situ from ꢀ-aminoisobutyric acid
methyl ester hydrochloride by treatment with N,N-diisopropylethyl-
amine, with commercially available N-(tert-butoxycarbonyl)-ꢀ-amino-
isobutyric acid. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
was used as coupling reagent and 1.0 equivalents of 1-hydroxy-
benzotriazole (HOBt) was added to catalyse the reaction (Jacobsen et
al., 2011). A small quantity of (I) (about 5 mg) was dissolved in ethyl
acetate (30 ml). Needle-shaped crystals appeared as water vapour
diffused into the solution at room temperature. Data were first
collected under ambient conditions because of a temporary failure of
the low-temperature device. When the cooling unit was available
again, data were recorded for a second crystal taken from the same
batch. Although there were no obvious differences in appearance,
this crystal proved to be a different polymorph. We thus had data for
two concomitant forms, A (data collected at low temperature) and B
Figure 3
The crystal packing of (I) in (a) polymorph A and (b) polymorph B, both
viewed along the short a axis.
shifted one residue towards the N-terminal end of the peptide,
corresponding to atoms O2 and O3 in Fig. 1 rather than atoms
O3 and O4 used for (I) (Tables 2 and 3). Furthermore, the
Aib* residue in every second molecule in the tape adopts a
conformation corresponding to the opposite helical handed-
ness (Fig. 2b and Table 1). All such structures have two mol-
ecules in the asymmetric unit. The same hydrogen-bonding
pattern is also observed for the benzyl ester analogue of (I)
(
CSD refcode BAJROT10; Van Roey et al., 1983) and for one
out of three Xaa-Aib* peptides. Molecules in Table 1 with two
,ꢀ-disubstituted amino acid residues, where at least one is
(ambient). Several other crystals were subsequently tested to find a
good specimen for collection of a low-temperature data set for form
B (the original crystal had unfortunately been lost), but only crystals
of form A were found, suggesting that A was the dominant poly-
morph in the crystalline sample. Crystals of form A can also be cooled
and heated without being converted to form B.
ꢀ
different from Aib, are evidently too crowded to form tape
motifs and instead form various simple hydrogen-bonded chains.
Recent studies have revealed the importance of n!ꢂ*
C
O !C
O hyperconjugative interactions between
i
i+1
consecutive amide groups in stabilizing 3 -helical, ꢀ-helical
10
Polymorph A of (I)
and polyproline II conformations (Bretscher et al., 2001;
Hodges & Raines, 2006; Jakobsche et al., 2010), in particular
when the distance d from atom O to atom C is less than
Crystal data
i
i+1
3
˚
C
M = 302.37
14
H N
26 2
O
5
V = 1704.7 (13) A
Z = 4
˚
.2 A (Bartlett et al., 2010). In a 3 -helix, one such interaction
10
3
r
ꢀ1
ꢀ1
can be worth as much as 1.3 kcal mol
(5.4 kJ mol ;
kcal mol = 4.184 kJ mol ) (Bartlett et al., 2010). If an
ester is the electron-density acceptor, it has been found that an
Monoclinic, P2 =n
Mo Kꢀradiation
1
a = 6.116 (3) A˚
ꢀ
1
ꢀ
1
ꢀ1
ꢃ= 0.09 mm
T = 105 K
1
˚
b = 15.662 (7) A
˚
c = 17.967 (8) A
0.78 ꢅ 0.22 ꢅ 0.13 mm
ꢀ
1
ꢂ
n!ꢂ* C O !C
O interaction can provide 0.7 kcal mol
ꢁ= 97.878 (6)
i
i+1
ꢄ
Acta Cryst. (2011). C67, o283–o287
Gebreslasie et al.
Two polymorphs of C14H N
26 2
O
5
o285

organic compounds
Table 1
Main torsion angles ( ) in the crystal structures of protected dipeptides in the CSD.
ꢂ
Abbreviations: Boc is tert-butoxycarbonyl, Cbz is carboxybenzyl, B = Aib, B* is another ꢀ,ꢀ-disubstituted amino acid, I is isoleucine, V is valine, A is alanine, F is
phenylalanine, Me is methyl, Bn is benzyl, B is tert-butyl and L is leucine.
t
Compound or CSD refcode Sequence
’
1
†
1
’
2
2
Inverse‡
Polymorph (IA)
Polymorph (IB)
BAJROT10
Boc-B-B-OMe
58.96 (19)
56.4 (3)
59.6
61.5
62.6
40.82 (19)
42.5 (3)
52.0
32.8
33.3
ꢀ45.6 (2)
ꢀ50.5 (3)
ꢀ51.5
177.0
ꢀ50.47 (18)
ꢀ49.1 (3)
138.4
Boc-B-B-OMe
Boc-B-B-OBn
Boc-B-B*-OMe
i
PARDUH
ꢀ179.4
177.3
179.2
PUXHOF
VEYQAR
AJOLEQ
Boc-B*-B*-OMe
Cbz-B*-B*-OMe
Boc-B-I-OMe
55.0
65.5
63.9
42.7
26.6
45.8
44.3
33.3
41.8
46.3
45.8
42.8
47.1
48.7
44.1
50.7
46.7
44.5
ꢀ56.0
ꢀ35.5
ꢀ68.0
122.1
ꢀ57.2
ꢀ78.9
133.3
ꢀ34.7
ꢀ50.8
ꢀ29.8
ꢀ148.1
ꢀ44.2
170.54
ꢀ174.9
ꢀ177.9
ꢀ24.4
ꢀ36.2
ꢀ9.6
i
i
57.2
i
CAPZIC
GANPEQ
Boc-B*-V-OBn
t
Cbz-B-A-O B
58.9
57.8
5
8.8
56.1
8.4
60.8
4.3
62.1
3.7
58.1
8.4
i
i
OBAZIA
OFUXOC
PASGUL
XOWVAG
Boc-B*-A-OMe
Boc-B*-L-OMe
Boc-B-F-OMe
Boc-B-L-OMe
Boc-V-B*-OMe
ꢀ95.1
5
145.8
ꢀ72.3
122.7
6
i
i
ꢀ75.9
1.6
5
122.0
ꢀ164.0
ꢀ0.5
ꢀ80.7
112.9
55.2
5
ꢀ165.7
i
i
i
i
LAGFII
TIRJOT
ZAQVUI
73.2
76.6
90.6
ꢀ127.3
ꢀ156.2
32.2
32.2
t
Cbz-A-B-O B
Cbz-L-B*-OMe
ꢀ51.0
ꢀ44.7
ꢀ53.1
ꢀ43.7
= C9—N2—C10—C13 and
†
For (I), with reference to Fig. 1, the listed torsion angles are: ’
1
= C5—N1—C6—C9,
1
= N1—C6—C9—N2, ’
2
2
= N2—C10—C13—O5. ‡ To facilitate
1
comparison between structures, molecules indicated by ‘i’ have been inverted to obtain the same sign for the first torsion angle ’.
Data collection
Table 2
Hydrogen-bond geometry (A, ) for polymorph A of (I).
˚
ꢂ
Bruker APEXII CCD area-detector
diffractometer
Absorption correction: multi-scan
11873 measured reflections
4100 independent reflections
2595 reflections with I > 2ꢄ(I)
D—Hꢃ ꢃ ꢃA
D—H
Hꢃ ꢃ ꢃA
Dꢃ ꢃ ꢃA
D—Hꢃ ꢃ ꢃA
(
T
SADABS; Bruker, 2007)
min = 0.917, Tmax = 0.988
R
int = 0.048
i
i
N1—H1ꢃ ꢃ ꢃO3
N2—H2ꢃ ꢃ ꢃO4
0.840 (19)
0.86 (2)
0.98
2.12 (2)
2.44 (2)
2.51
2.963 (2)
3.227 (2)
3.298 (2)
3.511 (2)
175.6 (18)
151.6 (17)
137
i
C3—H32ꢃ ꢃ ꢃO2
ii
Refinement
2
C11—H112ꢃ ꢃ ꢃO1
0.98
2.57
160
2
R[F > 2ꢄ(F )] = 0.050
wR(F ) = 0.126
S = 1.02
H atoms treated by a mixture of
independent and constrained
refinement
Symmetry codes: (i) x ꢀ 1;y;z; (ii) x þ 1;y;z.
2
˚
ꢀ3
Áꢅmax = 0.28 e A
4
1
100 reflections
96 parameters
Áꢅmin = ꢀ0.24 e A˚
ꢀ3
Table 3
Hydrogen-bond geometry (A, ) for polymorph B of (I).
˚
ꢂ
Polymorph B of (I)
D—Hꢃ ꢃ ꢃA
D—H
Hꢃ ꢃ ꢃA
Dꢃ ꢃ ꢃA
D—Hꢃ ꢃ ꢃA
i
i
Crystal data
N1—H1ꢃ ꢃ ꢃO3
0.86 (2)
0.85 (2)
2.16 (2)
2.44 (2)
3.008 (3)
3.197 (3)
170 (2)
148 (2)
˚
V = 1756.0 (8) A
3
N2—H2ꢃ ꢃ ꢃO4
C
14
26
H N
O
2 5
M
r
= 302.37
Z = 4
Mo Kꢀradiation
ꢃ= 0.09 mm
T = 293 K
Symmetry code: (i) x þ 1;y;z.
Monoclinic, P2 =n
1
˚
a = 6.0679 (15) A
ꢀ1
˚
b = 33.743 (9) A
˚
ꢂ
c = 8.583 (2) A
ꢁ
0.80 ꢅ 0.11 ꢅ 0.10 mm
Positional parameters were refined for H atoms bonded to N
atoms. Methyl H atoms were positioned with idealized geometry and
= 92.266 (3)
˚
fixed at C—H = 0.98 (form A, 105 K) or 0.96 A (form B, 293 K).
Data collection
Uiso(H) values were set at 1.2Ueq(N) for N—H groups or at 1.5Ueq(C)
for methyl groups.
Bruker APEXII CCD area-detector
diffractometer
Absorption correction: multi-scan
10165 measured reflections
3105 independent reflections
1584 reflections with I > 2ꢄ(I)
For both polymorphs, data collection: APEX2 (Bruker, 2007); cell
refinement: SAINT-Plus (Bruker, 2007); data reduction: SAINT-
Plus. Program(s) used to solve structure: SHELXS97 (Sheldrick,
(SADABS; Bruker, 2007)
min = 0.814, Tmax = 0.991
Rint = 0.052
T
2
008) for polymorph A; SHELXTL (Sheldrick, 2008) for poly-
Refinement
2
morph B. Program(s) used to refine structure: SHELXL97 (Shel-
drick, 2008) for polymorph A; SHELXTL for polymorph B.
Molecular graphics: SHELXL97 for polymorph A; SHELXTL for
polymorph B. Software used to prepare material for publication:
SHELXL97 for polymorph A; SHELXTL for polymorph B.
2
R[F > 2ꢄ(F )] = 0.042
wR(F ) = 0.125
S = 1.00
H atoms treated by a mixture of
independent and constrained
refinement
2
˚
ꢀ3
Áꢅmax = 0.15 e A
3
1
105 reflections
97 parameters
Áꢅmin = ꢀ0.18 e A˚
ꢀ3
ꢄ
o286 Gebreslasie et al.
26 2
Two polymorphs of C14H N O
5
Acta Cryst. (2011). C67, o283–o287

organic compounds
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ꢄ
Acta Cryst. (2011). C67, o283–o287
Gebreslasie et al.
Two polymorphs of C14H N
26 2
O
5
o287