Conformational switching caused by biphenyl substitution at the C α position: Ethyl 2-benzyl-2-(formylamino)-3-phenylpropionate and ethyl 3-(1,1′-biphenyl-4-yl)-2-(formylamino-2-(4-phenylbenzyl) propionate

Article abstract of DOI:10.1107/S0108270104013150

The title compounds, C₁₉H₂₁NO₃ and C ₃₁H₂₉NO₃, are derivatives of α-aminoisobutyric acid, with benzyl and dibenzyl substitution. The pseudo-peptide formed by the N-formyl and ethyl ester su

Full text of DOI:10.1107/S0108270104013150

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
Kotha & Brahmachary, 2000). The effects of benzyl and
phenyl substitution at the Cꢀ position of Aib have been
studied via crystal structure analyses. The two title
compounds, (I), and (II), crystallize in the same (P21/c) space
group from n-propanol±methanol (1:1) and 2-propanol solu-
tions, respectively.
ISSN 0108-2701
Conformational switching caused
by biphenyl substitution at the Ca
position: ethyl 2-benzyl-2-(formyl-
amino)-3-phenylpropionate and ethyl
3-(1,10-biphenyl-4-yl)-2-(formylamino)-
2-(4-phenylbenzyl)propionate
Lakshminarasimhan Damodharan,a Vasantha Pattabhi,a*
Manoranjan Beherab and Sambasivarao Kothab
aDepartment of Crystallography and Biophysics, University of Madras, Guindy
Campus, Chennai 600 025, India, and bDepartment of Chemistry, Indian Institute
of Technology, Powai, Mumbai 400 076, India
Correspondence e-mail: pvasantha@hotmail.com
Received 4 May 2004
Accepted 1 June 2004
Online 30 June 2004
The title compounds, C19H21NO3 and C31H29NO3, are
derivatives of ꢀ-aminoisobutyric acid, with benzyl and
dibenzyl substitution. The pseudo-peptide formed by the
N-formyl and ethyl ester substitution at the Cꢀ position
switches from a trans±trans to a trans±cis con®guration as a
result of biphenyl substitution. The packing of the compounds
is stabilized by NÐHÁ Á ÁO and CÐHÁ Á ÁO hydrogen bonds.
Comment
ꢀ-Aminoisobutyric acid (Aib), which is achiral, has well
established structural effects (Karle et al., 1994; Ramesh &
Balaram, 1999; Formaggio et al., 2000). Similarly, benzyl
substitution at the Cꢀ position provides rigidity to the peptide
backbone, and this conformational restriction is useful
Figure 1
The molecular structures of (a) (I) and (b) (II), showing 50% probability
displacement ellipsoids and the atomic numbering schemes.
in peptide motif design (Studer & Seebach, 1995; Damo-
dharan et al., 2002; Karle & Balaram, 1990; Polese et al., 1996;
Acta Cryst. (2004). C60, o527±o530
DOI: 10.1107/S0108270104013150
# 2004 International Union of Crystallography o527

organic compounds
The molecular structures of the title compounds are shown
in Fig. 1. Terminal atoms C18 and C17 of the ethyl ester side
chains of (I) exhibit disorder. The bond angles at atoms C2
and C9 of (I), and at C2 and C15 of (II), are signi®cantly larger
than normal tetrahedral values because of the presence of the
bulky substitutions [115.4 (2)ꢁ at C2 and 115.8 (3)ꢁ at C9 in (I),
and 115.9 (2)ꢁ at C2 and 116.4 (2)ꢁ at C15 in (II)]. The angles
between benzene rings A and B are 61.4 (2) and 61.8 (1)ꢁ in (I)
and (II), respectively; the angle between rings A and C in (II)
is 18.1 (1)ꢁ, and that between rings B and D in (II) is 39.8 (2)ꢁ.
The additional phenyl substitution causes the molecules to be
arranged along the longest axis (viz. the a axis) in (II), and a
herring-bone packing arrangement is seen in both structures.
The N-formyl and ethyl ester chains form a pseudo-peptide,
the backbone of which adopts a trans±trans conformation in
Figure 4
A stereoview of the packing of (II), showing the NÐHÁ Á ÁO interactions.
(I) [C16ÐC1ÐN1ÐC19 (') = 178.8 (3)ꢁ, O17AÐC16Ð
C1ÐN1 ( ) = 170.5 (5)ꢁ and O17BÐC16ÐC1ÐN1 ( ) =
169.8 (7)ꢁ; as a result of disorder, adopt two values] and a
trans±cis conformation in (II) [C28ÐC1ÐN31ÐC32 (') =
178.4 (2)ꢁ and N31ÐC1ÐC28ÐO29 ( ) = 5.4 (3)ꢁ; Fig. 2].
This conformational switching may be due to the additional
phenyl ring substitutions on either side of the Cꢀ atom.
The N-formyl side chain is planar and in a folded confor-
mation in both compounds [C1ÐN1ÐC19ÐO19 = 4.4 (5)ꢁ
and C1ÐN31ÐC32ÐO33 = 0.7 (4)ꢁ for (I) and (II), respec-
tively]. The ethyl ester side chains adopt different conforma-
tions in the two compounds, viz. ap (antiperiplanar) and +sc
(synclinal) in (I), and +ac (anticlinal) in (II) [C16ÐO17AÐ
C17AÐC18A =
171.9 (10)ꢁ ( ap) and C16ÐO17BÐ
C17BÐC18B = 82 (2)ꢁ (+sc) in (I) (two conformations as a
result of the disorder), and C28ÐO29ÐC29ÐC30 = 93.8 (4)ꢁ
(+ac) in (II)]. The switch from ap/+sc to +ap can be attrib-
uted to the biphenyl substitutions (Fig. 3).
Intramolecular NÐHÁ Á ÁO and CÐHÁ Á ÁO hydrogen bonds
are present in both structures. The N1ÐC1ÐC16 angle is
105.0 (2)ꢁ, possibly as a result of the presence of an intra-
molecular N1ÐHÁ Á ÁO16 hydrogen bond, whereas the corre-
sponding angle (N31ÐC1ÐC28) in (II) is 110.2 (2)ꢁ (Fig. 4).
Figure 2
A stereoview of the superposition of (I) (black) and (II) (grey), showing
the conformational switching of the ethyl ester chain from trans±trans in
(I) to cis±trans in (II).
3
2
1
The bifurcated N31ÐH31Á Á ÁO29(x, y, z)/O33(x,
y, z
)
2
hydrogen bond may be the reason for the widening of this
bond angle.
The packing of both structures is stabilized by CÐHÁ Á ÁO
and NÐHÁ Á ÁO interactions. Atom O19 of the N-formyl group
in (I) forms an intermolecular C5ÐH5Á Á ÁO19 hydrogen bond,
which is replaced by an N31ÐH31Á Á ÁO33 hydrogen bond in
(II) (Tables 1 and 2, and Figs. 3 and 4).
Experimental
Reaction of benzyl bromide, (1), with ethyl isocyanoacetate in the
presence of a phase-transfer catalyst, such as tetrabutylammonium
sulfate, in acetonitrile/potassium carbonate gave a coupling product.
Figure 3
A stereoview of the packing of (I), showing intramolecular NÐHÁ Á ÁO
interactions and intermolecular CÐHÁ Á ÁO interactions.
ꢀ
o528 Lakshminarasimhan Damodharan et al.
C19H21NO3 and C31H29NO3
Acta Cryst. (2004). C60, o527±o530

organic compounds
Hydrolysis of the coupling product with concentrated HCl in the
presence of diethyl ether gave the formyl derivative (I).
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.062
wR(F2) = 0.161
S = 1.05
3802 re¯ections
w = 1/[ꢄ2(F2o) + (0.0598P)2
+ 0.3098P]
where P = (F2o + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢅmax = 0.22 e A
3
Ê
0.11 e A
245 parameters
H-atom parameters constrained
Áꢅmin
=
Table 1
Hydrogen-bonding geometry (A, ) for (I).
ꢁ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
N1ÐH1Á Á ÁO16A
N1ÐH1Á Á ÁO16B
C5ÐH5Á Á ÁO19i
C2ÐH2BÁ Á ÁO19
C9ÐH9AÁ Á ÁO19
0.86
0.86
0.93
0.97
0.97
2.22
2.11
2.46
2.57
2.64
2.657 (15)
2.55 (2)
3.314 (3)
3.168 (3)
3.170 (3)
111
111
152
119
114
Similarly, compound (4) was prepared from p-iodobenzyl bromide,
(3). A Suzuki±Miyaura coupling reaction (Kotha et al., 2002) of (4)
with benzeneboronic acid in the presence of Pd0 as catalyst gave the
cross-coupling product (II).
Symmetry code: (i) x; 12 y; z
.
1
2
Compound (II)
Crystal data
C31H29NO3
Mr = 463.55
Monoclinic, P21=c
Mo Kꢀ radiation
Cell parameters from 5898
re¯ections
ꢂ = 2.0±28.0ꢁ
ꢃ = 0.08 mm
T = 293 (2) K
Ê
a = 26.761 (5) A
1
Ê
b = 10.9424 (19) A
Ê
c = 8.5818 (15) A
ꢁ = 95.068 (3)ꢁ
V = 2503.2 (8) A
Rectangular block, colorless
0.54 Â 0.45 Â 0.45 mm
3
Ê
Z = 4
Dx = 1.230 Mg m
3
Data collection
Bruker SMART CCD area-detector
diffractometer
Rint = 0.052
ꢂmax = 28.0ꢁ
! scans
h = 34 ! 34
k = 14 ! 14
l = 11 ! 10
21 471 measured re¯ections
5898 independent re¯ections
2853 re¯ections with I > 2ꢄ(I)
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.080
wR(F2) = 0.161
S = 1.05
5898 re¯ections
w = 1/[ꢄ2(F2o) + (0.0465P)2
+ 0.6112P]
where P = (F2o + 2Fc2)/3
(Á/ꢄ)max = 0.001
Compound (I)
3
Ê
Áꢅmax = 0.19 e A
3
Ê
0.12 e A
316 parameters
H-atom parameters constrained
Áꢅmin
=
Crystal data
C19H21NO3
Mr = 311.37
Monoclinic, P21=c
Mo Kꢀ radiation
Cell parameters from 3802
re¯ections
Table 2
Hydrogen-bonding geometry (A, ) for (II).
ꢂ = 2.1±27.9ꢁ
Ê
a = 9.980 (2) A
ꢁ
Ê
1
Ê
b = 11.853 (3) A
ꢃ = 0.08 mm
T = 293 (2) K
Ê
c = 14.575 (4) A
ꢁ = 94.147 (4)ꢁ
V = 1719.6 (7) A
Rectangular block, colorless
0.52 Â 0.43 Â 0.42 mm
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
3
Ê
N31ÐH31Á Á ÁO29
N31ÐH31Á Á ÁO33ii
C15ÐH15BÁ Á ÁO33
C2ÐH2AÁ Á ÁO33
0.86
0.86
0.97
0.97
2.12
2.21
2.49
2.55
2.556 (2)
2.936 (3)
3.137 (3)
3.139 (3)
111
142
124
119
Z = 4
Dx = 1.203 Mg m
3
Data collection
1
2
Symmetry code: (ii) x; 32 y; z
.
Bruker SMART CCD area-detector
diffractometer
Rint = 0.023
max = 27.9ꢁ
ꢂ
! scans
h = 12 ! 12
k = 13 ! 15
l = 18 ! 19
13 797 measured re¯ections
3802 independent re¯ections
2295 re¯ections with I > 2ꢄ(I)
H atoms were positioned geometrically and treated as riding, with
Ê
CÐH distances of 0.93±0.97 A and NÐH distances of 0.86 A.
Ê
ꢀ
Acta Cryst. (2004). C60, o527±o530
Lakshminarasimhan Damodharan et al. C19H21NO3 and C31H29NO3 o529

organic compounds
For both compounds, data collection: SMART (Bruker, 1999); cell
re®nement: SAINT (Bruker, 1999); data reduction: SAINT;
program(s) used to solve structure: SHELXS97 (Sheldrick, 1997);
program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997);
molecular graphics: ORTEP-3 (Farrugia, 1997); software used to
prepare material for publication: SHELXL97.
References
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The authors thank the Council of Scienti®c and Industrial
Research, and the Department of Science and Technology,
India, for ®nancial support.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: NA1665). Services for accessing these data are
described at the back of the journal.
È
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ꢀ
o530 Lakshminarasimhan Damodharan et al.
C19H21NO3 and C31H29NO3
Acta Cryst. (2004). C60, o527±o530