Conformational properties of O-alkylated benzamides

Article abstract of DOI:10.1016/j.tet.2011.11.078

In this article, we report the synthesis, solid-state and solution-state conformational studies of O-alkylated aromatic benzamides based on two scaffolds. Intramolecular hydrogen bonding provides conformational pre-organization and side chains can interact with each other within a molecule. In the solid-state three-dimensional arrangement, the molecules further interact with each other through non-covalent interactions. Given, the demonstrated potential of this class of scaffolds to act as helix mimetics for the inhibition of protein-protein interactions (PPIs), these results provide key insight for future inhibitor design.

Full text of DOI:10.1016/j.tet.2011.11.078

Tetrahedron 68 (2012) 4485e4491
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conformational properties of O-alkylated benzamides
,
,
Panchami Prabhakaran a b, Valeria Azzarito a b, Tia Jacobs a, Michaele J. Hardie a, Colin A. Kilner a,
Thomas A. Edwards b c, Stuart L. Warriner a b, Andrew J. Wilson a
,
,
,b,
*
a School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom
b Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom
c Institute of Structural and Molecular Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
In this article, we report the synthesis, solid-state and solution-state conformational studies of O-alky-
lated aromatic benzamides based on two scaffolds. Intramolecular hydrogen bonding provides confor-
mational pre-organization and side chains can interact with each other within a molecule. In the solid-
state three-dimensional arrangement, the molecules further interact with each other through non-
covalent interactions. Given, the demonstrated potential of this class of scaffolds to act as helix mi-
metics for the inhibition of proteineprotein interactions (PPIs), these results provide key insight for
future inhibitor design.
Received 29 September 2011
Received in revised form 18 November 2011
Accepted 24 November 2011
Available online 1 December 2011
Keywords:
Aromatic oligoamides
Foldamer
Ó 2011 Elsevier Ltd. All rights reserved.
Conformational analyses
1. Introduction
geometrical relationship between monomers; a range of diverse
architectures2 have been elucidated by different research groups.
The design, synthesis and structural investigations of non-
natural oligomers that adopt well defined secondary, tertiary and
quaternary structures represent a major effort within the research
community.1,2 Such oligomers offer potential as functional archi-
tectures that recapitulate the complexity of nature’s biopolymers.3
In defining conformational preference and long range inter/intra-
molecular order, non-covalent interactions are the dominant driv-
ing forces and have been utilized to determine the preferred
architecture adopted by a range of foldamers4 and more broadly in
generating molecules with desired shapes and properties.1e4 As for
many biological systems, hydrogen bonding features frequently as
a driving force for conformational pre-organization5 and has been
extensively exploited for foldamers.6 Indeed, as for proteins, the
amide linkage is often selected for foldamer assembly due to the
robust synthetic methods available for synthesis and presence of
handles to constrain conformation through intramolecular in-
teraction between backbone NH and C]O groups,7 the amide NH
and side chain acceptor groups4c,8 or the amide NH and heterocy-
clic rings.9 Aromatic oligoamides are advantageous in that the rigid
aromatic framework allows conformation to be determined ex-
clusively by the cis/trans preference of the amide linkage, in-
teraction with other backbone/side chain heteroatoms and the
We10 and others,11 recently described a class of aromatic oligoa-
mides based on a para-amino benzoic acid monomer functional-
ized with different side chains through O-alkylation.
This template is able to adopt an extended rod-shaped confor-
mation mediated in part by the amide NHs, which participate in
S(5) type12 intramolecular H-bonding with alkoxy oxygens thus
preventing rotation around the AreNH bond (Scheme 1a).13 How-
ever, rotation around the AreCO axis is feasible as evident from
conformational analyses by 2D NMR. For this scaffold, the side
chains extending from the backbone have been shown to mimic the
spatial projection of the side chains of an a
-helix14 and efficient
inhibitors of the p53ehDM2 interaction have been identified.15 The
considerable attention devoted to helix mimetics and their use as
inhibitors of proteineprotein interactions (PPIs) in recent years,16
warranted a more detailed investigation of the conformational
behaviour within this family of aromatic oligoamides. We therefore
became interested in studying conformational features of 2- and 3-
O-alkylated aromatic oligoamides17 in which the nature of intra-
molecular H-bonding between the alkoxy oxygen and the amide
proton differs (S(5) versus S(6)). We hypothesized that in scaffold 2
(Scheme 1b), the amide NH would form a six-membered intra-
molecular H-bond and in contrast to scaffold 1, the rotation around
the AreCO bond would be arrested rather than around the AreNH
bond.18 In addition, we were keen to probe how side-chaineside-
chain interactions might control/stabilise the conformation. This
point is noteworthy given the need to understand the role of non-
* Corresponding author. Tel.: þ44 (0)1133431409; e-mail address: a.j.wilson@
leeds.ac.uk (A.J. Wilson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.078

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P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
Fig. 1. Structures of 2-O-alkylated oligoamides 1a,b,10 1c,d and 3-O-alkylated oligoa-
mides 2aec.
Scheme 1. Role of non-covalent interactions in defining the conformational behaviour
of (a) 3-O-alkylated and (b) 2-O-alkylated oligoamides.
covalent interactions in small molecule based drug design;19 whilst
the influence of side chains upon conformational preference is well
studied for aliphatic oligomers made up of
a and b
-amino acids,20 it
is less explored in aromatic oligoamides comprising monomers
possessing different side chains.21 Herein we report the synthesis,
solid-state22 and solution-state conformational analyses of model
systems based on the two scaffolds in order to rationalise the effect
of non-covalent interactions in driving the preferred conformation.
The results reveal differences in the strength of hydrogen bonding
within both scaffolds and show that even with simple aromatic and
aliphatic substituents, side chain orientation is subject to subtle
steric and non-covalent effects. These results are anticipated to aid
in ongoing efforts to design bioactive helix mimetics.
Fig. 2. Single crystal X-ray structures of 1a, 1c and 1d shown in stick (aec) and CPK
(def) representations, respectively.22 The figures were made using PyMOL.23
2. Results and discussion
Table 1
In order to study the role of non-covalent interactions in con-
trolling the conformational properties of O-alkylated para-amino
benzoic acid derived oligomers, we selected the simplest deriva-
tiveda dimerdas a model system to study. This model possesses
all the key features of more extended oligomers, i.e., a linking
amide between monomers and the potential for different orienta-
tions (syn and anti) of the two side chains with respect to one an-
other to be observed (Scheme 1). Therefore synthesis of 3-O-
alkylated benzamides 1aed (Fig. 1) with a range of different side
chains was performed as previously reported.10 Similarly, following
the same synthetic strategy, 2-O-alkylated benzamides 2aec
(Fig. 1) were synthesized (see Supplementary data).
Hydrogen bonding parameters observed in the crystal structures of scaffold 1 and 2
Compound
dNeH/O
:NeH/O
Angle of inclinationa
1a
1c
1d
2a
2b
2.385
2.138
2.201
1.957
1.961
96.54
109.36
108.73
139.55
140.49
157.0
158.22
161.45
162.32
163.85
a
Angle measured joining 1-C1, 1-C4 and 2-C4 atoms.
and the alkoxy oxygen unit. However, the orientation of side chains
differs from one molecule to another and is mainly dependent on
the packing of the molecules in the crystal lattice (vide infra).
In the crystal structure of 1a and 1c, the side chains are oriented
on the same side of the backbone (syn) whereas in the hetero-
functionalized molecule 1d, the naphthyl and isobutyl groups are
on different sides (anti). This latter result contrasts with the ob-
servations made by Hamilton and co-workers24 who reported the
solid-state packing properties of a series of benzamides, which
were functionalized with isobutyl groups. The use of isobutyl
groups in this earlier study is noteworthy as they have been shown
in other work to possess a strong propensity to interdigitate.25 In
compound 1c, even though the two benzyl groups are oriented in
2.1. Solid-state conformational analyses
Single crystals suitable for X-ray diffraction analyses were
grown either by slow evaporation of the solvent mixture or by the
diffusion method (see Experimental section). The solid-state con-
formation of the molecules 1a, 1c and 1d based on scaffold 1 is
shown in Fig. 2. The hydrogen bonding parameters and the angle of
inclination of the backbones are given in Table 1. A common feature
observed in the crystal structures of these oligomers is the presence
of S(5) intramolecular hydrogen bonding between the amide NH

P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
4487
the same direction, they do not exhibit any
p
e
p
stacking inter-
be attributed to the rotation of the aryl ring around AreCO or
AreNH bond.
actiondthis implies that additional flexibility or larger groups are
necessary in order to exploit non-covalent interactions to bias the
syn/anti ratio in these oligomers (see below). Nonetheless, the
backbones of these molecules retain the same curvature as shown
in Fig. 4. The NH/O distance measured in these molecules is
A clear picture showing the matching of backbone curvatures
irrespective of the side chains in each scaffold is given in Fig. 4. The
crystal structures were superimposed by using the software
MaestroÒ and RMSD (root mean square deviation) values were
calculated.28 In the superimposition of 2a and 2b, the RMSD value
ꢀ
ꢀ
w2.1e2.4 A. The NH/O distance in 1a (2.385 A) is particularly
noteworthy as this is suggestive of a weak interaction; although the
solution studies (see below) point to a strong interaction, this result
indicates (a) that additional forces in the solid-state can supersede
the driving force for intramolecular hydrogen bonding and such
forces (e.g., side chain sterics) may also be present in solution; (b)
rotation around the AreNH bond is clearly possible for this class of
benzamide even if there is a strong thermodynamic bias against
this. The degree of curvature of the backbone measured as the angle
of inclination of two aromatic rings on the backbone is w 157e161ꢀ
(angle measured joining 1-C1, 1-C4 and 2-C4; numbering of back-
bone is given in supplementary data).11b,26
ꢀ
(calculated based on 1-C1, 1-C4, 2-C1 and 2-C4 atoms) is 0.070 A
and is supported by the measured angle of inclination (Table 1). The
difference in curvature of 1a and 2a (difference in angle of in-
clination is 5ꢀ) is reflected in the relatively higher RMSD value
ꢀ
(0.153 A) in the superimposition of these molecules.
The crystal structures of 2a and 2b based on scaffold 2 are given
in Fig. 3. In molecule 2a, the isopropyl groups are oriented on op-
posite sides and this is in contrast to the conformation of 1a as
described above. On the other hand, in the heterofunctionalized
molecule 2b, the 2-(naphthyl)methyl and isopropyl groups are
oriented on the same face and they interact through CeHe
p in-
ꢀ
teraction with a distance of 2.7e2.8 Adthis illustrates that steri-
cally larger groups are capable of interaction with each other, which
contrasts with the lack of interaction observed between flat aro-
matic rings in 1d. The intramolecular NH/O distance measured in
ꢀ
this series is w1.9e2.0 A and is in the same range as observed in
foldamers constrained with six-membered intramolecular H-
bonding.27 The curvature of the backbone of scaffold 2 (given in
Table 1) is slightly lower (w162e164ꢀ) compared to scaffold 1 and
is attributed to the difference in the intramolecular hydrogen
bonding. The angle is higher in 1d compared to 1a and 1c. Similarly
the angle is higher for 2b than for 2a. In both series the angle of
inclination is higher for the molecules found to adopt the anti
conformation in the solid state, hence the higher values for 2b and
1d compared to the other molecules in their respective series may
Fig. 4. Superimposition of crystal structures showing the orientation of backbone;
(a) crystal structures of 1a and 1c based on scaffold 1; (b) crystal structures of 1c and
1d; (c) 2a and 2b; (d) 1a and 2a.
Each of the crystal structures exhibits instructive solid-state
packing features. The difference in orientation of side chains in
molecules within a scaffold depends on other non-covalent in-
teractions. Based on the solid-state conformational analyses, it
seems clear that the orientation of side chains largely depends on
intermolecular side-chaineside-chain interactions. For example, in
compound 1c, benzyl groups from different molecules interact
through pep stacking as shown in Fig. 5.
In compounds 1a and 2a, even though they differ in confor-
mation, hydrophobic interactions between the isopropyl side
chains from different molecules are observed in the three-di-
mensional packing as shown in Fig. 6. The methyl unit of the ester
group also participates in making a hydrophobic channel in the
three-dimensional arrangement.
Three-dimensional packing diagrams for heterofunctionalized
oligomers 1d and 2b showing the side-chain interactions are given
in Fig. 7. In the three-dimensional arrangement of the hetero-
functionalized oligomer 1d, the isobutyl group of one molecule
interacts with the naphthyl unit of another molecule through
ꢀ
CeHe
p
interaction (3.14e3.2 A) and this may be the driving force
for the molecule to adopt a conformation with side chains pointing
on opposite sides (Fig. 7a). In the case of oligomer 2b (Fig. 7b), an
intramolecular CeHe
naphthyl units is observed as noted above. The molecules in three-
dimensions arrange through a combination of , benzylic CHep
p interaction between the isopropyl and the
p
e
p
ꢀ
interactions (2.727 A) and hydrophobic interactions as observed for
other oligomers.
Thus, the solid-state studies provide evidence for pre-
organization based on intramolecular H-bonding and the different
Fig. 3. Single crystal X-ray structures of 2a and 2b shown in stick (a,b) and CPK (c,d)
representations, respectively.22 The figures were made using PyMOL.23

4488
P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
Fig. 7. (a) Partial packing diagrams for heterofunctionalized oligomers: (a) 1d showing
CeHe interaction; (b) packing of 2b through stacking interactions. The figures
were made using PyMOL.23
Fig. 5. Packing diagram for 1c showing the side-chaineside-chain interaction through
stacking. The figure was prepared using PyMOL.23
p
pep
pep
2.2. Solution-state conformational analyses
Whilst the solid-state structures provide useful information on
the influence that different and perhaps competing non-covalent
interactions may have on the conformational properties of para-
amino benzoic acid derived oligomers, understanding these effects
in solution is central to understanding the conformational prop-
erties in the context of
a-helix mimetic design. Detailed NMR
studies were performed to understand the conformational prop-
erties of these molecules further. The down field shifts of amide
protons (Table 2) in the 1H NMR spectra of 1 and 2 clearly show the
presence of intramolecular H-bonding. A higher shift of S(6) hy-
drogen-bonded amide protons in scaffold 2 (>9.8 ppm) in com-
parison to scaffold 1 (<9 ppm) is in support of studies performed on
a different class of oligomers.27,29 The negligible change in chemical
shift upon dilution of 1a and 2a provides evidence that in-
termolecular hydrogen bonding is negligible in nature, which is
further evidenced by the small temperature coefficients for the NH
resonance in 1a (ꢁ1.2 ppb Kꢁ1) and 2a (4.4 ppb Kꢁ1).
Table 2
Chemical shift data, kinetic constants and t1/2 based on H/D exchange in 10% CD3OD/
CDCl3 for dimers 1 and 2
Compound
d
NHa
d
COa
kH/D (minꢁ1
)
t1/2 (min)
1a
2a
1b
1c
1d
2b
2c
8.78
163.1
161.9
162.9
162.8
162.8
161.5
161.1
0.0263ꢂ0.0006
26.4ꢂ0.6
10.17
8.76
8.74
8.80
9.97
10.01
0.00368ꢂ0.00006
188ꢂ3
d
Fig. 6. Packing diagram of 1a (top) and 2a showing side-chaineside-chain hydro-
phobic interactions (isopropyl groups are shown in spheres). The figure was made
using PyMOL.23
d
d
d
d
d
d
d
d
d
orientationsof side chains foreach scaffold illustratesthe propensity
for free rotation around the AreCO or AreNH bond in 1 and 2, re-
spectively. The side chains can interact with each other in an intra or
intermolecular fashion, noting that there does not appear to be
a specific driving force in favour of a syn or anti conformation and
that crystal packing seems to determine whether these interactions
are inter or intramolecular. Finally, the backbone curvatures of
scaffold 1 and 2 differ by 5ꢀ due to the nature of intramolecular
hydrogen bonding.
a
dH or dC measured in CDCl3.
2.2.1. H/D exchange studies. In order to understand the relative
strength of hydrogen bonds (five-membered vs six-membered) in
the two scaffolds, H/D exchange studies were performed. The rel-
ative rates of a hydrogen/deuterium exchange in a 1H NMR study
are affected by a number of parameters; the acidity of the NH group
(which may be affected by electronic substituent effects), the steric

P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
4489
accessibility of the NH group and the strength of hydrogen bonding.
More acidic H atoms are anticipated to exchange more rapidly
whereas sterically inaccessible protons and strongly hydrogen-
bonded atoms are anticipated to have a slower rate of ex-
change.30 A detailed interpretation in this case is difficult because
an increase in acidity might be anticipated to result in a stronger
hydrogen bonding interaction. Nonetheless, the rate of exchange is
correlated with strength of hydrogen bonding to an extent. The
experiment was performed on dimers 1a and 2a in a 10% CD3OD/
CDCl3 system to ensure pseudo first order kinetics (Fig. 8). The ki-
netic parameters for the compounds are given in Table 2. The half-
life for the H/D exchange studies revealed that the amide NH of the
2-O-alkylated dimer (six-membered) exchanges an order of mag-
nitude more slowly than the 3-O-alkylated (five-membered) ana-
logue. Taken together with the chemical shift data, this result
suggests a more stable hydrogen bond for the six-membered sys-
tem relative to the five-membered analogue.
Fig. 9. Partial 2D 1He1H NOESY spectrum of 1a (500 MHz, CDCl3) at (a) 298 K and
(b) 212 K.
Fig. 8. H/D exchange kinetics for dimers 1a and 2a.
2.2.2. 2D NMR studies. In dimers based on scaffold 1, the NOEs
between NH and inter residual aromatic protons (NH to 1-C2H, NH
to 1-C6H) illustrate the possibility of free rotation around AreCO
bond (Fig. 9). The 2D data is supported by the single crystal X-ray
diffraction data discussed previously. In order to study the effect of
temperature on conformational flexibility due to free rotation
about the AreCO bond and to understand the most favoured con-
formation at low temperature, NOESY spectra were taken at low
temperature (212 K). In the NOESY spectrum of 1a taken at low
temperature, the amide NH exhibits an NOE to C6H (Fig. 9) and not
with C2H, whereas in the spectra taken at room temperature it
gives NOEs to both C2H and C6H. Thus, at low temperature, the
favoured conformation is the anti conformation in which isopropyl
groups are positioned on opposite sides.
In molecules based on scaffold 2, e.g., 2a, the NH resonance
exhibits NOEs with intra residual aromatic protons (NH to 2-C3H,
NH to 2-C5H, Fig. 10). This is indicative of free rotation around the
AreNH axis, which is supported by the solid-state conformational
studies. Similarly to the observations for 1a, the low temperature
NOESY spectrum of 2a suggests that the anti conformation becomes
dominant as the ratio of the intensities of the NOEs (NH to 2-C5H/
NH to 2-C3H) changes from 2.6:1 to 10:1.
The remaining benzamides in each series give similar NOESY
spectra at room temperature (see Supplementary data), i.e., there is
evidence for the prevalence of both syn and anti conformations. For
both series 1 and 2, the intensities of the NOEs supporting the
presence of syn and anti conformations change depending on the
side chains present (see Supplementary data). More intense NOEs
indicative of the syn conformation are observed in 1b and 1d. Be-
cause NOEs are dependent upon the relaxation properties of the
nuclei under interrogation (and are therefore affected by a number
Fig. 10. Partial 2D NOESY spectrum of 2a (500 MHz, CDCl3) at (a) 212 K and (b) 298 K.
of parameters), this data must be treated with caution, however
one interpretation is that CHe
p interactions between the napthyl
and isopropyl/isobutyl groups in 1b and 1d may offset the intrinsic
preference for the anti conformation.

4490
P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
2.3. Computational studies
4. Experimental section
A conformational search by employing a full Monte Carlo search
in MacromodelÒ was performed using the MMFFs (Merk Molecular
Force Fields) force fields method. Whilst more detailed density
functional theory studies have been performed on the conforma-
tional properties of arylamides that suggest MMFF’s for prediction
of aromatic oligaomide structure is limited,13c the analysis pre-
sented below is sufficient for comparison and in agreement with
the crystallographic results. Energy minimisation was made on
dimers 1a and 2a in water and chloroform media, respectively,
which cover a sufficient range of polarities to compare with the
solid-state structures (1a was crystallized from a solvent mixture of
methanol and tetrahydrofuran, 2a was crystallized from chloro-
form). The superimposition of the energy minimized structure and
the crystal structure demonstrates the accuracy of the predicted
model for both the molecules (RMSD value calculated (based on 1-
4.1. Single crystal X-ray crystallographic studies
4.1.1. Crystal data of 1a. Prismatic crystals of 1a were obtained by
the slow diffusion of methanol into a solution of compound in
tetrahydrofuran. A crystal of size 0.07ꢃ0.20ꢃ0.20 mm was used for
data collection;
q
range¼2.63ꢄ
q
ꢄ30.57ꢀ, crystals belong to mono-
clinic; space group P21/c; formula¼C21H24N2O7; formula
ꢀ
ꢀ
ꢀ
weight¼416.42; a¼11.1751(8) A, b¼12.8604(9) A, c¼14.9153(12) A,
b
¼100.532(4)ꢀ; volume¼2107.5(3); Z¼4; D(calculated): 1.314 g/
cm3;
m
¼0.095 mmꢁ1; reflections collected 22,549; independent
reflections 6318; observed reflections 3752 [I>2s(I)]; R val-
ue¼0.0421, wR2¼0.0954. CCDC 846379 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
ꢀ
C1, 1-C4, 2-C1 and 2-C4 atoms), for 1a and 2a are 0.045 A and
ꢀ
0.019 A, respectively) by showing the same results in terms of
4.1.2. Crystal data of 1c. Needle shaped crystals of 1c were obtained
by the slow evaporation of solution in a solvent mixture of ethyl ac-
etate and hexane. Crystals belong to triclinic space group P-1 with
one molecule in the asymmetric unit. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were placed in calculated
positions and refined using a riding model. All Uiso(H) values were
constrained to be 1.2 times (1.5 for methyl) Ueq of the parent atom.
The exception is the NH hydrogen, which was fully refined with
preferred conformations (Fig. 11).31
an isotropic model.
A colourless prism of approximate size
0.04ꢃ0.08ꢃ0.22 mm was used for data collection. Multiscan acqui-
sition.
q
range¼2.73ꢄ
q
ꢄ27.24ꢀ, formula¼C29H24N2O7; formula
ꢀ
ꢀ
ꢀ
weight¼512.50; a¼7.1879(10) A, b¼12.1852(15) A, c¼15.8896(19) A,
3
ꢀ
¼69.944(5)ꢀ,
b
¼86.962(6)ꢀ,
¼82.412(6) ; volume¼1295.8(3) A ;
g
ꢀ
a
Z¼2; D(calculated): 1.314 g/cm3;
m
¼0.095 mmꢁ1; reflections col-
lected 10,335; independent reflections 4996; observed reflections
6564 [I>2
s
(I)]; R value¼0.0759, wR2¼0.2367. CCDC 846380 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Fig. 11. Superimposition of the solid-state conformation 1a and 2a (in blue or green
colour) with its lowest energy conformation generated using molecular modelling
ꢀ
ꢀ
(yellow). Key distances: 1a 2-NH/2-O¼2.385 A (crystal structure) versus 2.194 A
ꢀ
ꢀ
(modelling); 2a 2-NH/1-O¼1.957 A (crystal structure) versus 1.857 A (modelling).
4.1.3. Crystal data of 1d. Single crystals of 1d were grown by slow
evaporation of a mixture of ethyl acetate and hexane. Colourless rod
shaped crystal of dimension 0.04ꢃ0.07ꢃ0.30 was used for the data
3. Conclusion
collection;
q
range¼2.704ꢄ
q
ꢄ27.80ꢀ, crystals belong to monoclinic;
In summary, we have described the synthesis and conforma-
tional studies of O-alkylated benzamides based on two different
scaffolds. Intramolecular hydrogen bonding acts as a pre-organizing
force in both scaffolds to promote an extended conformation and
restrict rotation around one of the aryl amide axes. Rotation around
the remaining axes is permitted and may be influenced by the side
chains present. H/D exchange data suggested an increased stability
of the six-membered over the five-membered analogues. In the 3-O-
alkylated series 1, there is evidence to suggest the anti conformation
is favoured whereas in the 2-O-alkylated series the distribution
between syn and anti is more equitable. With the simple aliphatic
and aromatic side chains used in this study, some evidence for in-
termolecular side-chaineside-chain interactions and subtle steric
and/or non-covalent interactions was identified in the solid-state
structures and in solution. These interactions were not sufficient to
bias the conformation in favour of the syn orientation, however the
results provide insight as to how this might be achieved; flexible and
larger side chains, together with functional groups capable of mak-
ing more directed and high affinity interactions should be used.
Overall the results point to a complex interplay of interactions in
defining the conformational properties of longer O-alkylated ben-
space group P21/n; formula¼C30H28N2O7; formula weight¼528.54;
ꢀ ꢀ ꢀ
V¼2640.1(4); Z¼4; D(calculated): 1.314 g/cm3;
a¼7.7976(7) A, b¼30.135(3) A, c¼11.4892(9) A,
b
¼102.069(4)ꢀ;
m
¼0.095 mmꢁ1, re-
flections collected 21,037; independent reflections 5985; observed
reflections 3354 [I>2
s
(I)]; R value¼0.0506, wR2¼0.1329. CCDC
846381 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
4.1.4. Crystal data of 2a. Yellow needle shaped crystals of 2a were
grown by slow evaporation of a chloroform solution. Despite long
exposures and high power, the crystal diffracted weakly and conse-
quently the complete structure of the molecule was not determined.
Compound 2a crystallizes in the triclinic space group P1 with
one molecule of in the asymmetric unit. All non-hydrogen atoms
were refined anisotropically. All hydrogen atoms could be located in a
difference Fourier map but, in the final stages of the refinement,
they were placed in calculated positions and refined using a rid-
ing model. Yellow needle of size 0.28ꢃ0.09ꢃ0.04 mm was used for
the data collection; multiscan acquisition;
q
range¼2.02ꢄ
q
ꢄ28.44ꢀ;
ꢀ
zamides. Given such structures have been shown to act as
mimetics, these results will be considered in our ongoing efforts to
develop -helix mimetics tailored to a range of biological targets.
a
-helix
formula¼C21H24N2O7; formula weight¼416.42; a¼6.5749(7) A,
b¼12.8076(15) A, c¼13.3529(17) A,
a
¼101.778(6)ꢀ,
b
¼100.815(6)ꢀ,
ꢀ
ꢀ
3
ꢀ
a
g
¼90.011(6)ꢀ; V¼1080.3(2) A ; Z¼2; D(calculated)¼1.28 Mg/m3;

P. Prabhakaran et al. / Tetrahedron 68 (2012) 4485e4491
4491
G. J. Chem. Commun. 2008, 712e714; (g) Li, C.; Wang, G.-T.; Yi, H.-P.; Jiang, X.-K.;
Li, Z.-T.; Wang, R.-X. Org. Lett. 2007, 9, 1797e1800.
5. Jefferey, G. A.; Saenger, W. Hydrogen Bonding in Biological Structures; Springer:
m
¼0.097 mmꢁ1
;
reflections collected 36,646; independent
reflections¼5330 [R(int)¼0.0641]; observed reflections¼3481
[I>2
s(I)]; absorption correction max. and min. transmission¼0.9961
Berlin, 1991.
ꢁ
6. (a) Delsuc, N.; Godde, F. d. r.; Kauffmann, B.; Leger, J.-M.; Huc, I. J. Am. Chem. Soc.
2007, 129, 11348e11349; (b) Mandity, I. n. M.; Fulop, L.; Vass, E.; Toth, G. K.;
Martinek, T. A.; Fulop, F. Org. Lett. 2010, 12, 5584e5587.
and 0.9734; R value¼0.0446, wR2¼0.0981. CCDC 846382 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
ꢁ
€ €
ꢁ
€ €
7. (a) Guo, L.; Almeida, A. M.; Zhang, W.; Reidenbach, A. G.; Choi, S. H.; Guzei, I. A.;
Gellman, S. H. J. Am. Chem. Soc. 2010, 132, 7868e7869; (b) Vasudev, P. G.;
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9. (a) Hu, Z.-Q.; Hu, H.-Y.; Chen, C.-F. J. Org. Chem. 2006, 71, 1131e1138; (b)
Mousseau, J. J.; Xing, L.; Tang, N.; Cuccia, L. A. Chem.dEur. J. 2009, 15,
10030e10038.
4.1.5. Crystal data of 2b. Single crystals of 2b were grown by slow
evaporation of a methanol solution. A colourless prism of approxi-
mate size 0.30ꢃ0.16ꢃ0.15 mm was used for data collection. Multi-
scan acquisition.
q
range¼1.92ꢄ
q
ꢄ30.69ꢀ, formula¼C30H30N2O8;
formula weight¼546.56; crystals belong to triclinic; space group P1;
10. Plante, J.; Campbell, F.; Malkova, B.; Kilner, C.; Warriner, S. L.; Wilson, A. J. Org.
Biomol. Chem. 2008, 6, 138e146.
ꢀ
ꢀ
ꢀ
a¼10.5500(10) A, b¼11.3420(11) A, c¼12.6649(12) A,
a
¼101.747(5)ꢀ,
11. (a) Ahn, J.-M.; Han, S.-Y. Tetrahedron Lett. 2007, 48, 3543e3547; (b) Saraogi, I.;
Incarvito, C. D.; Hamilton, A. D. Angew. Chem., Int. Ed. 2008, 47, 9691e9694; (c)
Shaginian, A.; Whitby, L. R.; Hong, S.; Hwang, I.; Farooqi, B.; Searcey, M.; Chen,
J.; Vogt, P. K.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 5564e5572.
12. (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120e126; (b) Bernstein, J.; Davis, R. E.;
Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555e1573.
13. (a) Tew, G. N.; Liu, D.; Chen, B.; Doerksen, R. J.; Kaplan, J.; Carroll, P. J.; Klein, M.
L.; DeGrado, W. F. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5110e5114; (b) Yin, H.;
Frederick, K. K.; Liu, D.; Wand, A. J.; DeGrado, W. F. Org. Lett. 2005, 8, 223e225;
(c) Pophristic, V.; Vemparala, S.; Ivanov, I.; Liu, Z.; Klein, M. L.; DeGrado, W. F. J.
Phys. Chem. B 2006, 110, 3517e3526.
3
ꢀ
ꢀ
b
¼99.324(5)ꢀ,
¼104.299(5) ; V¼1401.3(2) A ; Z¼2; D(calculated):
g
1.295 Mg/m3;
m
¼0.095 mmꢁ1; reflections collected 89,846; in-
dependent reflections 8518 [R(int)¼0.0594]; observed reflections
6564 [I>2
s(I)]; R value¼0.0502; wR2¼0.1349. CCDC 846383 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
14. The side chains mimic i, iþ3 (and or iþ4) and iþ7 residues of an
a-helix.
Acknowledgements
15. Plante, J. P.; Burnley, T.; Malkova, B.; Webb, M. E.; Warriner, S. L.; Edwards, T. A.;
Wilson, A. J. Chem. Commun. 2009, 5091e5093.
16. Saraogi, I.; Hamilton, A. D. Biochem. Soc. Trans. 2008, 36, 1414e1417; (a) Davis, J.
M.; Tsou, L. K.; Hamilton, A. D. Chem. Soc. Rev. 2007, 36, 326e334; (b) Campbell,
F.; Plante, J. P.; Edwards, T. A.; Warriner, S. L.; Wilson, A. J. Org. Biomol. Chem.
2010, 8, 2344e2351; (c) Wilson, A. J. Chem. Soc. Rev. 2009, 38, 3289e3300; (d)
Haridas, V. Eur. J. Org. Chem. 2009, 5112e5128; (e) Marimganti, S.; Cheemala,
M. N.; Ahn, J.-M. Org. Lett. 2009, 11, 4418e4421.
This work was supported by the European Research Council
[ERC-StG-240324].
Supplementary data
17. Manuscript is in preparation.
Experimental details including 1H, 13C, 2D NMR. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tet.2011.11.078.
18. Yin, H.; Lee, G.-i.; Sedey, K. A.; Rodriguez, J. M.; Wang, H.-G.; Sebti, S. M.;
Hamilton, A. D. J. Am. Chem. Soc. 2005, 127, 5463e5468.
€
19. (a) Bohm, H.-J.; Schneider, B. ProteineLigand Interactions from Molecular Rec-
ognition to Drug Design; Wiley-VCH: 2003; (b) Giralt, E.; Peczuh, M. W.; Sal-
vatella, X. Protein Surface Recognition: Approaches for Drug Discovery; Wiley-
VCH: 2010.
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