Modular solid-phase synthesis of teroxazoles as a class of α-helix mimetics

Article abstract of DOI:10.1002/ejoc.201200339

α-Helices are ubiquitous structural elements of proteins and are important in molecular recognition. Small molecules mimicking α-helices have proven to be valuable biophysical probes or modulators of protein-protein interactions. Here, we present modeling studies and the modular solid-phase synthesis of teroxazole derivatives as a new class of α-helix mimetics. The synthesis is compatible with a variety of functional groups and should thus be generally applicable for generating diversely substituted oligo-oxazole scaffolds. The teroxazole scaffold is predicted to be polar and to project peptidomimetic side chains at positions i, i+3, and i+6 of an α-helix, which complements projection patterns of existing helix mimetics. The scaffold retains sufficient conformational flexibility to conform to induced-fit models of protein-protein interaction inhibition. Copyright

Full text of DOI:10.1002/ejoc.201200339

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FULL PAPER
DOI: 10.1002/ejoc.201200339
Modular Solid-Phase Synthesis of Teroxazoles as a Class of α-Helix Mimetics
Cristiano Pinto Gomes,[a][‡] Alexander Metz,[b][‡] Jan W. Bats,[a] Holger Gohlke,[b] and
Michael W. Göbel*[a]
Keywords: Protein–protein interactions / Conformation analysis / Molecular dynamics / Peptidomimetics / Helical
structures
α-Helices are ubiquitous structural elements of proteins and
are important in molecular recognition. Small molecules
mimicking α-helices have proven to be valuable biophysical
probes or modulators of protein-protein interactions. Here,
we present modeling studies and the modular solid-phase
synthesis of teroxazole derivatives as a new class of α-helix
mimetics. The synthesis is compatible with a variety of func-
tional groups and should thus be generally applicable for
generating diversely substituted oligo-oxazole scaffolds. The
teroxazole scaffold is predicted to be polar and to project
peptidomimetic side chains at positions i, i+3, and i+6 of an
α-helix, which complements projection patterns of existing
helix mimetics. The scaffold retains sufficient conformational
flexibility to conform to induced-fit models of protein-protein
interaction inhibition.
concentrations.[9,12] However, terphenyls are rather hydro-
phobic, which led to the development of other scaffolds that
are more hydrophilic and/or amphiphilic including oligo-
Introduction
α-Helices are ubiquitous structural elements of proteins
and are important in molecular recognition.[1] Accordingly,
small molecules mimicking α-helices have proven to be
valuable biophysical probes or modulators of protein-pro-
tein interactions (PPI).[2] Typically, only some of the side
chains of an α-helix form interaction “hot spots” in PPI.[3]
Imitating these interactions by using α-helix mimetics thus
offers a route to the rational development of PPI modula-
tors.[4]
pyridines,[13]
phenylpyridals,[14]
phenylenaminones,[15]
benzoylureas,[16] oxazole-pyridazine-piperazines (Scheme 1,
II) and oxazole-pyrrole-piperazines,[17] 1,4-dipiperazino
benzenes,[18] 5-6-5 imidazole-phenyl-thiazoles, terphthal-
imides,[19] biphenyl 4,4Ј-dicarboxamides,[20] oligobenz-
amides,[21] and 6/6/6/6 trans-fused polycyclic ethers.[22]
Initial approaches to mimic α-helices with non-peptidic
compounds began more than two decades ago.[2a,2c,5] Small
α-helix mimetics, such as derivatives of allenes, alkylidene
cycloalkanes, spiranes, biphenyls,[6] bicyclic indanes,[7] and
benzodiazepinediones[8] often mimic α-helix positions that
are at close range. A pioneering achievement was the design
and synthesis of terphenyl derivatives (Scheme 1, I) by the
Hamilton group.[9] Such extended scaffolds are substituted
with R groups that mimic the position and orientation of
Cα–Cβ launch vectors of side chains on one “face” of an α-
helix. Terphenyl derivatives have been shown to inhibit Bak/
Bcl-XL[10] and p53/HDM2[11] interactions at submicromolar
Scheme 1. Terphenyl (I), oxazole-pyridazine-piperazine (II), and
teroxazole (III) scaffolds for α-helix mimicry. R1–R4 = CH3 or pep-
tidomimetic side chain. The inter-ring torsion angles, ν and ω, of
III are highlighted in bold. Oxazole rings of III are labeled A, B,
and C.
[a] Institute of Organic Chemistry and Chemical Biology,
Department of Biochemistry, Chemistry, and Pharmacy,
Goethe-University,
Max-von-Laue-Str. 7, 60438 Frankfurt, Germany
Fax: +49-69-798-29464
E-mail: m.goebel@chemie.uni-frankfurt.de
[b] Institute for Pharmaceutical and Medicinal Chemistry,
Department of Mathematics and Natural Sciences,
Heinrich-Heine-University,
Universitätsstr. 1, 40225 Düsseldorf, Germany
[‡] Both authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200339.
Here, we describe molecular modeling studies and the
modular solid-phase synthesis of teroxazole derivatives
(Scheme 1, III)[23] as a new class of α-helix mimetics. The
modeling studies suggest that substituted teroxazoles are
hydrophilic and preferentially project R groups with launch
vectors similar to those of side chains at positions i, i+3,
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and i+6 of an α-helix. This suggestion was confirmed by project peptidomimetic side chains fulfilling distance and
single-crystal structures. This projection pattern comple- angular requirements of an α-helix, and to conform to in-
ments that of previous scaffolds and covers a broader re- duced-fit models of protein-protein interaction inhibi-
gion on the α-helix surface, which may be advantageous tion.[15]
when it comes to mimicking interactions between two heli-
ces that wrap around each other and/or are not arranged in
a collinear way.
Results and Discussion
Modeling Studies
Computation of relative molecular mechanics Poisson–
Boltzmann surface area (MM-PB/SA)[24] effective energies
as a function of inter-ring torsion angles ν and ω reveal that
teroxazoles can adopt low-energy conformations with an α-
helix-like arrangement of side chains (Scheme 1, III; Fig-
ure 1a). The conformation with both torsion angles eclipsed
(ν = 0°, ω = 0°) has the lowest energy. Rotating one or both
of the torsion angles by 180° increases the effective energy
by approximately 2 and 4 kcalmol–1, respectively. The pre-
valence of the (ν = 0°, ω = 0°) conformation can be ex-
plained by a parallel orientation of the ring dipoles leading
to a more favorable solvation contribution (data not
Figure 2. Mutual orientation of teroxazole rings in aqueous solu-
shown). The rotation around ν or ω is hindered by an en-
ergy barrier of ≈5.5 kcalmol–1, but nonetheless occurs mul-
tiple times during a molecular dynamics (MD) simulation
of 250 ns length (Figure 2). The torsion angle distributions
from the MD trajectory also reveal significant deviations of
ν and ω of up to 50° from a coplanar orientation of the
rings. This observation is in good agreement with the MM-
PB/SA computations that yield an energetic cost of
tion. The inter-ring torsion angles, υ and ω, of 13a in explicit sol-
vent were calculated from a MD trajectory of 250 ns length at inter-
vals of 1 ns. Depicted are the inter-ring torsion angles (a) ν and
(b) ω as a function of the simulation time (left panels) and in terms
of histograms (right panels) with bins of 1°. The inter-ring torsion
angles are defined in Scheme 1, III.
Superimposing the substituents R1–R4 of coplanar ter-
≈3 kcalmol–1 for such a deviation. The apparent torsional oxazole conformations onto Cβ atoms of a canonical α-heli-
flexibility is expected to enable the teroxazole scaffold to cal octapeptide reveals that the teroxazole scaffold can
Figure 1. Preferred conformation of a teroxazole scaffold in aqueous solution. (a) Relative MM-PB/SA[36] effective energies of terox-
azole 13a as a function of the inter-ring torsion angles ν and ω (Scheme 1, III). (b) Superimposition of Cβ atoms of side chains at positions
i, i+3, and i+6 of a canonical α-helical octapeptide onto the corresponding substituent atoms of R1–3 of a teroxazole in a low-energy
conformation (ν = 0°, ω = 0°). (c) Analogous alignments with the teroxazole scaffold reversed with respect to the α-helix axis. (d) Making
use of the substituent R4 of a rotated ring C (ν = 0°, ω = 180°). (e) If ring A is rotated instead (ν = 180°, ω = 0°), it is possible to align
all four substituents R1–4 with α-helix side chains at positions i, i+2, i+6, and i+7. Below, the α-helix/α-helix-mimetics superimpositions
were rotated by 90°. The N-terminus of the α-helix is oriented towards the viewer. The relative MM-PB/SA effective energies of the
conformations of 13a used for (b) or (c), (d), and (e) are 0.30, 2.48 and 1.96 kcalmol–1, respectively. Graphics by gnuplot[39] and VMD.[40]
2
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Teroxazoles as a Class of α-Helix Mimetics
closely mimic the arrangement of peptide side chains (Fig- Starting from these precursors, construction of a peptide
ure 1b–e). Good agreement is found for the minimum en- followed by further oxazole building transformations is ex-
ergy conformation (ν = 0°, ω = 0°) with ring A pointing pected to result in the desired heterocycles (Scheme 2).
towards the N-terminus of the α-helix, mimicking α-helix
positions i, i+3, and i+6 [root mean square deviation
(RMSD) = 0.35 Å; Figure 1b]. Reversing the orientation of
the teroxazole scaffold with respect to the α-helix axis does
not change the positional agreement between substituent
atoms and Cβ atoms but impairs the orientational agree-
ment between the respective bonds (Figure 1c). Rotating
ring C by 180° (ν = 0°, ω = 180°; Figure 1d) allows the
substituent at R4 to be used. In this conformation the dis-
tance between the substituents in ring A or B and ring C is
increased, which results in a poorer superimposition with
respect to Cβ atoms (RMSD = 1.03 Å). Because R3 and R4
are located on opposite edges of ring C, it is not possible
Scheme 2. Retrosynthetic disconnection of the teroxazole scaffold.
to align them to amino-acid side chains located on one
Wipf and Miller,[27] showed that β-hydroxy amides can
“face” of an α-helix. Nevertheless, in situations where the
be efficiently converted to C5-substituted oxazole subunits.
mimicked α-helix is deeply buried, one could imagine mak-
The reaction conditions are very mild and therefore com-
ing use of all four substituents arranged as side chains in
patible with a variety of functional groups [e.g., amides, es-
positions i, i+2, i+6, and i+7 (RMSD = 0.84 Å, Figure 1e).
ters, 9H-fluoren-9-ylmethoxycarbonyl (Fmoc), Boc, Alloc,
The side chains now form two pairs [(i, i+7) and (i+2, i+6)],
and Cbz]. Kessler et al.[28] extended this concept by apply-
each of which is located on one “face” of an α-helix. Alter-
ing it to solid-phase synthesis to offer a valuable tool for the
natively, if substituent R3 or R4 is not required to mimic
rapid construction of highly-substituted oxazole moieties.
an important interaction site, it can be used to fine-tune
Based on these findings we developed a general solid-phase
physicochemical and pharmacokinetic properties.
strategy for the preparation of a teroxazole scaffold. This
Terphenyl[10–12] and oxazole-pyridazine-piperazine[17] de-
procedure allows incorporation of structurally different side
rivatives mimic side chain positions i, i+3/i+4, and i+7. In
chains into the framework employing a modular concept.
both cases, the side chains are located on one “face” of an
Moreover, the method should be appropriate for use in par-
α-helix. On the contrary, the side chain positions i, i+3, and
allel synthesis. The retrosynthetic approach is shown in
i+6 addressed by coplanar teroxazole derivatives cover a
Scheme 2. The strategy includes incorporation of four com-
broader region on the α-helix surface that is rarely ad-
ponents to introduce structural diversity. Substituted β-hy-
dressed by other α-helix mimetics.[25] This broader region
droxy-α-amino acids and a simple carboxylic acid are re-
may be advantageous to mimic interactions between two
quired as building blocks for the synthesis. These mono-
helices that wrap around each other and/or are not ar-
mers can be readily connected by using standard amide
ranged in a collinear way. α-Helix mimetics based on ter-
bond-forming reactions [1-hydroxybenzotriazole (HOBt)/
phenyl scaffolds are rather hydrophobic (Scheme 1, I with
diisopropylcarbodiimide (DIC)], allowing rapid and ef-
R1–R4 = CH3; logP = 3.34) that may compromise the water
ficient access to peptidic precursors for further transforma-
solubility and, hence, the biocompatibility. Among
tions. We chose a solid-phase approach that benefits from
others[13,19] oxazole-pyridazine-piperazine scaffolds[17a] have
the facile purification and reaction work-up owing to the
been developed as more polar alternatives to enhance solu-
immobilized substrate. The key step involves a modified
bility (Scheme 1, II with R1–R4 = CH3; logP = 0.96). Like-
Gabriel–Robinson cyclization of the peptidic precursor.[27]
wise, the teroxazole scaffold introduced here is polar and
The required β-ketoamide is generated by oxidation of the
should offer increased solubility (Scheme 1, III with R1–
side chain alcohol and subsequently converted into the ox-
R4 = CH3: logP = 0.34). These modeling studies suggest
azole by cyclodehydration. Repeating the cycle of peptide
teroxazoles as a new class of α-helix mimetics, the R-groups
coupling, oxidation, and cyclodehydration led to the desired
of which point in the directions of side chains of the α-helix
teroxazole compounds.
that are preferentially located on one face of the helix.
Synthesis of the Building Blocks
Chemistry
The building blocks were prepared by aldol addition of
We envisioned a fast and reliable procedure to prepare protected glycine derivative 1[29] and corresponding alde-
substituted teroxazoles starting from easily available precur- hydes to yield β-hydroxy-α-amino acid tert-butyl esters 2 as
sors. Owing to the fact that naturally occurring oligo-ox- racemic mixtures of diastereomers (Scheme 3). At this
azoles bearing a C2–C4 linkage pattern are derived from stage both diastereomers could be separated by column
serine containing substrates,[26] substituents at C5 can be chromatography for analytical purposes. However, because
obtained from functionalized β-hydroxy-α-amino acids. the newly generated stereocenters are lost in the oxidation-
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cyclodehydration sequence to form the resin-bound oxazole cyclodehydration as before. Resin-bound teroxazole deriva-
moiety, there is no need for a stereoselective aldol reaction tives 12 were finally cleaved from the support under acidic
or a separation of stereoisomers. Subsequent cleavage of the conditions and purified by column chromatography afford-
tert-butyl esters under strongly acidic conditions afforded ing 13.
the hydrochloride salt of the amino acids that were sub-
sequently protected resulting in 3. Finally, the secondary
hydroxy groups were converted into the trityl ethers in the
presence of in situ generated trityl triflate[30,31] to provide
the orthogonally protected β-hydroxy-α-amino acids 4.
Scheme 3. General synthesis of orthogonally protected β-hydroxy-
α-amino acids bearing nonpolar residues: (a) (i) 1 m Lithium hexa-
methyldisilazide (LHMDS), THF, –78 °C; (ii) RCHO, THF,
–78 °C; (iii) 1 m HCl, THF, 0 °C. (b) 6 m HCl, reflux. (c) N-(9H-
Fluoren-9-ylmethoxycarbonyloxy)succinimide, Na2CO3, 1,4-diox-
ane/water (1.2:1), 0 °C to room temp. (d) TrtCl, AgOTf, 2,6-luti-
dine, CH2Cl2, 0 °C to room temp. (2a: R = CH2CH2NHCbz; 2b
and 3b: R = Et; 2c, 3c, and 4: R = iBu; 2d and 3d: R = CH2-1-
naphthyl)
Solid-Phase Synthesis of Teroxazole Derivatives
The synthesis was performed on Rink amide 4-methyl-
benzhydrylamine hydrochloride salt (MBHA) resin (5) at a
scale of 0.25 mmol by using standard solid-phase tech-
Scheme 4. Solid-phase synthesis of the teroxazole scaffold: (a) Pip-
eridine/DMF (1:4). (b) Fmoc-protected amino acid 3, HOBt,
DIC, NMP. (c) Fmoc/Trt-protected amino acid 4, HOBt, DIC,
niques and Fmoc/triphenylmethyl (Trt) synthetic pro-
cedures (Scheme 4). The resin-bound Fmoc group was re-
moved with piperidine in dimethylformamide (DMF; 20%,
v/v), followed by attachment of Fmoc-protected β-hydroxy-
α-amino acids 3 to the solid support in the presence of
HOBt/DIC. Treatment of the resin with piperidine and cou-
pling of Fmoc/Trt-protected β-hydroxy-α-amino acids 4
NMP. (d) Dess–Martin periodinane, CH2Cl2. (e) PPh3, I2, DIPEA,
CH2Cl2. (f) TFA/TIPS/CH2Cl2 (1:5:94). (g) Carboxylic acid, HOBt,
DIC, NMP or acetic anhydride, DIPEA, NMP. (h) TFA/TIPS/H2O
(95:2.5:2.5). (13a: R1–R4 = Me; 13b: R1 = Et, R2 = iBu, R3 = Me,
R4 = Bn; 13c: R1–R3 = iBu).
Applying this methodology, teroxazole derivatives 13a–
with HOBt/DIC formed the immobilized dipeptides 6. The c (Scheme 5) were synthesized starting from protected β-
corresponding β-ketoamides 7 were obtained by oxidation hydroxy-α-amino acids in overall yields of 19–24%, corre-
of the hydroxy group with Dess–Martin periodinane sponding to average yields per step above 90%. Solid-phase
(DMP). Subsequent treatment of the ketone with PPh3/I2 syntheses are normally conducted on a small scale provid-
afforded oxazole derivatives 8 by a Robinson–Gabriel cyclo- ing only small quantities of target compounds. However,
dehydration.[27] Cleavage of the trityl ether with 1% tri- 13a–c could be obtained in quantities of around 20 mg, suf-
fluoroacetic acid (TFA) in dichloromethane in the presence ficient for most scientific purposes (0.25 mmol of resin-
of a scavenger and removal of the Fmoc group with pip- bound NH2).
eridine were followed by coupling of 4 with HOBt/DIC to
We also synthesized a set of monooxazoles bearing dif-
provide resin-bound β-hydroxyamides 9. After oxidation to ferent types of side chains and functional groups to demon-
the β-ketoamide with Dess–Martin periodinane, cyclodehy- strate the structural diversity accessible by our method
dration with PPh3/I2 resulted in resin-bound bioxazole de- (Scheme 6). The products obtained comprise alkyl, aryl, ba-
rivatives 10. Removal of the Fmoc protecting group with sic, and acidic residues.
piperidine was followed by coupling of the terminal carbox-
To obtain the precursors of 14f and 14g, we had to mod-
ylic acid (HOBt/DIC). After cleavage of the trityl ether with ify some reaction conditions and protecting groups
diluted TFA, peptides 11 were subjected to oxidation and (Scheme 7). In the case of 14f it was necessary to use milder
4
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Teroxazoles as a Class of α-Helix Mimetics
Single crystals of 13a and 13b suitable for X-ray crystal-
lographic analysis were obtained by slow solvent evapora-
tion (ethyl acetate). These structures confirm the coplanar
orientation of the oxazole rings found to be energetically
favorable in the modeling studies, with ν/ω values of 178.6/
179.4° and 6.9/–6.1° for 13a and 13b, respectively (Fig-
ure 3).
Scheme 5. Teroxazole derivatives 13a–c synthesized in this study.
Figure 3. Single-crystal structures of (a) 13a and (b) 13b.
Conclusions
Scheme 6. Structures of the substituted monooxazoles 14a–g.
A modular solid-phase synthesis of a series of α-helix
mimetics based on a teroxazole scaffold is presented. The
synthesis starts from substituted β-hydroxy-α-amino acids,
is compatible with a variety of functional groups, and
should thus be applicable for generating diversely substi-
tuted oligo-oxazole scaffolds. Molecular modeling studies
demonstrate that teroxazoles are able to mimic the side
chains i, i+3, and i+6 of an α-helix, which cover a broader
region on the α-helix surface than peptidomimetic side
chains presented by terphenyl or oxazole-pyridazine-piper-
azine scaffolds. Furthermore, the teroxazole scaffold is
found to be more hydrophilic than the terphenyl scaffold
and as hydrophilic as the oxazole-pyridazine-piperazine
scaffold, which should result in improved solubility and bio-
compatibility. At present, a series of teroxazoles synthesized
with the methods presented above is being evaluated for its
potential to act as protein-protein interaction modulators.
Scheme 7. Modified preparation of unprotected β-hydroxy-α-
amino acids: (a) TFA/CH2Cl2 (1:1), room temp. (b) (i) 1 m
LHMDS, THF, –78 °C; (ii) R2CHO, THF, –78 °C; (iii) 1 m HCl,
THF, 0 °C. (c) H2, Pd/C, 1 bar, room temp.
Experimental Section
conditions for the cleavage of the tert-butyl ester 2a to pre- Conformational and Physicochemical Properties: The inter-ring tor-
sion angles ν and ω (Scheme 1, scaffold III and Figure 1a) are cru-
cial for the conformational properties of the teroxazole scaffold.
Hence, the respective torsion angle potential was parameterized for
use with other parameters of the molecular mechanics general
AMBER force field (GAFF).[32] Conformations of the bioxazole
derivative 2Ј,5,5Ј-trimethyl-[2,4Ј-bioxazole]-4-carboxamide (28, see
Supporting Information) were optimized at the MP2/6-31G* level
by using Gaussian 03,[33] with the inter-ring torsion angles υ and ω
constrained at intervals of 15° over a range of 360°. Likewise, the
conformations were optimized constrained to the same inter-ring
vent premature loss of the Cbz group. The deprotection was
achieved with a mixture of TFA/CH2Cl2 (1:1) at room tem-
perature affording 15. The tert-butyl ester of O’Donnell im-
ine 1 needed to be replaced during the preparation of 14g
because the carboxyl group at the side chain of the aldehyde
already contained this protecting group. When benzyl ester
16 was used in the aldol reaction yielding 17, subsequent
hydrogenolysis at atmospheric pressure removed the benzyl
group furnishing free β-hydroxy-α-amino acid 18 that was
further protected as shown in Scheme 3.
torsion angles
– by using the GAFF force field within
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AMBER 9.[34] Torsion potential energies for each torsion angle po-
sition were obtained by subtracting the GAFF molecular mechan-
ics energy, devoid of the contribution of the inter-ring torsion, from
the MP2/6-31G* energy of the corresponding optimized structures.
A new molecular mechanics torsion angle potential was then deter-
mined by fitting the appropriate GAFF term to these torsion po-
tential energies. This torsion angle potential was used for both in-
ter-ring torsions ν and ω of teroxazole 13a (Figure 1a with R1–4
= CH3) in the calculations below. Partial charges for the bi- and
teroxazoles were derived by multiconformational RESP fitting[35]
to the HF/6-31G* electrostatic potentials of the optimized confor-
mations with coplanar rings.
was coupled to the resin. Washing with CH2Cl2 (5ϫ) was followed
by treatment (2 h) of the resin with DMP (0.1 m, 7.5 mL,
0.75 mmol) in CH2Cl2. The resin was washed with CH2Cl2 (5ϫ),
NMP (5ϫ) and CH2Cl2 (5ϫ), and a solution of PPh3 (656 mg,
2.50 mmol), iodine (635 mg, 2.50 mmol) and DIPEA (871 μL,
5.00 mmol) in CH2Cl2 (17 mL) was added. After shaking (12 h),
the Trt protecting group was cleaved, and the resin was washed
with NMP (5ϫ). The Fmoc protecting group was removed and
Fmoc-O-trityl-l-threonine (438 mg, 0.75 mmol) was coupled to the
resin-bound amine. The resin was washed with CH2Cl2 (5ϫ),
treated (2 h) with a solution of DMP (0.1 m, 7.5 mL, 0.75 mmol)
in CH2Cl2 and washed with CH2Cl2 (5ϫ), NMP (5ϫ) and CH2Cl2
(5ϫ). A solution of PPh3 (656 mg, 2.50 mmol), iodine (635 mg,
2.50 mmol) and DIPEA (871 μL, 5.00 mmol) in CH2Cl2 (17 mL)
was added and agitated (12 h), followed by washing with CH2Cl2
(5ϫ) and NMP (5ϫ). After removal of the Fmoc protecting group,
phenylacetic acid (102 mg, 0.75 mmol) was attached to the resin-
bound amine. The resin was washed with CH2Cl2 (5ϫ), the trityl
protecting group was removed and a solution of DMP (0.1 m,
7.5 mL, 0.75 mmol) in CH2Cl2 was added. The suspension was agi-
tated (2 h), washed with CH2Cl2 (5ϫ), NMP (5ϫ) and CH2Cl2
To determine the conformational preferences of 13a, relative MM-
PB/SA[36] effective energies were calculated for conformations that
had been optimized by using the GAFF force field with the inter-
ring torsion angles constrained at intervals of 5° over a range of
360° (Figure 1b). Next, minimization, equilibration, and MD simu-
lations of 13a in explicit solvent was carried out with the AM-
BER 9 program package by using the GAFF force field and stan-
dard procedures (TIP3P water model, PBC, PME, SHAKE, time
step of 2 ps). The distribution of torsion angles was analyzed over
a MD trajectory of 250 ns length (Figure 2).
(5ϫ) and treated (12 h) with
a solution of PPh3 (656 mg,
2.50 mmol), iodine (635 mg, 2.50 mmol) and DIPEA (871 μL,
5.00 mmol) in CH2Cl2 (17 mL). The resin was washed with CH2Cl2
(5ϫ), NMP (5ϫ) and CH2Cl2 (5ϫ), followed by cleavage of the
resin. The brown residue was purified by column chromatography
(silica gel; n-hexane/ethyl acetate, 1:1) and recrystallized (cyclohex-
ane), providing 13b (25 mg, 23%) as a colorless solid. M.p. 185–
logP values of α-helix mimetics in Scheme 1 were calculated by
Molinspiration MiLogP,[37] which has been shown to have good
predictive power (root mean square error = 1.10) in a recent study
on a dataset of ≈96000 compounds.[38]
General Procedures for Solid-Phase Reactions
187 °C. R = 0.52 (ethyl acetate/n-hexane, 9:1). IR (KBr): ν = 3471
˜
f
Coupling of Carboxylic Acids or Protected Amino Acids: A solution
of the corresponding carboxylic acid or protected amino acid
(3 equiv.), HOBt·H2O (3 equiv.) and DIC (3 equiv.) in N-methyl-2-
pyrrolidone (NMP; 3 mL) was stirred (10 min) at room tempera-
ture and added to the resin-bound amine. The suspension was agi-
tated until the reaction was complete (monitored by the Kaiser
test). The resin was washed with NMP (5ϫ).
(m), 3350 (w), 3276 (w), 3131 (m), 2957 (m), 2871 (w), 1689 (s),
1649 (m), 1628 (m), 1586 (m), 1551 (w), 1496 (w), 1455 (m), 1419
(m), 1386 (w), 1368 (w), 1350 (w), 1248 (w), 1198 (m), 1161 (w),
1096 (w), 1064 (s), 1034 (s), 985 (w), 946 (w), 801 (w), 773 (w), 729
(m), 696 (m), 669 (w), 567 (w) cm–1. 1H NMR (250 MHz, CDCl3):
δ = 0.94 [d, J = 6.7 Hz, 6 H, (CH3)2CH], 1.27 (t, J = 7.6 Hz, 3 H,
CH3CH2), 2.13 [m, 1 H, (CH3)2CH], 2.61 (s, 3 H, ArCH3), 2.95 (d,
J = 7.2 Hz, 2 H, iPrCH2), 3.12 (q, J = 7.6 Hz, 2 H, CH2CH3), 4.08
(s, 2 H, CH2Ph), 5.43 (br. s, 1 H, NH2), 6.85 (br. s, 1 H, NH2),
7.17–7.30 (m, 5 H, C6H5) ppm. 13C NMR (101 MHz, CDCl3): δ =
11.8, 12.1, 19.4, 22.4, 28.3, 34.5, 34.5, 124.7, 126.1, 127.2, 128.7,
128.7, 128.8, 135.0, 150.8, 153.1, 153.1, 155.3, 158.2, 161.8,
163.8 ppm. C24H26N4O4 (434.49): calcd. C 66.34, H 6.03, N 12.89;
found C 66.11, H 5.95, N 12.88.
Acylation with Anhydrides: A mixture of the corresponding an-
hydride (2ϫ5 equiv.) and N,N-diisopropylethylamine (DIPEA;
2ϫ5 equiv.) in NMP (5 mL) was added to the resin-bound amine
and agitated (2ϫ30 min) at room temperature. After the reaction
was complete (monitored by the Kaiser test) the resin was washed
with NMP (5ϫ).
Removal of Fmoc Protecting Groups: The resin-bound Fmoc-pro-
tected amine was treated with 20% piperidine in DMF (1ϫ5 min,
1ϫ20 min, 1ϫ10 min) and washed with NMP (5ϫ).
2ЈЈ,5,5Ј,5ЈЈ-Tetramethyl-[2,4Ј:2Ј,4ЈЈ-teroxazole]-4-carboxamide (13a):
Monomers used: Fmoc-l-threonine, Fmoc-O-trityl-l-threonine
and acetic anhydride. The reaction gave 13a as colorless solid
(24%). M.p. 254–255 °C from ethyl acetate/n-hexane. Rf = 0.12
Removal of Triphenylmethyl Protecting Groups: A mixture of TFA/
triisopropylsilane (TIPS)/CH2Cl2 (1:5:94) was added to the resin-
bound Trt-protected alcohol, agitated (2ϫ10 min, 3ϫ5 min) at
room temperature and washed with CH2Cl2 (5ϫ).
(ethyl acetate/n-hexane, 9:1). IR (KBr): ν = 3455 (m), 3338 (w),
˜
3272 (w), 3190 (m), 2929 (w), 1674 (s), 1648 (m), 1634 (w), 1622
(m), 1592 (m), 1575 (w), 1552 (m), 1429 (m), 1372 (w), 1334 (m),
1307 (w), 1291 (w), 1244 (m), 1206 (m), 1180 (w), 1122 (m), 1053
(s), 983 (m), 945 (w), 936 (w), 799 (w), 768 (w), 745 (w), 735 (w),
Cleavage from the Resin: The resin-bound oxazole derivative was
treated with a mixture of TFA/TIPS/H2O (95:2.5:2.5) at room tem-
perature (2 h). After washing the solid support with CH2Cl2 (3ϫ),
the filtrate and washings were combined and concentrated in
vacuo.
1
696 (w), 680 (m), 630 (w) cm–1. H NMR (250 MHz, CDCl3): δ =
2.48 (s, 3 H, CH3), 2.69 (s, 3 H, CH3), 2.72 (s, 3 H, CH3), 2.73 (s,
3 H, CH3), 5.91 (br. s, 1 H, NH2), 6.97 (br. s, 1 H, NH2) ppm. 13C
NMR (63 MHz, CDCl3): δ = 11.67, 11.69, 11.8, 13.7, 124.2, 125.4,
129.1, 149.9, 150.2, 153.3, 154.1, 155.0, 160.5, 165.0 ppm.
C14H14N4O4 (302.29): calcd. C 55.63, H 4.67, N 18.53; found C
55.71, H 4.78, N 18.25.
Preparation of Teroxazoles
Typical
Procedure:
2ЈЈ-Benzyl-5-ethyl-5Ј-isobutyl-5ЈЈ-methyl-
[2,4Ј:2Ј,4ЈЈ-teroxazole]-4-carboxamide (13b): Rink amide MBHA
resin (391 mg, 0.25 mmol, 0.64 mmol/g loading) was swelled in
NMP (1 h), followed by removal of the Fmoc protecting group.
After coupling of amino acid 3b (R = ethyl, mixture of isomers,
267 mg, 0.75 mmol), the Fmoc protecting group was removed and
compound 4 (R = isobutyl, mixture of isomers, 469 mg, 0.75 mmol)
Benzyl 3-(4ЈЈ-Carbamoyl-5,5Ј,5ЈЈ-triisobutyl-[2Ј,4:2ЈЈ,4Ј-teroxazole]-
2-yl)propanoate (13c): Monomers used: Fmoc-protected β-hydroxy-
α-amino acid 3c (R = isobutyl, mixture of isomers), Fmoc/Trt-pro-
tected β-hydroxy-α-amino acid 4 (R = isobutyl, mixture of isomers)
6
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Job/Unit: O20339
/KAP1
Date: 08-05-12 10:14:07
Pages: 9
Teroxazoles as a Class of α-Helix Mimetics
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and monobenzyl succinate (23). The reaction gave 13c as a colorless
semi-solid (19%). Rf = 0.42 (n-hexane/ethyl acetate, 1:1). IR (KBr):
ν = 3471 (m), 3353 (w), 3279 (w), 3142 (w), 2958 (s), 2926 (m),
˜
2870 (m), 1734 (s), 1686 (s), 1647 (w), 1624 (m), 1588 (m), 1546
(w), 1466 (m), 1430 (w), 1387 (w), 1368 (w), 1340 (w), 1196 (w),
1166 (m), 1095 (w), 1031 (m), 801 (w), 792 (w), 751 (w), 698 (m),
1
645 (w), 582 (w), 512 (m) cm–1. H NMR (400 MHz, CDCl3): δ =
[9]
0.96 [d, J = 6.7 Hz, 6 H, (CH3)2CH], 0.99 [d, J = 6.5 Hz, 6 H,
(CH3)2CH], 1.00 [d, J = 6.5 Hz, 6 H, (CH3)2CH], 2.03–2.22 [m, 3
H, (CH3)2CH], 2.92 (t, J = 7.6 Hz, 2 H, CH2CH2), 2.94 (d, J =
7.2 Hz, 2 H, iPrCH2), 3.00 (d, J = 7.1 Hz, 2 H, iPrCH2), 3.04 (d,
J = 7.1 Hz, 2 H, iPrCH2), 3.14 (t, J = 7.4 Hz, 2 H, CH2CH2), 5.14
(s, 2 H, CH2Ph), 5.65 (br. s, 1 H, NH2), 6.95 (br. s, 1 H, NH2),
7.28–7.40 (m, 5 H, Ph) ppm. 13C NMR (101 MHz, CDCl3): δ =
22.29, 22.30, 22.4, 23.4, 28.06, 28.07, 28.3, 31.0, 34.3, 34.4, 34.5,
66.6, 125.1, 126.1, 128.2, 128.3, 128.5, 129.9, 135.7, 152.9, 153.2,
153.6, 155.3, 156.5, 162.0, 163.8, 171.6 ppm. HRMS (MALDI):
calcd. for C32H40N4O6+H+ [M + H+] 577.3021; found 577.3020.
[10]
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CCDC-866342 (for 13a) and -866343 (for 13b) contain the supple-
mentary 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.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, characterization data for all new com-
1
pounds, H and 13C NMR spectra and the crystal structure of bi-
oxazole 28.
[17]
Acknowledgments
Financial support by the Förderfonds der Goethe-Universität is
gratefully acknowledged. H.G. is grateful to the Zentrum für Infor-
mations- und Medientechnologie of the Heinrich-Heine-University,
Düsseldorf, for computational support and to the Strategischer
Forschungsfond of the Heinrich-Heine-University, Düsseldorf, for
financial support.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20339
/KAP1
Date: 08-05-12 10:14:07
Pages: 9
C. Pinto Gomes, A. Metz, J. W. Bats, H. Gohlke, M. W. Göbel
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Received: February 13, 2012
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20339
/KAP1
Date: 08-05-12 10:14:07
Pages: 9
Teroxazoles as a Class of α-Helix Mimetics
Helical Peptide Mimetics
A teroxazole scaffold, designed to be a heli-
cal peptide mimetic, has been prepared by
modular solid-phase synthesis. This meth-
od for synthesizing diversely substituted
oligo-oxazole scaffolds is versatile. The
teroxazole scaffold is hydrophilic and mim-
ics side chains i, i+3, and i+6, which covers
a broader region on the α-helix surface
than previous α-helix mimetics.
C. Pinto Gomes, A. Metz, J. W. Bats,
H. Gohlke, M. W. Göbel* ................. 1–9
Modular Solid-Phase Synthesis of Terox-
azoles as a Class of α-Helix Mimetics
Keywords: Protein–protein interactions /
Conformation analysis / Molecular dy-
namics
/
Peptidomimetics
/
Helical
structures
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9