Solid-phase synthesis of tris-benzamides as α-helix mimetics

Article abstract of DOI:10.1021/co100056c

Small molecules mimicking α-helices are of great interest since numerous protein-protein interactions use helical structures at the interface. With a goal of generating libraries of α-helix mimetics, an efficient solid-phase synthetic method was developed

Full text of DOI:10.1021/co100056c

LETTER
pubs.acs.org/acscombsci
Solid-Phase Synthesis of Tris-Benzamides as r-Helix Mimetics
Tae-Kyung Lee and Jung-Mo Ahn*
Department of Chemistry, University of Texas at Dallas, Richardson, Texas 75080, United States
S Supporting Information
b
ABSTRACT: Small molecules mimicking R-helices are of great interest
since numerous protein-protein interactions use helical structures at
the interface. With a goal of generating libraries of R-helix mimetics, an
efficient solid-phase synthetic method was developed to produce tris-
benzamides. The tris-benzamide scaffold was designed to place three
side-chain functional groups found at the i, i þ 4, and i þ 7 positions of an
R-helix, emulating one helical face. The synthetic strategy involves simple
and iterative reactions of removal of an allyl ester, formation of an amide
bond via an O f N acyl migration, and an O-alkylation. A small library of
twenty tris-benzamides containing a variety of functional groups was
prepared in high purity (83-99%) to demonstrate the versatility of the
synthetic approach. This methodology allowed the facile and rapid con-
struction of R-helix mimetics that would facilitate the identification of
small molecules for target proteins.
KEYWORDS: R-helix mimetics, tris-benzamide scaffold, solid-phase synthesis, protein-protein interaction
t the interface of protein-protein interactions (PPI),
R-helical structures are frequently found and mediate
To date, a number of R-helix mimetics have been reported based
A
on scaffolds like indanes,18 terphenyls,19 tris-pyridylamides,20
trans-fused polycyclic ethers,21 tris-benzamides,22 pyridazines,23
dipiperazinobenzenes,24 and 2,5-terpyrimidinylenes.25 Most of
these scaffolds project three functional groups corresponding
to the side chains of amino acids found at the i, i þ 4 (or i þ 3),
and i þ 7 positions of an R-helix, constituting one helical face.
The utility of R-helix mimetics was well demonstrated by studies
of disrupting various protein-protein interactions including Bcl-xL/
Bak19b and MDM2/p53.22d Recently, amphiphilic R-helix mimetics
were also designed based on a bis-benzamide scaffold to present the
functional groups found on two opposing helical sides.26
numerous key cellular functions, such as enzyme activity, protein
synthesis, transcription, DNA binding, immune response, and
signal transduction.1 PPI through R-helices is thus recognized as
attractive targets to intervene for treating diverse human diseases
including cancer, neurological disorder, and viral infection.2,3 This
indicates that helical peptides are of high interest in developing
new therapeutic candidates. However, short peptides often lose
their well-defined structures or adopt less organized conforma-
tions in solution, resulting in decreased binding affinities to their
targets.4,5 In addition, short peptides are prone to be proteolytically
degraded, especially in an extended conformation, and have diffi-
culty in penetrating cellular membranes.6,7 These factors severely
compromise effective use of short peptides as PPI modulators.
Several strategies have been developed to stabilize helical
conformations in short peptides. In addition to restricting tor-
sional rotations in peptide backbones by incorporating non-natural
amino acids like Aib,8 arranging side chains in close proximity
by forming a covalent bond or noncovalent interaction was found
to enhance helicity of peptides.9-15 Furthermore, foldamers like
β-peptides have demonstrated stable helical conformations, as well
as a resistance to proteases.16
Primary sequences of R-helical segments in peptides and
proteins can guide initial design of suitable R-helix mimetics.
However, generating a number of R-helix mimetics has been
frequently practiced to rapidly identify compounds with high
potency in disrupting protein complex formations by exploring
diverse functional groups as substituents for increasing their
binding affinity to target proteins. In addition, fine-tuning of the
substituents is often required to optimize initial leads because
R-helix mimetics may have slightly different spatial arrangements
of functional groups from an ideal helix, or a helical segment
corresponding to R-helix mimetics may adopt a slightly altered
helical structure from an ideal one. Therefore, constructing
libraries of R-helix mimetics are of great use and solid-phase
technique will be a suitable synthetic platform because of its facile
achievement of complete conversion of reactions through the use
As an alternative approach, nonpeptidic R-helix mimetics have
been developed to reproduce side chain functional groups found
in R-helical segments.3,17 They are composed of rigid and
preorganized scaffolds that are designed to place their substitu-
ents in the same spatial arrangement as an R-helix does. Due
to their nonpeptidic structures, R-helix mimetics acquire high
resistance to proteolytic cleavages and effective cell permeability.
Received: November 3, 2010
Published: December 01, 2010
r
2010 American Chemical Society
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ACS Combinatorial Science
LETTER
of excessive reagents and easy separation of unreacted reagents
from products bound on solid supports.
Scheme 1. Solid-Phase Synthesis of Tris-Benzamides 10a
Among many R-helix mimetics reported to date, the tris-
benzamides22a that we recently developed appear to be ideal
to build combinatorial libraries because of its straightforward
and high-yielding reactions involved in the synthesis. The tris-
benzamide scaffold can easily place three functional groups cor-
responding to the side chains of the ith, i þ 4th (or i þ 3rd),
and i þ 7th residues of an R-helix, and these three substituents
organize one side of two helical turns. Solution-phase synthesis of
tris-benzamides can be achieved by using simple amide bond
formation and O-alkylation reactions that are compatible for solid-
phase strategy. With readily available starting materials, we have
thus developed a parallel solid-phase synthetic method for efficient
and rapid construction of tris-benzamides as R-helix mimetics.
The solution-phase synthesis of tris-benzamides started from a
commercially available 4-amino-3-hydroxybenzoic acid and pro-
ceeded in the N f C direction by carrying out iterative amide
bond formation and O-alkylation reactions. The construction
of tris-benzamides in the opposite C f N direction by using
two 3-alkoxy-4-aminobenzoates has not been successful because
of the significantly lowered nucleophilicity of the 4-amino group
and electrophilicity of the 1-benzoic acid group, as well as a
potential steric hindrance from a 3-alkoxy substituent (Scheme S1
in Supporting Information).22a Thus, a solid-phase synthetic
route was also sought in the same N f C direction with the
N-terminus of a tris-benzamide anchored to a solid support.
Since the weak nucleophilicity of the 4-amino-3-hydroxybenzo-
ate 1 also resulted in a poor loading yield to 2-chlorotritylchloride
(2-CTC) resin, a glycine was introduced as a spacer to achieve
efficient loading. In addition, the ammonium group of the glycine
moiety was found to improve the solubility of tris-benzamides in
water.
To demonstrate the synthetic feasibility of tris-benzamides
containing a glycine at the N-terminus and optimize reaction
conditions that would be later applied to solid-phase synthesis,
a Boc-Gly-tris-benzamide bearing three benzyl groups S6 was
synthesized in solution-phase (Scheme S1 in Supporting Infor-
mation). Instead of the methyl ester used in the previously re-
ported synthesis of tris-benzamides,22a an allyl ester was em-
ployed as a protecting group for the 1-benzoic acid group since
saponification with a hydroxide unexpectedly brought in cleavage
of glycine anilides. In contrast, selective removal of an allyl ester
was easily accomplished in a mild condition by using Pd0 in both
solution- and solid-phase without affecting the anilide bond.10c
An allyl 4-amino-3-hydroxybenzoate 1 was prepared from a
4-amino-3-hydroxybenzoic acid by acid-catalyzed esterification
and used as a submonomer in the synthesis of tris-benzamides
(Scheme 1). After the benzoate 2 was prepared by coupling
Boc-Gly to 1, it was treated with benzyl bromide and NaH yielding
the monobenzamide 3a with the first benzyl group that represents
a side chain at the i position in high yield (Scheme 1). The syn-
thesis of the tris-benzamide S6 was completed from the mono-
benzamide 3a in 22% yield over 8 steps by iterating the steps of
the allyl ester removal, O-acylation, O f N acyl migration,27 and
O-alkylation, placing three benzyl groups that correspond to the
side chains at the i, i þ 4 (or i þ 3), and i þ 7 positions of a helix
(Scheme S1 in Supporting Information).
a Reagents and conditions: (a) Boc-Gly, PyBOP, DIEA, DCM, rt, 12 h;
(b) NaH, Bn-Br, DMF, rt, 3 h for 3a, NaH, iPr-Br, DMF, rt, 12 h for 3b;
(c) 50% TFA/DCM, rt, 4 h; (d) (1) 2-CTC resin, DIEA, DMF, rt, 4 h,
(2) 10% DIEA/MeOH, DMF, rt, 4 h; (e) Pd(PPh3)4, PhSiH3, CHCl3,
rt, 1 h; (f) 1, PyBOP, DIEA, DMF, rt, 20 h; (g) NaH, TBAB, DMF, rt,
1 h; (h) R2-X (or R3-X), Cs2CO3, TBAB, DMF, rt, 12 h (or 24 h);
(i) 10% TFA/DCM, rt, 10 min for 10a, (1) 1% TFA/DCM, rt, 5 min,
(2) TFA/TIS/H2O (95:2.5:2.5), rt, 1 h for 10b.
to the resin can be achieved without an activating or coupling step.
Second, final products can be released from the resin with a weak
acid in a fully protected form that may contain even acid-labile
protecting groups like Boc and tBu. This allows that released and
protected products can be readily used for further reactions if
necessary. Third, the sterically bulky trityl linker makes a second-
ary amine formed by reacting the resin with a glycinylbenzoate
unreactive during the construction of tris-benzamides.
With the 2-CTC resin as a polymer support, each reaction step
was examined in solid-phase (Scheme 1 and Scheme S2 and
Table S1 in Supporting Information). As the first residue, a
glycinylbenzoate 3 that already bears an alkyl group was used
because the 3-hydroxyl group of an unalkylated glycinylbenzoate
(e.g., 2 or S7) underwent an O-capping reaction with the
Optimization of these reaction steps in solid-phase started with
choosing an adequate solid support/linker system. As a widely
used polymer support, polystyrene-based 2-chlorotritylchloride
(2-CTC) resin has several advantages.28 First, efficient attachment
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LETTER
Table 1. O-Alkylation of the Resin-Bound Phenol 7a
Chart 1. Substituents Placed on Tris-Benzamides to Repre-
sent the Side Chains of Amino Acids in an R-Helix
(8a{1} and 8a{2} in 80% and 84% purity, respectively; entry 1
and 4 in Table 1), this reaction condition brought in theformation
of a small amount of byproducts.
To carry out the reaction with minimal formation of the by-
products and in turn to achieve a higher purity, stoichiometry of
the reactants, and additive was varied. The alkylation reaction
with 2 equiv of a base and 5 equiv of an alkyl bromide in the
presence of 2 equiv of TBAB was found to be the most effec-
tive and resulted in products without the byproduct formation
in comparable yields (76% with benzyl bromide and 79% for
2-naphthylmethyl bromide; entry 2 and 5, respectively). The
yield of the O-alkylation reaction was further increased by
repeating the reactions twice (84-86%; entries 2 and 5). The
reactive alkyl halides do not appear to need TBAB since com-
parable yields were obtained without it (entries 3 and 6).
Other alkyl substituents like isopropyl and isobutyl groups
were introduced to the phenol 7a in a similar manner by using
2-bromopropane and 1-bromo-2-methylpropane. These alkyl-
ation reactions were found to be substantially slower than those
with the reactive alkyl halides, requiring 24 h even for lower con-
versions. However, repeating the alkylation reactions twice again
resulted in acceptable yields in the production of 8a{3} and
8a{4} (89% and 88%, respectively; entries 8 and 11). Unlike the
alkylation reactions with the reactive alkyl bromides, TBAB
clearly assisted to obtain higher conversions with the less reactive
alkyl bromides (entry 9 and 12). Accordingly, chemset 8a{1-4}
containing two hydrophobic functional groups (R1 and R2) that
represent the side chains at the i and iþ4 positions of a helix was
efficiently prepared on the 2-CTC resin.
In addition to the hydrophobic functional groups, hydrophilic
ones like 3-carboxypropyl (CPr) and 4-aminobutyl (ABu)
groups were also introduced as R2 to represent the side chains of
Glu and Lys, respectively. The optimized reaction condition for
less reactive alkyl halides allowed to the preparation of chemset
8b{5-6} in 78% and 84% purities, respectively (entry 13 and
14) with t-butyl 4-bromobutyrate29 and 4-(t-butoxycarbonyla-
mino)butyl tosylate.30 The t-butyl protecting groups of the
hydrophilic substituents can be easily removed with TFA at high
concentrations at the end of the synthesis.
Starting from the resin-bound benzoate 4, the synthesis of
the bis-benzamide 8 that contains two substituents was carried
out over the four steps of the ally ester removal, O-acylation
with the submonomer 1, O f N acyl migration, and O-alkyl-
ation. Iteration of these reactions with various alkyl halides
finished the construction of the tris-benzamide 9 that has three
functional groups to mimic amino acids at the i, i þ 4, and i þ 7
positions of a helix. As already demonstrated with the benzoate
4, these steps proceeded in high efficiency with the bis-
benzamide 8 resulting in the crude tris-benzamide 9 in overall
purity of 31-93%.
a Reaction conditions: the phenol 7, an alkyl halide, Cs2CO3, TBAB,
DMF, rt. b Purity was determined by analytical RP-HPLC. c O-Alkyl-
ation reaction was repeated twice.
2-chlorotrityl linker during the loading step, lowering yields of
the subsequent O-alkylation reactions (Scheme S2 and Table S1
in Supporting Information). After removing the Boc protecting
group, the glycinylbenzoate containing a 3-alkyloxy substituent
was reacted with the 2-CTC resin yielding the resin-bound
3-alkyoxybenzoate 4.
The subsequent removal of the allyl ester with Pd(PPh3)4 and
coupling of the resulting carboxylic acid 5 with the submonomer
1 then led to the production of a mixture of the O- and N-acyl
products (6 and 7, respectively) although the former was the major
product. Because of the poor reactivity of the 4-amino group, the
O-acyl product 6 was formed along with the desired N-acyl prod-
ucts 7. To convert the O-acyl product 6 into the N-acyl product 7,
several bases (e.g., Cs2CO3, NaOCH3, and NaH) were examined
for the O f N acyl migration27 in solid-phase, and NaH was found
to be the most efficient despite its heterogeneous reaction condi-
tion (see Supporting Information for the solid-phase O f N acyl
migration).
With the resin-bound phenol 7, O-alkylation reactions with a
variety of alkyl halides were examined (Table 1). Hydrophobic
functional groups, such as benzyl, 2-naphthylmethyl (NAP), iso-
propyl, and isobutyl groups, were installed on the 3-hydroxyl
group of 7a to represent the side chains of Phe, Trp, Val, and Leu,
respectively (Chart 1). In the beginning, O-alkylation reactions
were carried out by using Cs2CO3 (5 equiv) and an alkyl bromide
(10 equiv) in the presence of tetrabutylammonium bromide
(TBAB, 5 equiv) in DMF for 12 h at room temperature. Although
the reactions with reactive alkyl halides, in particular benzyl
bromide and 2-naphthylmethyl bromide, showed complete con-
sumption of the phenol 7a and gave products with high yields
Upon completion of the solid-phase synthesis, the resin-bound
tris-benzamide 9a was treated with 10% TFA in DCM releasing
chemset 10a{1-4,1-4} that contains a benzyl group as R1 and
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LETTER
Table 2. Characterization of the Synthesized Tris-Benzamide 10
’ EXPERIMENTAL PROCEDURES
compound
R1
R2
R3
purity (%)a
yield (%)b
General Procedure for Solid-Phase Removal of an Allyl
Ester. A resin-bound allyl ester (0.05 mmol) was swollen in
CHCl3 (6 mL) for 30 min and treated with Pd(PPh3)4 (5.8 mg,
0.005 mmol) and phenylsilane (0.062 mL, 0.50 mmol). After the
reaction mixture was manually stirred for 1 h at room tempera-
ture, the resin was filtered, washed with DMF (6 mL ꢀ 3) and
DCM (6 mL ꢀ 3), and dried in vacuo.
10a{1,1}
10a{1,2}
10a{1,3}
10a{1,4}
10a{2,1}
10a{2,2}
10a{2,3}
10a{2,4}
10a{3,1}
10a{3,2}
10a{3,3}
10a{3,4}
10a{4,1}
10a{4,2}
10a{4,3}
10a{4,4}
10b{5,5}
10b{5,6}
10b{6,5}
10b{6,6}
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
iPr
iPr
iPr
iPr
Bn
Bn
93
88
84
96
93
88
88
98
87
83
86
98
83
97
98
93
95
83
95
99
12
43
14
22
82
79
43
8
Bn
NAPc
iPr
Bn
Bn
iBu
NAP
NAP
NAP
NAP
iPr
Bn
NAP
iPr
General Procedure for Solid-Phase Coupling of the Sub-
monomer 1. A resin-bound carboxylic acid (0.05 mmol) was
swollen in DMF (6 mL) for 30 min and reacted with the sub-
monomer 1 (48 mg, 0.25 mmol), PyBOP (130 mg, 0.25 mmol),
and DIEA (0.086 mL, 0.50 mmol). After the reaction mixture was
shaken at room temperature for 20 h, the resin was filtered,
washed with DMF (6 mL ꢀ 3) and DCM (6 mL ꢀ 3), and dried
in vacuo.
iBu
Bn
47
31
30
8
iPr
NAP
iPr
iPr
iPr
iBu
iBu
Bn
8
General Procedure for Solid-Phase O f N Acyl Migration.
A resin-bound O-acyl intermediate (0.05 mmol) was swollen in
DMF (6 mL) for 30 min and treated with NaH (60% suspension
in oil, 8.0 mg, 0.20 mmol) and TBAB (66 mg, 0.20 mmol). After
the reaction mixture was manually stirred for 1 h at room tem-
perature, the resin was filtered and washed with DMF (6 mL ꢀ 5),
DMF/H2O (4:1, 6 mL ꢀ 5), DMF (6 mL ꢀ 5) and DCM
(6 mL ꢀ 5), and dried in vacuo.
iBu
NAP
iPr
66
26
26
6
iBu
iBu
iBu
CPrd
CPr
ABu
ABu
CPr
ABue
CPr
ABu
17
6
13
General Procedure for Solid-Phase O-Alkylation. A resin-
bound phenol (0.05 mmol) was swollen in DMF (6 mL) for
30 min and treated with Cs2CO3 (33 mg, 0.10 mmol), TBAB
(33 mg 0.10 mmol), and an alkyl halide (0.25 or 0.50 mmol).
After the reaction mixture was shaken at room temperature for
12 h (or 24 h), the resin was filtered and washed with DMF
(6mLꢀ 3). This procedure was repeated, then the resin was filtered,
washed with DMF/H2O (4:1, 6 mL ꢀ 5), DMF (6 mL ꢀ 5), and
DCM (6 mL ꢀ 5), and dried in vacuo.
a Purity was determined by analytical RP-HPLC. b Isolation yield after
precipitation. c NAP, 2-naphthylmethyl. d CPr, 3-carboxypropyl. e ABu,
4-aminobutyl.
hydrophobic substituents (Bn, NAP, iPr, and iBu) as R2 and R3.
Whereas the purity of the crude products 10a{1-4,1-4} was
found to be outstanding over ten steps (49-93%), it was further
improved (83-98%) by a simple purification step of precipitation
in THF/H2O. Final products were obtained in quantity of 4-36
mg in high purity (83-98%) with overall yields ranging from 8%
to 82% (Table 2). To obtain tris-benzamides containing hydro-
philicsubstituents, the tris-benzamide 9b was treated with1%TFA
in DCM, and the resulting TFA salts were precipitated with water.
This allowed the preparation of tBu-protected tris-benzamides
that can be readily used for further reactions if desired. The
tBu-protected tris-benzamides was treated with TFA/TIS/H2O
(95:2.5:2.5), producing chemset 10b{5-6,5-6} bearing the hy-
drophilic side chains (CPr and ABu) as R2 and R3 in high purity
(83-99%).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, HRMS,
b
1H and 13C NMR spectra of compounds 1-3, S1-S7, S11-S12
and HRMS, H NMR spectra, and HPLC chromatograms of
1
10a{1-4,1-4} and 10b{5-6,5-6}. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
In summary, we have developed a solid-phase strategy for the
synthesis of R-helix mimetics by using a tris-benzamide scaffold
that was designed to place three side chain functional groups of
amino acids found at the i, i þ 4, and i þ 7 position of an R-helix.
The solid-phase synthesis involves four iterative steps of allyl
ester removal, O-acylation, O f N acyl migration, and O-alkyl-
ation. After optimizing each reaction step, a small library of tris-
benzamides containing a variety of substituents was efficiently
constructed on 2-CTC resin. Both hydrophobic (benzyl, 2-naphthyl-
methyl, isopropyl, and isobutyl) and hydrophilic (3-carboxypro-
pyl and 4-aminobutyl) functional groups were introduced as
substituents to make structurally diverse R-helix mimetics. To
demonstrate proof of concept, twenty tris-benzamides were
synthesized in high purity with moderate to outstanding yields.
This solid-phase synthetic route offers rapid access to a library
of R-helix mimetics as an effective tool for identifying potent
inhibitors of protein-protein interactions involving R-helices at
the interface.
Corresponding Author
*Mailing address: 800 W. Campbell Rd., Richardson, TX 75080.
Tel: (972) 883-2917. Fax: (972) 883-2925. E-mail: jungmo.ahn@
utdallas.edu.
Author Contributions
T.K.L and J.M.A. conceived and designed the experiments.
T.K.L. performed the experiments. T.K.L. and J.M.A. cowrote
the manuscript and Supporting Information.
Funding Sources
This work was supported in part by the American Diabetes Associa-
tion (07-07-JF-02), the Robert A. Welch Foundation (AT-1595),
and the Texas Advanced Research Program (009741-0031-2006).
’ ABBREVIATIONS:
ABu, 4-aminobutyl; CPr, 3-carboxypropyl; CTC, chlorotritylchlo-
ride; DCM, dichloromethane; DIEA, N,N-diisopropylethylamine;
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LETTER
DMF, N,N-dimethylformamide; NAP, naphthylmethyl; PPI,
protein-protein interaction; PyBOP, benzotriazol-1-yloxytri-
(pyrrolidino)phosphonium hexafluorophosphate; TBAB, tetra-
butylammonium bromide; TFA, trifluoroacetic acid; THF,
tetrahydrofuran; TIS, triisopropylsilane
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