scaffold described by Hamilton is the terphenyl scaffold,11
which has inspired a wide range of related frameworks.12ꢀ16
Until recently, synthetic R-helix mimicry focused on replica-
tion of only the hydrophobic face of the R-helix, typically the
i, i þ 3/4 and i þ 7 residues. Rebek and Hamilton later
introduced R-helix mimetics in which heteroatoms were in-
corporated into the scaffold to improve aqueous solubility.17
Around 50% of the R-helices that are found in proteins are
amphipathic.18 Synthetic R-helix mimetics that can mimic
both faces of an R-helix might improve the synthetic ligand’s
binding affinity as well as its selectivity profile. Recently,
elaboration of previously reported R-helix mimetic scaffolds
has allowed for mimicry of both faces of the R-helix.19 Novel
and diverse amphipathic R-helix mimetics would be welcomed
to enrich the pool of potential leads for drug discovery.
mimic the iand iþ 7 side chains on one face of an R-helix, and
the i þ 2 and i þ 5 side chains on the other. It is hypothesized
that the desired structural integrity of 1 will be maintained by
an intramolecular hydrogen bond between the NH of the
amide in the upper subunit and the CO of the amide in the
lower subunit.20 It should be noted that we do not seek a rigid
hydrogen bond, since the i, i þ 7 and the i þ 2, i þ 5 side
chains of an R-helix are staggered, not eclipsed. The amides
will restrict the flexibility of the R2 and R3 groups, further
preorganizing the helix mimetic.
The synthesis of 2, a derivative of 1where R1 =R2 =R3 =
R4 = Me, is illustrated in Scheme 1. Briefly, selective
nitration of 3-bromophenol (3), followed by O-methylation
and nitro group reduction afforded aniline 6. A Sonogashira
cross-coupling reaction of 6 with trimethylsilylacetylene
delivered 7, whose TMS group was subsequently removed
with potassium carbonate in MeOH to yield 8. Meanwhile,
the carboxylic acid of 2-bromo-4-nitrobenzoic acid (9) was
esterified, then the nitro group was chemoselectively reduced,
diazotized and finally quenched with water to deliver methyl
2-bromo-4-hydroxybenzoate (10). After methylation of the
hydroxyl group of 10, a second Sonogashira reaction be-
tween 8 and 11 furnished 1,2-diphenylacetylene 12. Acetyla-
tion, saponification, then coupling of the liberated carboxylic
acid to methylamine gave the target molecule 2.
To examine if the intramolecular hydrogen bond exists as
proposed, we performed 1H NMR (400 MHz) titrations of 2
in CDCl3 with d6-DMSO (Figure 2).23 Hydrogen bonding
results in deshielding, and an increasingly downfield-shifted
proton resonance is indicative of stronger hydrogen bond-
ing.24 The acetamide NH (δH 9.14 ppm) is significantly
downfield of both the benzamide NH in 2 (δH 6.10 ppm),
and the acetamide NH in the control compound N-(4-
methoxy-2-((trimethylsilyl)ethynyl)phenyl)acetamide (δH
7.78 ppm), neither of which can engage in intramolecular
hydrogen bonding. Unlike the benzamide NH, the acet-
amide NH in 2 is protected from exchange with residual
water in the sample (sharper resonance). Furthermore,
with increasing concentrations of d6-DMSO, the benza-
mide NH resonance shifts downfield as a consequence
of stronger hydrogen-bonding interactions with DMSO.
On the other hand, negligible changes in the acetamide
NH chemical shift are observed, suggesting DMSO cannot
contend with the postulated intramolecular hydrogen
bond. As anticipated, other chemical shifts were largely
unchanged. Collectively, these data confirm the existence
of the designed intramolecular hydrogen bond.
Figure 1. A generic amphipathic R-helix mimetic based on a 1,2-
diphenylacetylene scaffold.
Rotation about the central axis of 1,2-diphenylacety-
lenes can be biased through the formation of an intramo-
lecular hydrogen bond.20 Furthermore, 1,2-diphenylacetyl-
enes constrained in this way have been proposed as
potential β-strand mimetics.21 Motivated by our interest
in mimicking amphipathic BH3 R-helices of pro-apoptotic
proteins, such as Bak and Bim, that engage the oncoproteins
Bcl-xL and Mcl-1,22 we asked if the 1,2-diphenylacetylene
framework incorporating a similar intramolecular hydrogen
bond could function as a scaffold suitable to elicit mimicry
of both faces of an R-helix. Toward this goal, we designed
molecule 1 (Figure 1) in which the R groups are intended to
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conditions that reflect those encountered in biological
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