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the opposing face. We herein report a second generation derivative
of (S)-1 wherein the introduction of a pyridine nitrogen atom
further influences the projection of side chains from the same face
through a second intramolecular hydrogen bond.
Covalently preorganized systems are predicted to exhibit
greater free energies of binding, which has largely been attributed
to a reduced entropic penalty.20 While some doubt has been cast
on this widely held notion,21 non-covalent interactions that can
influence desired conformations of the ligand while still allowing
induced fit events to occur at the protein surface are expected to
deliver potent ligands. Toward this end, and inspired by Hamilton’s
terephthalamide design, we devised molecule (S)-2 based on an
isocinchomeronic acid core. Key distinctions between our design
and the terephthalamide (S)-1 include a pyridine nitrogen and
the replacement of the tertiary amide with a secondary amide;
together, these modifications were designed to furnish an addi-
tional intramolecular hydrogen bond to influence the projection
of all three side chains from the same face of the scaffold. MM2
energy minimization studies indicated that the three side chains
in (S)-2 are projected from the same face (Fig. 2A) and overlay well
with the corresponding i, i + 3/4, and i + 7 side chains in a poly-
Figure 2. (A) An MM2 energy-minimized conformation of (S)-2 (left; cyan, colored
by atom type (red = oxygen; blue = nitrogen; white = polar hydrogens)) in which
two intramolecular hydrogen bonds encourage projection of all side chains from the
same face of the mimetic. (B) (S)-2 overlaid with a poly-alanine
chains highlighted). (C) Overlay of (S)-2, its enantiomer (R)-2 (yellow, colored by
atom type) and a poly-alanine -helix. Images generated with PyMOL.
a-helix (key side-
alanine
a-helix (Fig. 2B). For comparison, a similarly energy-
a
minimized conformation of the (R)-enantiomer of 2 is provided
in Figure 2C, which demonstrates comparable mimicry of the i, i
+ 3/4, and i + 7 side chains.
Initially, we attempted to synthesize compound (S)-2 through
the chemistry depicted in Scheme 1. However, enlisting various
reagents and conditions to oxidize the aromatic methyl group of
5, which included KMnO4, Jones reagent and SeO2 at room temper-
ature to reflux in solvents such as dioxane and pyridine, were to no
avail. We revised our synthetic plan, and an alternative, expedient,
and efficient synthesis of (S)-2 was developed beginning with inex-
pensive 2,6-dichloronicotinic acid (7), as shown in Scheme 2. By
analogy with our previous work,22 ortho-selective SNAr of 7 with
isopropanol and NaH occured through a cyclic, six-membered tran-
sition state involving the sodium salt of the carboxylic acid to
furnish 8.22 Amidation of the carboxylic acid under standard
conditions followed by a Stille coupling delivered 10. Oxidative
cleavage of the vinyl group in 10 was effected with KMnO4 to give
6. The resulting carboxylic acid of 6 was coupled to L-leucine
methyl ester to afford (S)-11, which was subsequently saponified
under mild conditions to yield the target molecule (S)-2.
1H NMR was next enlisted in order to verify the presence of the
Scheme 1. Reagents and conditions: (a) isopropanol, NaH, toluene, 95 °C, 16 h; (b)
two engineered intramolecular hydrogen bonds.
a-Helix mimetic
isobutylamine, HBTU, DIPEA, DMF, rt, 16 h.
(S)-2 was not chosen for NMR experiments because the carboxylic
acid proton would be expected to protonate the pyridine nitrogen,
complicating the study. In biological systems, the carboxylic acid of
(S)-2 would be ionized, and so unable to interfere with the
formation of an intramolecular hydrogen bond. Thus, methyl ester
(S)-11 was selected as a suitable surrogate for this analysis. First,
dilution experiments in CDCl3 revealed that the overlapping chem-
experiment, the midpoint of the merged NH signals was selected
and is indicated as the black line in Figure 3. The chemical shift of
these merged signals decreased marginally over the course of the
titration but an increase (downfield shift), rather than a decrease
(upfield shift), would be indicative of hydrogen bonding with
DMSO.23 Concomitantly, the non-exchangeable aromatic H–C3 of
(S)-11 (blue line) also shifted upfield to the same degree, and so
we concluded that these changes were insignificant. In sharp
contrast, however, the NHs of control compounds 12 (red line)
and (S)-13 (green line) experienced downfield shifts of just over
1 ppm upon titrating 12.7% d6-DMSO into their CDCl3 solutions,
which is consistent with increased intermolecular hydrogen
bonding; the lack of this phenomenon with (S)-11 suggests that
its NHs were shielded from hydrogen bonding to the co-solvent.
Taken together, these NMR experiments established that both
NHs in (S)-11 were engaged in intramolecular hydrogen bonding,
thus confirming that strategically-fashioned non-covalent
interactions within this isocinchomeronic acid derivative can
influence the projection of all three side-chains from the same face,
providing good mimicry of the i, i + 3/4, and i + 7 side chains of an
ical shifts of the two amide NHs were unchanged (DdH <0.002 ppm
over 100-fold dilution), indicating intramolecular rather than
intermolecular, hydrogen bonding (data not shown).18 Analogous
NMR experiments with control compounds 12 and (S)-13, which
are unable to form intramolecular hydrogen bonds, revealed subtle
but distinct changes in the chemical shifts of the NH protons
(DdH = 0.036 ppm over 10-fold dilution), while other chemical
shifts, such as those of the benzoyl group, remained constant,
corroborating the deduction that the hydrogen bonding in (S)-11
was intramolecular. More conclusive proof of the intramolecular
hydrogen bonds in (S)-11 was acquired by titration of d6-DMSO into
a CDCl3 solution of (S)-11 (Fig. 3). DMSO is a hydrogen bond
acceptor and it causes the chemical shifts of exchangeable NH
protons to move downfield.23 The two NHs of (S)-11 appeared at
almost the same chemical shift—for the purposes of this
a-helix.