Synthesis of the phenylpyridal scaffold as a helical peptide mimetic

Article abstract of DOI:10.1002/chem.201000315

Phenylpyridal- and phenyldipyridal-based scaffolds have been designed and synthesized as novel helical peptide mimetics. The synthesis required optimisation and selective alkylation in producing 2,6-functionalized 3-hydroxypyridine derivatives for a convergent scheme. The pyridine analogues were coupled by a series of Suzuki/Stille types cross-coupling reactions. A series of biaryl and ter-aryl substituted heterocycles were produced. The synthetic approach was concise and high yielding allowing large variability at the wanted sidechain attachment points. A number of compounds were synthesised to show the versatility of the strategy.

Full text of DOI:10.1002/chem.201000315

FULL PAPER
DOI: 10.1002/chem.201000315
Synthesis of the Phenylpyridal Scaffold as a Helical Peptide Mimetic
Gregory T. Bourne,*[a, b] Daniel J. Kuster,[a] and Garland R. Marshall[a]
Abstract: Phenylpyridal- and phenyldi-
pyridal-based scaffolds have been de-
signed and synthesized as novel helical
peptide mimetics. The synthesis re-
quired optimisation and selective alky-
lation in producing 2,6-functionalized
logues were coupled by a series of
Suzuki/Stille types cross-coupling reac-
tions. A series of biaryl and ter-aryl
substituted heterocycles were pro-
duced. The synthetic approach was
concise and high yielding allowing
large variability at the wanted side-
chain attachment points. A number of
compounds were synthesised to show
the versatility of the strategy.
Keywords: alkylation
· biaryls ·
cross-coupling · helical structures ·
proteomimetics
3-hydroxypyridine derivatives for
a
convergent scheme. The pyridine ana-
Introduction
late a single smooth distribution centered at (f=À62, y =
À43) in Ramachandran dihedral coordinates.[5] Thus, a good
À
In proteins, helices are frequently found to act as structural
scaffolds, orienting important side chains for molecular rec-
ognition.[1–3] Networks of intra-residue hydrogen bonds sta-
bilize the helical backbone. Hydrogen bonds are flexible
and compensatory, so helical backbones are not rigid. Con-
sequently, the residues projected by a helix are also flexible
in their relative orientations. Rigidifying the helical back-
bone may improve the thermodynamics of binding and opti-
mize the physicochemical profile of a helical peptidomimet-
ics.[2]
Organic scaffolds opens the door to stabilizing helical
mimetics with various strategies beyond the hydrogen
bond.[2–4] The challenge of organic helix mimetics is to
design a scaffold that orients side-chain R groups so that
Ca Cb vectors are projected as in the target helix. A statisti-
cal population of helical conformations from high-resolution
X-ray crystallographic model structures was found to popu-
organic helical scaffold should reproduce the same Ca Cb
projection vectors for orientation of the side chains involved
in helix recognition.
Jacoby suggested 2,6,3’5’-substituted biphenyls as better
than allenes, alkylidene cycloalkanes and spiranes as helical
mimetics of side-chain positions i, i+1, i+3 and i+4.[6] The
Hamilton group suggested the terphenyl scaffold to mimic
positions i, i+1, i+3 and i+4.[7] More recently, the Sche-
partz group has suggested helical b-peptides as helical pepti-
domimetics and demonstrated their utility in the p53/hdm2
system.[8] Kelso et al. have used a motif of HXXXH com-
plexed with Pd(en)2+ to preorganize peptides into helices.[9]
Taylor has advocated the use of side-chain lactams for a sim-
ilar purpose.[10] Other helical mimetics, based on stereo-
chemical modification of the peptide Ca with a methyl
group and “stapled” hydrocarbon side chains, fall outside
the domain of organic helical scaffolds.
À
Helical scaffolds were designed and evaluated in silico
using molecular dynamics and ab initio methods.[2] Analysis
revealed that aromatic scaffolds such as Jacobyꢀs biphenyl
scaffold[6] and Hamiltonꢀs terphenyl scaffolds[7,11] and the
phenyldipyridal scaffold discussed herein are fundamentally
[a] Dr. G. T. Bourne, Dr. D. J. Kuster, Prof. G. R. Marshall
Department of Biochemistry and Molecular Biophysics
Washington University School of Medicine
St Louis Missouri 63110 (USA)
À
limited in accurately mimicking the torsional values of Ca
Fax : (+1)314-747-3330
E-mail: garland@biochem.wustl.edu
À
Cb “launch” vectors (Csp3 Csp3 bonds) of a native helical pep-
tide, due to their Csp2 Csp3 nature[4] 12]
[b] Dr. G. T. Bourne
À
Current Address: Institute for Molecular Bioscience
University of Qld, Brisbane 4072 (Australia)
Fax : (+7)334-2101
Consequently, these scaffolds can accurately mimic side-
chain surfaces only when they are long and flexible and,
therefore, able to compensate for such torsional preferences
in the launch vector. Indeed, Hamiltonꢀs group corroborated
the biological utility of the terphenyl scaffolds as helical-
E-mail: g.bourne@imb.uq.edu.au
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000315.
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mimetic ligands, but only for flexible hydrocarbon side
chains.
Preliminary studies on functionalizing pyridines: The B and
C rings (Y=OSEM, Scheme 2) were prepared using 3-hy-
droxypyridine 6 followed by bromination (Scheme 2). Has-
seberg et al. showed that when PG=OSEM, (B, C ring,
Figure 1), alkylation is easily achieved at the desired ortho
Our molecular modeling suggested that steric conflict be-
tween proximal hydrogens causes the angular twist in the bi-
phenyl and terphenyl scaffolds. The pyridine unit replaces
the steric bulk of a hydrogen with a smaller lone pair of
electrons of the nitrogen. Thus, the potential energy surface
is modified so that the conjugated ring systems populate
À
more co-planar angles, and Ca Cb vectors are more biased
towards the helical-mimetic configuration.
The proposed synthesis of the phenylpyridal helical pepti-
domimetic involves both approaches of Jacoby[6] and Hamil-
ton.[7,11] Interestingly, a similar approach by Hamilton, pro-
duced the ter-pyridal scaffold in a concise synthetic ap-
proach as a helix mimetics.[12] However, the synthesis
showed little flexibility to change the side chains attached to
the core scaffold. To demonstrate our strategy, a triaryl sur-
À
À
face Gln Leu mimetic Leu (compound I) was synthesized.
The aromatic rings were synthesised independently followed
by convergent Pd-based coupling reactions to combine the
fragments.
Results and Discussion
Synthesis of ring A: Arylstannanes 5a,b, or the arylboronic
acids 5c, can be easily prepared using simple starting mate-
rials (Scheme 1).[13] The dibromo species 3a or 3b was react-
ed with isobutylmagnesium bromide. A major side product
of cross-coupling reactions of Grignard reagents is transme-
talation between isobutyl magnesium bromide and the
benzyl bromide derivative 3a, 3b. This was then followed by
alkylation with a second equivalent of 3a, 3b to form a 1,2-
diphenyl ethane derivative. To increase the yield of the
wanted product and to decrease this dimerization, we inves-
tigated cross-coupling reactions in the presence of various
transition-metal catalysts. For our purposes, Li2CuCl4 in-
creased the yield[14] substantially (R=H, 81%; R=CH3,
61%). Without the catalysts, we obtained (<20%) of the
wanted materials. The final step required transmetalation to
give the desired products.
Figure 1. Synthesis of the proposed a-helix mimetics. A) Computational
mimicry of the helix overlaid with the ter-aryl analogues. B) Disconnec-
tion approach in producing the a-helix mimetics.
position to the OSEM group.[15] It is thought that during al-
kylation coordination between the lithium cation and the
oxygen of the SEM Group 7 stabilizes the reactive inter-
mediate. Alkylation then proceeds solely at the 2-position of
the pyridine ring; the authors showed, however, only one
case of alkylation (methylation). Koch et al. investigated
halogenations of 3-hydroxypyridines and observed low
yields for dibrominations, but high yields for di-iodina-
tions.[16]
Scheme 1. Synthesis of ring A. Compound 3a was purchased.
Scheme 2. Alkylation of dihalogenated species.
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Helical Peptide Mimetic
FULL PAPER
Table 1. Alkylation of the dihalogenated pyridine ring.
The initial dibromination of 3-hydroxypyridine under the
reported procedures gave a mixture of monobrominated
and dibrominated products that proved difficult to separate.
The best yield obtained was 17% and required a long-gradi-
ent chromatography followed by several recrystallizations.
The ratio by NMR was approximately 2:2:1, 2-bromopyri-
dine: 2,4-dibromopyridine: 2,6-dibromopyridine.[15,16] For io-
dination we obtained quantitative yield for the desired 2,6-
derivative, and found that we can obtain selective monobro-
minated, iodinated products as well. Protection of the alco-
hol with the metalation-directing SEM protecting group[16]
then afforded 7a–c.
We next examined the regioselectivity of alkylation by
simply treating the lithium derivative of 7a with NH4Cl
giving rise to the monobrominated species. An inspection of
the coupling patterns in the aromatic region of the NMR
spectra revealed two protons that signified ortho couplings
(J=8.8 Hz), while one of these protons also contained a
meta-coupling pattern to a third proton (J=2.7 Hz).
As our goal was to generate diverse libraries of a-helix
mimetics, we required a high-yielding route that allowed
multiple functionalizations. We reinvestigated this system
with a series of nucleophiles to determine the generality of
the procedure (Scheme 2, Table 1). Simple alkylations of the
dihalogenated pyridine with several nucleophiles (allyl bro-
mide and methyliodide) were successful. For example, treat-
ment of dibromopyridine with allyl bromide gave an 85%
yield.
We failed, however, when using other non-activated elec-
trophiles. The lithium salt of 7 was found to be stable at
À788C existing for long periods of time in the presence of a
non-activated alkyl halide. Upon quenching, we obtain the
monobrominated species as the major product. We can view
the desired pyridine moiety as a 1,2,3,4-tetrasubstituted aro-
matic (two halogens, an ether and a lone pair). Therefore,
alkylation proceeds for the non-hindered cases, methyl
iodide and allyl bromide, where attack at the carbon atom is
accessible.
To support this argument, we attempted alkylation with
propyl bromide, but this reaction failed. By HPLC we de-
tected <1% of the product. To confirm, we synthesized the
propyl species 8d separately through simple hydrogenation
of 8c for a control for HPLC identification. Hydrogenation
in a Parr generator at 1.5 atm for 6 h in EtOAc provided the
desired material quantitatively. Interestingly, using MeOH
in this reaction caused partial removal of the SEM group.
This low yield agreed with similar results showing that alky-
lations can be problematic.[18] Other studies have since
showed that copper catalysts/Grignard reagents can substan-
tially increase the respective yields.[19]
A hypothesis for the problematic alkylation follows. Ini-
tially, the desired 2-halogen–lithium exchange occurs in di-
ethyl ether. In THF, we obtain deprotonation at the 4-posi-
tion. This product can then undergo homo-transmetalation
with starting material at higher temperatures >708C, fol-
lowed by a second equilibrium giving rise to the tri-iodo
species in minute amounts. A further possible equilibrium
Entry Reactant
Electrophile Product
Yield [%][c]
1
NH4Cl
77[a]
2
3
4
5
6
MeI
69[a]
85[a]
<1[a,b]
57[b]
59[a]
ClSnACTHNURTGNENG(U nBu)3
DMF
MeI
7
8
9
81[a]
83[b]
8[a]
MeI
AHCTUNGTERG(NNUN CH2O)n
10
11
DMF
DMF
79[a]
73[a]
[a] À1008C, diethyl ether, lithium base. [b] À788C, THF, lithium base.
[c] All reactions performed in anhydrous conditions under an inert at-
mosphere.
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8441

G. T. Bourne et al.
exists which gives the 6-lithio species that is stabilized by
the electron-withdrawing effects of the dihalogenated spe-
cies. At even higher temperatures (close to 08C), we also
obtained a diene species in small amounts through decom-
position of the pyridine system. Alkylation, when using
nBuLi as the organic base, to a successful transmetalation
versus deprotonation required longer reaction times at
À1008C in anhydrous diethyl ether rather then at À788C in
THF with non-hindered fairly reactive electrophiles.
We further tested low-temperature alkylation using two
different electrophiles (DMF and paraformaldehyde). The
desired compounds 8j and 8i were obtained in 8 and 79%
yield, respectively. The low yield of 8j was anticipated due
to slow decomposition of paraformaldehyde to formalde-
hyde at a higher reaction tem-
Synthesis of pyridine-based B and C rings: Synthesis for the
final pyridine templates was accomplished using ethylene
glycol to form the acetal followed by a second transmetala-
tion (Scheme 3). At this stage the choice was between
Suzuki or Stille couplings. Fisher observed that the boronic
moiety in the 2-position of pyridine ring was unstable (when
performing Suzuki couplings).[20] This was reconfirmed by
several other authors who noted a slight deformation of the
boronic ester moiety due to the nitrogen.[21] As a matter of
fact, attempts to isolate the requisite pyridin-2-ylborane ad-
ducts have generally been problematic.[21] The C B bond
À
length may render it more labile in pyridin-2-yl. We chose
to investigate the Stille reaction, and thus synthesized the
organostannyl compounds 11a and 11b.
perature then the nominated
alkylation. This indicated that
the lower temperatures were
required for alkylation before
rearrangement and side-prod-
uct formation. We tested this
hypothesis through methyla-
tion of 7c in two different sol-
vent mixtures (diethyl ether
and THF) to obtain 8g and 8h
in high yield (81 and 83%, re-
spectively). The key to success-
ful transmetalation versus the
deprotonation reaction was
longer reaction times occurring
at À1008C in anhydrous dieth-
yl ether rather than À788C in
THF with sterically non-cum-
bersome, highly reactive elec-
trophiles.
Finally, we took 8h and per-
formed formylation under the
standard conditions to obtain
8k. By the preparation of 8k,
a synthetic route to functional-
ize pyridine simultaneously at
the 2-, 3-, 4-, and 6-positions
has been developed. Further-
more, since the iodo group at
the 6-position and the hydrox-
yl group at the 3-position are
present, these sites are readily
accessible for further chemical
modifications. Thus, develop-
ment of this synthetic method-
ology provided viable routes
to the targeted analogues and
demonstrated that one can
functionalize easily 4- of the 5-
positions available on the pyri-
dine ring.
Scheme 3. Synthesis of phenylpyridine-based A–B dimer.
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Helical Peptide Mimetic
FULL PAPER
For the Stille cross-coupling, a method described by Bald-
win et al.[23] was used. Baldwin and co-workers observed
that the PdCl2/PtBu3 catalytic system with copper(I) iodide
and cesium fluoride in DMF was most effective for coupling
aryl bromides, while palladium catalysts in combination with
copper(I) iodide and cesium fluoride was optimal when cou-
pling iodides and triflates. We decided to test the Stille reac-
tions between ring A and ring B. The yields were higher
when we performed the Stille coupling between the organo-
stannane of ring A and the iodide of ring B (Table 2). Inter-
estingly, the use of organoboronic acids for Suzuki coupling
gave much higher yields (Table 2, entry 3).
was removed quickly (analyzed by LC-MS), while the acetal
deprotection took longer with mild heating before the alde-
hyde was obtained.
The alcohol 14 was protected as the benzyl ether followed
by either a Wittig reaction or alkylation to produce a series
of helix templates. The alcohol was protected, since under
the Horner–Wadsworth–Emmons conditions, a stable be-
taine intermediate was produced. The benzyl protecting
group was used since the next step required the reduction of
the double bond, and the benzyl group could be removed si-
multaneously. Dehydroxylation of 15c using refluxing TFA/
Et3SiH gave 15d in 22% yield.[27]
Based on this general route, a number of helix mimetics
structurally similar to Jacobyꢀs biphenyl a-helix mimetics
were prepared. The initial library generated is shown is
Scheme 5 and was formed by simple alkylation of the
phenyl-pyrid-3-ol moiety followed by ammonolysis when re-
quired. The only difficulty was with purification of ana-
logues containing the propylamide (n=2) 17ab, 17bb, 17bc,
17bd (Scheme 4). Under aqueous acidic conditions (reverse-
phase HPLC conditions), the resultant library member de-
composed to the starting material and the allyl amide equiv-
alent. This was circumvented by performing purification
under non-aqueous conditions.
Table 2. Stille/Suzuki coupling to form biaryl compounds.
Entry[a]
Halide
Reagent 2[b]
Product[c]
Yield [%]
1
2
3
4b
9a
9a
11a
5b
5c
12[a]
37[b]
96[a]
4
5
9b
4a
5a
11b
44[b]
22[c]
[a] PdII
[c] PdIICl2, CsF, CuI, P
ACHTUNGTRENNUNG
N
ACHTNUGTRNENU(NG tBu)3. [b] [PdACHTNURTEGN(GNUN PPh3)4], CsF, CuI, PACHTNUGRTEN(NUGN tBu)3.
The next step required the removal of the protecting
groups (both the acetal and the SEM group). A test reaction
was carried out using the iodide 9a with TBAF. The condi-
tions for complete removal of both protecting groups re-
quired heating with the apolar solvent HMPA.[24] We applied
similar conditions to 12a, but only the SEM group was re-
moved for this phenyl-pyridal compound. We attempted a
two-step approach to remove the acetal using acid hydroly-
sis; however, this caused decomposition of our starting ma-
terial with no detectable product even under dilute acid con-
ditions. Therefore, a milder method for acetal removal was
required.
Scheme 4. Library generation.
We selected conditions reported by Marcantoni et al.
using cerium chloride in acetonitrile with NaI as catalyst.
(Scheme 3).[25] These conditions successfully removed the
acetal group and, not surprisingly, also removed the SEM
protecting group. A search of the literature did not reveal
any previous reference for the use of cerium chloride to
remove the SEM protecting group. The SEM group can
sometimes be problematic when attached to phenols,[24,26]
and cerium chloride may be useful for future use in depro-
tection of the SEM group. In our reaction, the SEM group
Phenylbipyridal a-helix mimetic: The desired a-helix mim-
etic was synthesized stepwise by initially producing the tri-
flate followed by Stille reaction with 11a. Deprotection with
CeCl3·7H2O, benzylation and
a
Horner–Wadsworth–
Emmons reaction produced the allyl intermediate 20 with
an E-orientation. Finally, hydrogenation reduced the double
bond and removed the benzyl ether protecting group, fol-
lowed by ammonolysis to give the targeted compound 1
(Schem 5).
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G. T. Bourne et al.
Acknowledgements
This research was supported in part by
NIH grant 5R01M68460 to G.R.M. We
would like to thank Dr. Yaniv Barda,
and Prof. Kevin D. Moeller for insight-
ful discussions.
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Conclusion
One of the most difficult tasks for the medicinal chemist is
finding new leads that mimic the discontinuous interacting
surface of proteins while meeting other important parame-
ters including ADME profile, molecular weight and pharma-
cokinetic parameters. Privileged structures represent an
ideal source of lead compounds, as they often already pos-
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term “privileged structure” has gained prominence in the lit-
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Privileged structures are by definition, however, generally
not structures in their own right, as they usually comprise
only the common core scaffold. For the medicinal chemists,
the true utility of privileged structures is the ability to syn-
thesize one library based upon a single core scaffold and
screen it against a variety of different receptors, yielding
several active compounds against different biological targets.
The biphenyl framework is without doubt a privileged struc-
ture, and as such is found in 4.3% of all known drugs.
In this project, we have used an analogous framework to
synthesize a small solution-based library of helix peptidomi-
metics. The frameworks, phenyl-pyridal and phenyl-dipyri-
dal, enable mimicking discontinuous surfaces, have a lower
logP then the biphenyl analogues and are expected to have
useful pharmacokinetic characteristics, including improved
solubility relative to other organic helical scaffolds. Finally,
the overall synthesis of these helix mimetics is both highly
convergent and high yielding.[29]
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Helical Peptide Mimetic
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(Australia)
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Bourne.pdf
Received: February 5, 2010
Published online: June 16, 2010
Chem. Eur. J. 2010, 16, 8439 – 8445
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8445