Facile iterative synthesis of 2,5-terpyrimidinylenes as nonpeptidic α-helical mimics

Article abstract of DOI:10.1021/jo100272d

A facile iterative synthesis of 2,5-terpyrimidinylenes that are structurally analogous to α-helix mimics is presented. Condensation of amidines with readily prepared α,β-unsaturated α-cyanoketones gives 5-cyano-substituted pyrimidines. Iterative transformation of the 5-cyano group into an amidine allows synthesis of 2,5-terpyrimidinylenes with variable groups at the 4-, 4′-, and 4′′-positions. These compounds are designed to mimic the i, i + 4, and i + 7 sites of an α-helix.

Full text of DOI:10.1021/jo100272d

pubs.acs.org/joc
to accrue sufficient interactions between the protein surfaces
Facile Iterative Synthesis of 2,5-Terpyrimidinylenes
as Nonpeptidic r-Helical Mimics
and stabilize their specific interaction with each other.9-12
Thus, the development of specific PPI inhibitors is a challen-
ging task as compared to enzyme inhibitors, which typically
have relatively small and deep binding pockets.
Laura Anderson,†,‡ Mingzhou Zhou,†,‡ Vasudha Sharma,‡
Jillian M. McLaughlin,‡ Daniel N. Santiago,†
Frank R. Fronczek,§ Wayne C. Guida,†,‡ and
Mark L. McLaughlin*,†,‡
Several different secondary and tertiary structures can be in-
volved in the PPI, and one that is the focus of this manuscript is
the R-helix. Hamilton et al. have discovered R-helix mimics that
act as submicromolar inhibitors of the Bcl-xL interaction with
the Bak peptide and the MDM2 interaction with the p53 peptide
derived from the p53 N-terminus.13,14 The Hamilton group has
reported several R-helix mimics, but none of them have been
more active than the best reported 1,4-terphenylene scaffolds
against the same targets in the same in vitro assays.15-19
Rebek et al. recognized the importance of Hamilton’s R-helix
mimic approach and published several examples of more polar
versions of the original Hamilton 1,4-terphenylene scaffold20-24
including a tetrameric heterocyclic R-helix mimic scaffold de-
signed to position four side chains in the i, i þ 4, i þ 7, and i þ 11
positions of an R-helix.24 Recently, Hamilton’s group has also
published a repetitive heterocyclic scaffold approach.25 The
intense efforts of these research groups to develop repetitive
heterocyclic scaffolds to mimic R-helices illustrates the very
strong potential importance of this class of compounds.
With the seminal work from the Hamilton group on the
1,4-terphenylene scaffold as a guide, we have developed a
facile iterative synthesis of 2,5-terpyrimidinylenes as struc-
turally analogous R-helix mimics.26,27 Figure 1 shows an
overlay of octa-alanine in an idealized R-helical conforma-
tion with its i, i þ 4, and i þ 7 methyl groups highlighted as
gold spheres and a 4,40,400-trimethyl-2,5-terpyrimidinylene
with its methyl groups highlighted as green spheres.
†Department of Chemistry, University of South Florida,
4202 E. Fowler Avenue, CHE 205, Tampa, Florida 33620,
‡Drug Discovery Department, H. Lee Moffitt Cancer Center,
12902 Magnolia Drive, MRC 4E, Tampa, Florida 33612, and
§Department of Chemistry, Louisiana State University,
232 Choppin Hall, Baton Rouge, Louisiana 70803
mmclaugh@cas.usf.edu
Received February 13, 2010
A facile iterative synthesis of 2,5-terpyrimidinylenes that are
structurally analogous to R-helix mimics is presented. Con-
densation of amidines with readily prepared R,β-unsaturated
R-cyanoketones gives 5-cyano-substituted pyrimidines. Itera-
tive transformation of the 5-cyano group into an amidine
allows synthesis of 2,5-terpyrimidinylenes with variable
groups at the 4-, 40-, and 400-positions. These compounds
are designed to mimic the i, iþ 4, and iþ 7sitesofanR-helix.
(9) Parthasarathi, L.; Casey, F.; Stein, A.; Aloy, P.; Shields, D. C.
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interactions will boost our understanding of them.1,2
Furthermore, PPI inhibitors can be the basis of important
therapeutic interventions.3-8 PPIs are typically shallow sur-
face interactions that occur over relatively large surface areas
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Published on Web 05/14/2010
DOI: 10.1021/jo100272d
r
2010 American Chemical Society

Anderson et al.
JOCNote
SCHEME 1. Representative Synthesis of Pyrimidines 4
FIGURE 1. A tube representation of an idealized R-helix of octa-
alanine (gold with transparent ribbon) with the i, iþ 4, and iþ 7methyl
groups highlighted as spheres. An overlay with a 4,40,400-trimethyl-2,5-
terpyrimidinylene with its methyl groups highlighted as green spheres is
˚
the desirable range for hydrophilic character for the ana-
logous 2,5-terpyrimidinylene scaffold (see Table 1 Supporting
Information A)
shown above. The rmsd for the highlighted methyl groups is 0.68 A.
For clarity, only polar hydrogens are shown. The details of these
calculations can be found in Supporting Information.
Pyrimidine monomers 4 were obtained in a few steps through
the condensation of commercially available amidines with read-
ily prepared R,β-unsaturated R-cyanoketones 3 (Scheme 1). For
instance, ester 1 was reacted with acetonitrile in anhydrous THF
in the presence of KO-t-amyl to obtain R-cyanoketone 2.29,30
These reactions were also carried out in presence of other bases,
including NaOMe,31 KO-t-Bu, and LDA (data not shown).
While the desired R-cyanoketone was obtained from the reac-
tions with these bases, the isolation and purification was tedious,
resulting in lower yields. KO-t-amyl afforded the products in
good yields with simpler purification conditions.
Treatment of compound 2 with N,N-dimethylformamide
dimethyl acetal (DMF-DMA) in THF gave 3 in excellent
yield.32 The efficiency of this step allowed us to obtain several
R,β-unsaturated R-cyanoketones bearing hydrophobic alkyl,
aryl, and heteroaromatic groups for introducing diversity in
the 4-position of pyrimidines. As shown in Scheme 1, monomers
4-1 and 4-4 were isolated in higher yields, and no further purifi-
cation was required since these compounds precipitated from
the reaction mixtures, whereas 4-2 and 4-3 required additional
purification. Encouraged by the excellent yields and purities
obtained when R0 = Ph, we next focused on the iterative
synthesis of the dimeric and trimeric 2,5-pyrimidines.
Compounds 5and 6were synthesized via conversion of the 5-
or 50-cyano group to a 5- or 50-carboxamidine salt (Scheme 2).
Several methods for this conversion have been reported,33,34
such as the Pinner,35 the thio-Pinner,36 or treatment with Na
or LiHMDS followed by aqueous hydrolysis,37 but none of
FIGURE 2. QikProp calculations for the most active terphenyl-
based Bcl-xL-Bak inhibitor. The analogous terpyrimidine-based
analogue shows improved hydrophilic character.
As seen with the Hamilton designed 1,4-terphenylene scaf-
fold,16 there is a good overlap of these positions, both in orien-
tation and distance. Residues at the i þ 4 position are one turn
plus 40°, and i þ 7 residues are 20° less than two turns of an
R-helix from the i position. Our 2,5-terpyrimidinylene scaffold
essentially replaces the phenyl rings of Hamilton’s 1,4-terphe-
nylene scaffold with pyrimidine rings, but these changes make
the synthesis of pyrimidine-based derivatives much easier be-
cause the pyrimidine synthetic chemistry is more convergent
and amenable to an iterative synthetic approach.
In addition, the pyrimidine for phenyl replacement gives the
resulting analogous pyrimidine scaffold improved hydrophili-
city according to QikProp calculations summarized in Figure 2
and Table 1, Supporting Information A. Structurally analogous
1,4-terphenylene and 2,5-terpyrimidinylene scaffolds show the
calculated log Poctanol/water values ranging from hydrophobic
behavior for the Hamilton 1,4-terphenylene scaffold28 to within
(29) Yaohui, J.; Trenkle, W. C.; Vowles, J. V. Org. Lett. 2006, 8, 1161–
1163.
(30) Radwan, M. A. A.; Ragab, E. A.; Shaaban, M. R.; El-Nezhawy, A.
O. H. ARKIVOC 2009, 7, 281–291.
(31) Sorger, K.; Stohrer, J. U.S. Patent 20070142661.
(32) Reuman, M.; Beish, S.; Davis, J.; Batchelor, M. J.; Hutchings, M. C.;
Moffat, D. F. C. J. Org. Chem. 2008, 73, 1121–1123.
(33) Hill, M. D.; Movassaghi, M. Chem.;Eur. J. 2008, 14, 6836–6844.
(34) Dunn, P. J. Comprehensive Organic Functional Group Transforma-
tions II; Elsevier: Amsterdam, Boston, 2005; pp 655-699.
(35) Balo, C.; Lopez, C.; Brea, J. M.; Fernandez, F.; Caamano, O. Chem.
Pharm. Bull. 2007, 55, 372–375.
(28) Yin, H.; Lee, G.-i.; Sedey, K. A.; Kutzki, O.; Park, H. S.; Orner, B. P.;
Ernst, J. T.; Wang, H. -G.; Sebti, S. M.; Hamilton, A. D. J. Am. Chem. Soc.
2005, 127, 10191–10196.
(36) Lange, U. E. W; Schafer, B.; Baucke, D.; Buschmann, E.; Mack, H.
Tetrahedron Lett. 1999, 40, 7067–7070.
(37) Bruning, J. Tetrahedron Lett. 1997, 38, 3187–3188.
J. Org. Chem. Vol. 75, No. 12, 2010 4289

Anderson et al.
JOCNote
SCHEME 2. Synthesis of Dimeric and Trimeric 2,5-Pyrimidines
FIGURE 3. ORTEP diagram of compound 6-1.
explored as R-helical mimics for the disruption of various
protein-protein interactions; our efforts in this direction
will be reported subsequently.
Experimental Section
See Supporting Information for the complete series.
5-Methyl-3-oxohexanenitrile (2a). A mixture of potassium
tert-pentylate (∼1.7 M in toluene, 136 mmol, 80 mL) and
anhydrous THF (20 mL) was cooled at 0 °C in an ice bath
under an argon atmosphere. Anhydrous acetonitrile (136 mmol,
7.14 mL) and methyl ester 1a (90 mmol, 10.57 g, 12 mL) were
added simultaneously to the cold solution. The reaction mixture
was allowed to warm to room temperature and stirred under an
argon atmosphere for 22 h. A precipitate was formed within a
few minutes (3-5 min) of stirring, and the reaction mixture
remained cloudy until completion. The reaction was monitored
by TLC and was stopped when the TLC indicated the consump-
tion of the ester (1a). The mixture was filtered, and the filtered
cake was washed thoroughly with hexanes (80 mL). The filtered
residue was then transferred to a separatory funnel and acidified
to pH ∼2-3 with saturated aq KHSO4 solution (180 mL). An
equal volume amount of DCM (180 mL) was used to extract the
desired compound (2a). The organic layer was collected and
washed with brine (100 mL), dried over Na2SO4, and concen-
trated under reduced pressure to yield 2a in 73% yield, as a pale
yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J = 0.8 Hz,
3H), 0.97 (d, J = 0.8 Hz, 3H), 3.43 (s, 2H), 2.11-2.25 (m, 1H),
2.49 (d, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 22.5,
24.7, 32.6, 51.1, 113.9, 197.2.
(E)-2-((Dimethylamino)methylene)-5-methyl-3-oxohexaneni-
trile(3a). R-Cyanoketone 2a (65.9 mmol, 825 mg) was dissolved
in dry THF (3 mL) under an argon atmosphere. N,N-Dimethyl-
formamide dimethyl acetal (85.6 mmol, 11.5 mL) was added,
and the mixture was stirred at room temperature. Progress of the
reaction was monitored by TLC until complete consumption of
starting material 2a was observed (16 h). The solvent was
evaporated under reduced pressure, and the desired compound
was obtained as an E . Z isomeric mixture. Isolated yield: 98%,
pale yellow solid, mp 43-45 °C. 1H NMR (400 MHz, CDCl3) δ
0.95 (d, J = 1.5 Hz, 3H), 0.96 (d, J = 1.5 Hz, 3H), 2.13-2.25 (m,
1H), 2.54 (dd, J = 7.0 Hz, 2H), 3.24 (s, 3H), 3.40 (s, 3H), 7.82 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 22.8, 25.8, 39.0, 48.1, 48.8,
80.8, 120.6, 157.6, 195.4. HRMS (ESI) calcd for C10H16N2O
[M þ H]þ 181.1341, found 181.1333. Note: If a precipitate
forms during the reaction, the mixture is cooled to 0 °C and
then filtered and rinsed with cold THF to isolate the desired
compound.
these alternatives were superior to the two-step hydroxyla-
mine route.38,39
The extensive literature on nitrile to amidine conversion
suggests that the difficulty of such a conversion can be
attributed to the ortho substitution on the pyrimidine ring.40
We found excess hydroxylamine followed by an in situ
reduction of the resulting amidoxime was the best route to
obtain the intermediate amidine salts. The N-hydroxylamine
mediated transformation of ortho-substituted arylnitrile
groups to arylcarboxamidines has been reported41 but has
not been used previously to prepare oligo-2,5-pyrimidines.
The resulting intermediate amidine salts were reacted with an
R,β-unsaturated R-cyanoketone to yield dimers 5.
Dimers as well as trimers were isolated. The R1, R2, and R3
groups of the 2,5-terpyrimidinylene scaffold were selected to
mimic hydrophobic groups found to play important roles in
binding similar to the Hamilton terphenylene compounds.28
The ORTEP diagram of the 40-benzyl-4-(1-methylethyl)-
400-(2-methylpropyl)-200-phenyl-2,50,20,500-terpyrimidinylene-5-
carbonitrile (6-1) crystal structure is shown in Figure 3. This
conformation places the three hydrophobic groups on the same
side of the long axis of the molecule, which is the conformer
needed to mimic the i, i þ 4, and i þ 7 residues of an R-helix.
In conclusion, a series of compounds based on novel 2,5-
terpyrimidinylenes was obtained through a facile iterative
condensation between amidines and R,β-unsaturated R-cya-
noketones in the presence of a base. This scaffold is being
(38) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala,
T. E. Synth. Commun. 1996, 26, 4351–4367.
(39) Nadrah, K.; Dolenc, M. S. Synlett 2007, 8, 1257–1258.
(40) von Angerer, S. Science of Synthesis; Thieme: Stuttgart, 2004;
pp 379-572.
(41) Basso, A.; Pegg, N.; Evans, B.; Bradley, M. Eur. J. Org. Chem. 2000,
23, 3887–3891.
4-Isobutyl-2-phenylpyrimidine-5-carbonitrile(4-5). Method A:
A mixture of compound 3a (1.66 mmol, 300 mg) and benzami-
dine hydrochloride (3.33 mmol, 521 mg) in ethanol (absolute,
10 mL) was stirred under reflux until TLC indicated completion
4290 J. Org. Chem. Vol. 75, No. 12, 2010

Anderson et al.
JOCNote
of the reaction. The mixture was brought to room temperature,
and the precipitate formed was filtered and rinsed with ice-cold
ethanol (3 ꢀ 5 mL). Compound 4-5 was isolated in 70% yield as
colorless crystals, mp 68-69 °C. 1H NMR (400 MHz, CDCl3) δ
1.05 (d, J = 6.7 Hz, 6H), 2.39 (m, 1H), 2.93 (d, J = 7.2 Hz, 2H),
7.49-7.59 (m, 3H), 8.50-8.53 (m, 2H), 8.93 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ 22.6, 28.9, 45.7, 106.7, 115.8, 129.0, 129.4,
132. 4, 136.4, 160.4, 165.7, 173.3. HRMS (ESI) calcd for
C15H15N3 [M þ H]þ 238.1344, found 238.1337. Method B:
Microwave-assisted reactions were also done in the presence
of base (e.g., Et3N or NaOEt) to obtain the desired pyrimidines.
For example, to a mixture of compound 3a (1.11 mmol, 200 mg)
and benzamidine hydrochloride (2.22 mmol, 350 mg) in ethanol
(5 mL) was added sodium ethoxide (1.11 mmol, 75.5 mg) sus-
pended in ethanol (1 mL). The reaction mixture was placed in
a microwave reactor for 40 min at 120 °C. A colorless precipi-
tate was formed upon cooling to room temperature. The pre-
cipitate was filtered and rinsed with ice-cold ethanol (2 ꢀ 3 mL)
to isolate compound 4-5 in 83% yield.
4-Benzyl-40-isobutyl-20-phenyl-2,50-bipyrimidine-5-carbo nitrile
(5-1). Step 1. To a mixture of compound 4-5 (4.21 mmol,
1000 mg) and hydroxylamine hydrochloride (10.53 mmol,
720 mg) in methanol (12 mL) was added triethylamine
(10.53 mmol, 1.46 mL). The reaction mixture was stirred under
reflux until TLC indicated the consumption of starting material
4-5. The solvent was removed under reduced pressure to obtain
a white crude solid. The crude was dissolved in DCM (50 mL),
washed with water (40 mL), dried over Na2SO4, and con-
centrated under reduced pressure to obtain intermediate
amidoxime, which was used in the next step without further
purification.
residue was added DCM (6 mL), and the white precipitate that
formed was removed by vacuum filtration. The filtrate was
concentrated under reduced pressure to obtain the crude acetate
salt of carboxamidine as a yellow solid, which was used without
further purification in the next step.
Step 3. To the crude carboxamidine salt dissolved in ethanol
(0.8 mL) were added compound 3a (0.69 mmol, 147 mg) and
triethylamine (1.38 mmol, 0.19 mL). The reaction mixture was
stirred under reflux for 2 h and then at room temperature for
18 h. A white precipitate was formed, which was filtered and
rinsed with cold ethanol (5 mL) to yield dimer 5-1 in 28% yield
after three steps as a white solid, mp 144-147 °C. 1H NMR (400
MHz, CDCl3) δ 0.92 (d, J = 6.7 Hz, 6H), 2.24-2.35 (m, 1H),
3.19 (d, J=7.1 Hz, 2H), 4.39 (s, 2H), 7.27-7.39 (m, 5H), 7.43-
7.56 (m, 5H), 9.02 (s, 1H), 9.38 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 22.8, 28.4, 43.4, 44.9, 106.3, 115.2, 127.6, 127.8, 128.8,
129.0, 129.2, 129.5, 131.5, 135.8, 137.4, 160.0, 160.7, 164.7,
165.8, 170.3, 172.0. HRMS (ESI) calcd for C26H23N5 [M þ
H]þ 406.2032, found 406.2049.
500-Cyano-4,400-diisobutyl-40-(2-phenylmethyl)-2-phenylterpyri-
midine (6-1). Repeat steps 1-3 as in synthesis of dimer 5-1
starting with 5-1. Isolated yield = 37% after three steps, white
solid, mp 188-189 °C. 1H NMR (400 MHz, CDCl3) δ 0.90 (d,
J = 6.7 Hz, 6H), 1.02 (d, J = 6.7 Hz, 6H), 2.22-2.36 (m, 2H),
2.95 (d, J = 7.2 Hz, 2H), 3.20 (d, J = 7.1 Hz, 2H), 4.77 (s, 2H),
7.17-7.25 (m, 5H), 7.49-7.54 (m, 3H), 8.52-8.58 (m, 2H), 9.03
(s, 1H), 9.38 (s, 1H), 9.52 (s, 1H). 13C NMR (100 MHz, CDCl3)
22.6, 22.8, 28.5, 29.2, 42.3, 44.7, 45.8, 107.6, 115.0, 126.8, 127.4,
128.56, 128.7, 128.8, 128.8, 129.3, 131.1, 137.8, 138.3, 159.6,
160.1, 160.3, 164.2, 164.6, 164.8, 169.0, 170.0, 173.8. HRMS
(ESI) calcd for C34H33N7 [M þ H]þ 540.2876, found 540.2869.
Step 2. The intermediate from step 1 (0.92 mmol, 250 mg) was
dissolved in glacial acetic acid (1 mL) and acetic anhydride
(1.01 mmol, 0.1 mL). After stirring for 5 min, potassium formate
prepared in situ from K2CO3 (5 mmol, 690 mg) and formic acid
(10 mmol, 0.37 mL) in methanol (2.5 mL) was added to the
mixture followed by the addition of 10% Pd/C (10 mol %,
98 mg). The reaction mixture was stirred at room temperature
until the TLC indicated the consumption of starting material.
The crude was filtered through Celite (1500 mg) and rinsed
with methanol (3ꢀ3 mL). The filtrate was concentrated under
reduced pressure to obtain a yellow crude residue. To this
Acknowledgment. We thank the NIH for financial sup-
port through grant NCI P01 CA118210. We also thank the
HTS-Chemistry Core Facility at Moffitt Cancer Center for
use of the Biotage initiator microwave synthesizer.
Supporting Information Available: Experimental proce-
dures, spectroscopic data for new compounds, and crystal
structure of compound 6-1. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4291