The isoxazole as a linchpin for molecules that target folded DNA conformations: Selective lateral lithiation and palladation

Article abstract of DOI:10.1016/S0040-4039(02)01845-2

3-(10′-Halo-9′-anthracenyl)-5-methyl-4-isoxazolecarboxylic acid ethyl esters served as a useful scaffold for highly efficient lateral metalation at the C(5), and Suzuki-Fu palladium catalyzed cross coupling at the C(10′).

Full text of DOI:10.1016/S0040-4039(02)01845-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7673–7677
The isoxazole as a linchpin for molecules that target folded
DNA conformations: selective lateral lithiation and palladation
Xiaochun Han, Chun Li, Kevin C. Rider, Alex Blumenfeld, Brendan Twamley and N. R. Natale*
301 Renfrew Hall, Department of Chemistry, University of Idaho, Moscow, ID 83844-2343, USA
Received 8 August 2002; accepted 30 August 2002
Abstract—3-(10%-Halo-9%-anthracenyl)-5-methyl-4-isoxazolecarboxylic acid ethyl esters served as a useful scaffold for highly
efficient lateral metalation at the C(5), and Suzuki–Fu palladium catalyzed cross coupling at the C(10%). © 2002 Published by
Elsevier Science Ltd.
We previously reported tripartite aryl-isoxazole-lexi-
tropins,1 which required doubly activated amidation for
efficient preparation.2 One of these molecules, NSC D
694332, was found to exhibit promising biological
activity: single digit micromolar inhibition of a dozen
cancer cell lines in the National Cancer Institute’s 60
cell line screening protocol.3–5 Experimentally, a DNA
array study with human genomic DNA showed a spec-
troscopic shift on exposure to NSC D 694332, consis-
tent with our expectation that this molecule would act
as an intercalating minor groove binding agent with
B-DNA.6 Therefore, we performed a COMPARE7,8
analysis with the NCI Standard Agent Database. Sur-
prisingly, this compound did not give a significant
correlation with agents of known mechanism of action
(Pairwise Correlation Coefficients 50.5); in contrast to
strong correlations usually observed for intercalating
agents. Therefore, we considered other possible DNA
targets.9 Our current working hypothesis resulted from
a molecular graphics study conducted with the coordi-
nates of human G-quadruplex DNA provided from the
recent breakthrough reported by Neidle (Fig. 1),10 and
indicated several potential promising modes11 of inter-
action with NSC D 694332. A binding study with
Hurley’s G-4a oligonucleotide sequence12 indicated a
fluxional potassium ion and time dependent fluores-
cence quenching that unquestionably evidences drug–
oligonucelotide interaction. Based on literature
precedent, this spectroscopic behavior can be explained
by binding in an external stacking orientation to this
putative molecular target. In order to use the isoxazole
required the development of synthetic methodology
that would work selectively and effectively in a very
sterically demanding environment. We herein report
promising progress towards that goal.
Lateral metalation has been used for the preparation of
functionalized isoxazoles.13,14 Previous reports have
indicated that lithium diisopropylamide (LDA) is usu-
ally required in the presence of an ester moiety, and
n-butyl lithium is known to add to esters selectively in
the presence of an alkyl isoxazole.14e
Initial studies (see Scheme 1 and Table 1) with LDA
indicated that good yields were possible for lateral
metalation and electrophilic quenching, even in the
presence of 10%-halogen groups on the anthracene ring,
including 10%-bromo (1b). The deprotonation we
observed proceeds more quickly than most of the lat-
eral metalations that we have previously studied, and
only 5–10 minutes are required. The orange to orange–
red anion color dissipates upon addition of electrophile,
which should be added slowly as the quenching is
exothermic. Deliberate introduction of 2 equiv. of base,
and 2 equiv. of benzyl bromide produces double elec-
trophile incorporation, an opportunity if subsequent
metalation is desired. We were gratified to observe that
n-butyl lithium also cleanly deprotonated non-halo-
genated anthracenyl isoxazole ester (1a), in somewhat
higher yield, a case wherein the steric bulk of the
anthracene likely serves to ‘protect’ the ester group
from nucleophilic attack by the alkyl lithium.
as
a scaffold to construct highly functionalized
molecules to bind folded DNA conformations, we now
Furthermore, the presence of a 10%-chloro on the
anthracene ring, as in (1c) served to improve the yield,
and products were obtained in synthetically useful
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01845-2

7674
X. Han et al. / Tetrahedron Letters 43 (2002) 7673–7677
Figure 1. (a) Solution structure of NSC D 694332, and distances calculated from NOE experiments for the predominant endo
conformation. The assignment rests primarily on the prominent NOE observed for the Ha proton and the peri-protons of the
anthracene, and the NOE distance between Hb and the protons of the adjacent pyrroles. (b) Side view of the results of a SGI
INSIGHT 2000 docking study, the minimum energy structure of NSC D 694332 and G-quadrulex DNA. It is apparent from this
model that the next logical SAR avenue for study is the C-5 of the isoxazole, and C-10 of the anthracene.
Scheme 1.

X. Han et al. / Tetrahedron Letters 43 (2002) 7673–7677
7675
Table 1. Lateral metalation of 3-(10%-halo-9%-anthracenyl)-
5-methyl-4-isoxazolecarboxylic acid ethyl esters18
Table 2. Suzuki coupling of 3-(10%-halo-9%-anthracenyl)-5-
methyl-4-isoxazolecarboxylic acid ethyl esters with aryl
boronates18
Product
X
H
H
H
Base
Electrophile
Yield (%)
Product
Aryl halide
Reaction conditions
Yield (%)
2a
3a
4a
LDA
n-BuLi
LDA
n-BuLi
LDA
n-BuLi
LDA
LDA
LDA
LDA
n-BuLi
LDA
Iodomethane
Iodomethane
Benzylbromide
Benzylbromide
Benzaldehyde
Benzaldehyde
Iodomethane
Benzylbromide
Benzaldehyde
Iodomethane
Iodomethane
Benzylbromide
Benzylbromide
Benzaldehyde
Benzaldehyde
50
59
58
68
69
76
55
62
70
58
69
71
75
77
82
6
7
8
1b
1c
1b
1c
1b
1c
THF, rt, 72 h
DMF, 120–125°C, 24 h
THF, rt, 72 h
DMF, 120–125°C, 24 h
THF, rt, 72 h
DMF, 120–125°C, 24 h
92
78
96
91
93
88
2b
3b
4b
2c
Br
Br
Br
Cl
pioneered in Fu’s laboratory15, namely, 2% Pd2(dba)3
and 4% P(t-Bu)3 at room temperature, and produced
the cross coupling products in excellent yields. While
the 10%-chloro (1c) required higher temperature (120–
125°C), the yields were also excellent. While previous
reports of Suzuki type cross-coupling of anthracenyl
bromides, and anthraquinone triflates have appeared,
this—to the best of our knowledge—is the first report
of the use of anthracenyl chlorides.16,17 Furthermore,
while the Suzuki reaction in the presence of other
heterocyclic systems have been reported—only a very
few of them p-deficient—this is the first instance in
which the transformation has been performed in the
presence of the isoxazole ring, a ring notorious for the
lability of the OꢀN bond in the presence of low valent
metals.
3c
4c
Cl
Cl
n-BuLi
LDA
n-BuLi
yields after isolation and purification. The X-ray struc-
ture of 3c (see Fig. 2) indicates the orientation of each
moiety in this benzyl bromide adduct to ethyl 3-(10%-
chloro-9%-anthracenyl)-5-methyl-4-isoxazole-carboxylate
(1c). The orthogonal relationship of isoxazole and
anthracene rings, and shielding of the carbonyl, is
clearly indicated.
Alas, the 10%-bromo (1b) with n-butyl lithium, appears
to undergo fast halogen–metal exchange, and subse-
quent proton transfer from the C-5 methyl group, for
de-halo product (1a) was observed. To confirm this, we
examined the quenching of this metalation with benz-
aldehyde, and the 10%-dehalogenated adduct (4a) was
observed.
Application of these methods towards optimization of
the biological activity of analogs of NSC D 694332 is
being studied in our laboratories, and our progress will
be reported in due course.
The observation that lateral metalation could proceed
in the presence of the aryl halogen atom, suggested the
opportunity for further elaboration of this scaffold via
palladium catalyzed cross coupling. Suzuki coupling of
aryl boronates with the 10%-bromo (1b) (see Scheme 1
and Table 2) proceeded readily with the modification
Acknowledgements
We would like to thank the University of Idaho
Research Council, and the National Cancer Institute
for financial support. We thank Drs. Ron Crawford
Figure 2. The X-ray structure of 3c.

7676
X. Han et al. / Tetrahedron Letters 43 (2002) 7673–7677
and Andrzej J. Paszczynski of the Environmental Bio-
technology Institute, University of Idaho, for use of
their computational facility. Dr. Dan Zaharevitz
assisted us with the COMPARE calculation and inter-
pretation. N.R.N. thanks the National Institute of Neu-
rological Disease and Stroke for Grant 2R15-NS38444.
X.H., C.L. and K.C.R. acknowledge the Malcolm and
Carol Renfrew Scholarship Endowment, University of
Idaho. We would like to thank Professor Kin Shing
Chan of The Chinese University of Hong Kong for
helpful discussions.
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A.; Scudiero, D. A.; Plowman, J.; Boyd, M. R. Proc. Am.
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18. All final compounds were characterized by 1H, 13C
NMR, and HR MS or elemental analysis. Selected spec-
tral data:
1
Compound 2a: mp 96–98°C; H NMR (CDCl3) l 8.55 (s,
1H), 8.02 (dd, J=7.1, 2.0 Hz, 2H), 7.61 (dd, J=7.1, 2.0
Hz, 2H), 7.49–7.34 (m, 4H), 3.66 (q, J=7.2 Hz, 2H), 3.33
(q, J=7.6 Hz, 2H), 1.51 (t, J=7.6 Hz, 3H), 0.28 (t,
J=7.2 Hz, 3H); 13C NMR (CDCl3) l 181.0, 161.9, 160.9,
131.4, 131.3, 129.0, 128.9, 126.7, 125.9, 125.6, 123.3,
110.8, 60.4, 21.6, 13.2, 11.9; MS (EI) m/z 176(9.24),
203(13.31), 214(12.02), 219(13.83), 243(23.65), 244(13.19),
345(100, M+). Anal. calcd for C22H19NO3: C, 76.50; H,
5.54; N, 4.06. Found: C, 76.70; H, 5.66; N, 3.83.
8. (a) Paull, K. D.; Lin, C. M.; Malspeis, L.; Hamel, E.
Cancer Res. 1992, 52, 3892–3900; (b) Hodes, L.; Paull, K.
D.; Koutsoukos, A.; Rubinstein, L. R. J. Biopharm. Stat.
1992, 2, 31–48.
9. (a) Ren, J.; Chaires, J. B. J. Am. Chem. Soc. 2000, 122,
424–425; (b) Ren, J.; Chaires, J. B. Biochemistry 1999, 38,
16067–16075.
1
Compound 3a: mp 82–84°C; H NMR (CDCl3) l 8.55(s,
1H), 8.03 (dd, J=7.0, 2.0 Hz, 2H), 7.53 (dd, J=7.0, 2.0
Hz, 2H), 7.48–7.24 (m, 4H), 3.67–3.57 (m, 4H), 3.50 (t,
J=7.5 Hz, 2H), 0.27 (t, J=7.2 Hz, 3H); 13C NMR
(CDCl3) l 178.8, 161.6, 160.8, 140.2, 131.4, 131.3, 129.0,
128.9, 128.8, 127.0, 126.7, 125.9, 125.6, 124.1, 123.2,
111.9, 60.4, 34.0, 29.5, 13.2; MS (EI) m/z 71(18.37),
149(96.13), 167(36.01), 243(21.04), 279(21.40), 375(14.53),
421(100, M+). Anal. Calcd for C28H23NO3: C, 79.79; H,
5.50; N, 3.32. Found: C, 79.98; H, 5.49; N, 3.41.
10. Parkinson, G. N.; Lee, M. P. H.; Neidle, S. Nature 2002,
417, 876–880.
11. (a) Read, M. A.; Neidle, S. Biochemistry 2000, 39, 13422–
13432; (b) Minimum energy structure of NSCD 694332
and quadrulex DNA. SGI INSIGHT 2000 docking study,
using the cvff forcefield, and all the solution molecules
(H2O) were removed. The whole DNA molecule was
constrained, the distance between first potassium and
C-10 hydrogen was fixed to <4.00 angstrom. After 3000
iterations using steepest descent minimization, the total
energy is −69.5315 kcal, electrostatic is −22.5767 kcal and
VdW is −46.9548 kcal.
1
Compound 4a: mp 145–147°C; H NMR (CDCl3) l 8.55
(s, 1H), 8.03 (dd, J=7.1, 2.0 Hz), 7.52 (dd, J=7.1, 2.0
Hz), 7.48–7.25 (m, 4H), 5.36 (m, 1H), 3.78–3.72 (m, 2H),
3.61 (q, J=7.2 Hz, 2H), 0.20 (t, J=7.2 Hz, 2H); 13C
NMR (acetone-d6) l 176.53, 160.72, 160.06, 144.10,
144.08, 131.16, 131.14, 130.77, 130.76, 128.46, 128.19,
127.46, 126.28, 126.27, 125.87, 125.42, 125.40, 125.33,
125.32, 123.29, 111.96, 71.72, 71.61, 59.65, 37.37, 37.33,
12.47; MS (EI) m/z 79(9.47), 107(12.19), 203(14.06),
219(15.74), 243(26.66), 285(21.19), 331(38.96), 437(100,
M+); HRMS (EI) calcd for C28H23NO4 (M+) 437.1628,
found 437.1626.
12. (a) Sun, D.; Thompson, B.; Cathers, B. E.; Salazar, M.;
Kerwin, S. M.; Trent, J. O.; Jenkins, T. C.; Neidle, S.;
Hurley, L. H. J. Med. Chem. 1997, 40, 2113–2116; (b)
Han, H.; Cliff, C. L.; Hurley, L. H. Biochemistry 1999,

X. Han et al. / Tetrahedron Letters 43 (2002) 7673–7677
7677
Compound 2b: Obtained as a yellow oil after chromato-
graphy on silica gel (Rf=0.26 in 3:2 benzene/hexane). H
122.62, 111.57, 60.13, 33.56, 29.07, 12.90; MS (EI) m/z
77(3.99), 91(10.41), 176(9.29), 227(11.66), 277(26.66),
409(21.55), 455(100, M+), 456(27.78%, (M+1)+),
457(43.07%, (M+2)+). Anal. calcd for C28H22ClNO3: C,
73.76; H, 4.86; N, 3.07. Found: C, 73.91; H, 4.93; N,
2.98.
1
NMR (CDCl3) l 8.56 (dd, J=6.9, 1.9 Hz, 2H), 7.59–7.40
(m, 6H), 3.64 (q, J=7.2 Hz, 2H), 3.29 (q, J=7.5 Hz, 2H),
1.46 (t, J=7.5 Hz, 3H), 0.29 (t, J=7.2 Hz, 3H); 13C
NMR (CDCl3) l 181.2, 161.6, 160.7, 131.8, 130.5, 128.5,
127.5, 126.9, 126.3, 125.6, 124.2, 110.9, 60.5, 21.6, 13.3,
11.9; MS (EI) m/z 176(38.02), 214(38.20), 283(14.69),
297(16.52), 321(36.05), 423(93.38, M+), 425(100, (M+2)+);
HRMS (EI) calcd for C22H18BrNO3 (M+, (M+2)+),
423.0470, 425.0453, found 423.0470, 425.0439.
1
Compound 4c: mp 119–121°C; H NMR (CDCl3) l 8.60
(dd, J=7.0, 2.0 Hz, 2H), 7.62–7.45 (m, 6H), 5.46 (m,
1H), 3.86–3.75 (m, 2H), 3.67 (q, J=7.2 Hz, 2H), 0.31 (t,
J=7.2 Hz, 2H); 13C NMR (CDCl3) l 176.25, 161.10,
159.98, 142.74, 131.14, 131.09, 128.69, 128.297, 128.291,
128.20, 126.74, 126.70, 126.65, 126.56, 125.84, 125.82,
125.67, 125.06, 122.36, 112.65, 72.54, 60.48, 37.08, 12.78;
MS (EI) m/z 77(13.45), 79(14.72), 105(19.34), 163(10.69),
176(14.33), 214(12.65), 277(23.69), 319(17.48), 365(44.89),
471(100, M+), 472(35.78, (M+1)+), 473(37.49%, (M+2)+).
Anal. calcd for C28H22ClNO4: C, 71.26 H, 4.70; N, 2.97.
Found: C, 71.08; H, 4.74; N, 2.84.
Compound 6: Colorless crystals from cyclohexane: mp
191.5–193°C; 1H NMR (CDCl3) l 7.63–7.27 (m, 13H),
3.68 (q, J=7.2 Hz, 2H), 2.88 (s, 3H), 0.33 (t, J=7.2 Hz,
3H); 13C NMR (CDCl3) l 176.6, 162.0, 161.2, 139.8,
139.1, 131.6, 131.5, 130.9, 130.1, 128.9, 128.8, 127.6,
126.3, 125.9, 125.5, 123.3, 111.9, 60.5, 13.8, 13.2; MS (EI)
m/z 252(13.86), 295(12.85), 319(17.91), 407(100, M+).
Anal. calcd for C27H21NO3: C, 79.59; H, 5.19; N, 3.44.
Found: C, 79.94; H, 5.09; N, 3.57.
Compound 7: Pale yellow crystals from 10:1 hexane/ethyl
Acetate: mp 203–204°C; 1H NMR (CDCl3) l 7.69–7.59
(m, 4H), 7.34–7.27 (m, 6H), 7.09–7.06 (m, 2H), 3.90 (s,
3H), 3.68 (q, J=7.2 Hz, 2H), 2.88 (s, 3H), 0.33 (t, J=7.2
Hz, 3H); 13C NMR (CDCl3) l 176.5, 162.0, 161.2, 159.6,
139.6, 132.7, 132.6, 131.1, 131.0, 130.5, 127.6, 126.3,
125.9, 125.4, 123.1, 114.4, 114.3, 111.9, 60.5, 55.83, 55.81,
13.8, 13.2; MS (EI) m/z 239(10.12), 325(12.01),
349(16.10), 437(100, M+). Anal. calcd for C28H23NO4: C,
76.87; H, 5.30; N, 3.20. Found: C, 76.64; H, 5.10; N,
3.24.
Compound 8: Colorless needles from 5:1 hexane/ethyl
acetate: mp 223–224°C; 1H NMR (CDCl3) l 7.65–7.59
(m, 1H), 7.36–7.24 (m, 12H), 3.68 (q, J=7.2 Hz, 2H),
2.88 (s, 3H), 2.21 (s, 3H), 0.34 (t, J=7.2 Hz, 3H); 13C
NMR (CDCl3) l 176.6, 168.8, 161.9, 161.2, 139.2, 137.9,
134.8, 132.24, 132.20, 130.9, 130.2, 127.5, 126.4, 125.9,
125.6, 123.3, 120.1, 111.9, 60.5, 25.0, 13.8, 13.3; MS (EI)
m/z 119(8.90), 162(8.12), 266(11.10), 278(11.20),
304(10.23), 320(10.10), 335(15.12), 352(16.93), 376(30.01),
393(9.91), 421(12.03), 439(11.45), 464(100, M+). Anal.
calcd for C29H24N2O4: C, 74.98; H, 5.21; N, 6.03. Found:
C, 75,21; H, 5.04; N, 6.25.
1
Compound 3b: mp 146–148°C; H NMR (CDCl3) l 8.54
(dd, J=7.0, 2.0 Hz, 2H), 7.55–7.25 (m, 6H), 3.63–3.56
(m, 4H), 3.22 (t, J=7.5 Hz, 2H), 0.29 (t, J=7.2 Hz, 3H);
13C NMR (CDCl3) l 178.9, 161.4, 160.6, 140.0, 131.8,
130.5, 129.0, 128.7, 128.5, 127.5, 127.0, 126.9, 126.3,
125.6, 124.1, 112.0, 60.5, 34.0, 29.5, 13.3; MS (EI) m/z
57(16.23), 70(11.01), 83(12.18), 91(21.42), 105(14.87),
131(9.84), 149(48.20), 176(37.33), 201(11.22), 214(25.70),
283(17.47), 323(29.30), 455(16.51), 499(94.35, M+),
501(100, (M+2)+); HRMS (EI) calcd for C28H22BrNO3
(M+, (M+2)+) 499.0783, 501.0767, found 499.0772,
501.0787.
1
Compound 4b: mp 113–114°C; H NMR (CDCl3) l 8.53
(dd, J=7.0, 2.0 Hz, 2H), 7.55–7.29 (m, 6H), 5.33 (m,
1H), 3.80–3.64 (m, 2H), 3.56 (q, J=7.2 Hz, 2H), 0.22 (t,
J=7.2 Hz, 3H); 13C NMR (CDCl3) l 176.7, 162.0, 160.5,
143.1, 131.8, 131.4, 131.3, 130.5, 129.1, 128.7, 128.6,
128.5, 127.5, 127.03, 127.01, 126.3, 126.1, 125.8, 125.7,
123.8, 113.0, 73.0, 60.9, 60.8, 37.54, 37.52, 13.2, 13.1; MS
(EI) m/z 79(54.88), 107(58.02), 176(100), 203(34.75),
214(61.75), 297(34.07), 323(48.64), 365(29.29), 411(57.93),
437(33.12), 515(89.54, M+), 517(90.18%, (M+2)+); HRMS
(EI) calcd for C28H22BrNO4 (M+, (M+2)+) 515.0732,
517.0716, found 515.0725, 517.0723.
1
Compound 2c: mp 99–101°C; H NMR (CDCl3) l 8.61
(dd, J=7.1, 2.0 Hz, 2H), 7.68–7.51 (m, 6H), 3.73 (q,
J=7.1 Hz, 2H), 3.37 (q, J=7.5 Hz, 2H), 1.56 (t, J=7.5
Hz, 3H), 0.39 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) l
180.8, 161.2, 160.2, 131.2, 131.0, 128.3, 126.7, 126.5,
125.9, 125.1, 122.8, 110.5, 60.1, 21.2, 12.9, 11.5; MS (EI)
m/z: 83(7.79), 176(10.84), 214(11.71), 253(13.43),
277(21.53),
379(100,
M+),
380(19.63%,
M+1),
381(25.86%, M+2). Anal. calcd for C22H18ClNO3: C,
69.57; H, 4.78; N, 3.69. Found: C, 69.61; H, 4.66; N,
3.88.
Compound 3c: Cubic crystals from cyclohexane: mp:
1
149–151°C; H NMR (CDCl3) l 8.54 (dd, J=7.0, 2.1 Hz,
2H), 7.61–7.29 (m, 6H), 3.63 (m, 4H), 3.24 (t, J=7.5 Hz,
2H), 0.33 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) l
178.52, 161.00, 160.10, 139.62, 131.13, 130.98, 128.59,
128.58, 128.30, 126.67, 126.61, 126.50, 125.86, 125.04,