Synthesis of a terbenzimidazole topoisomerase I poison via iterative borinate ester couplings

Article abstract of DOI:10.1016/j.tetlet.2003.10.007

A concise, efficient synthesis is described for a terbenzimidazole that acts as a potent topoisomerase I poison. The strategy involves iterative palladium-catalyzed borinate ester cross-couplings and should be applicable to the synthesis of analogs contai

Full text of DOI:10.1016/j.tetlet.2003.10.007

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8967–8969
Synthesis of a terbenzimidazole topoisomerase I poison via
iterative borinate ester couplings
Ben B. Wang and Paul J. Smith*
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
Received 2 September 2003; revised 29 September 2003; accepted 2 October 2003
Abstract—A concise, efficient synthesis is described for a terbenzimidazole that acts as a potent topoisomerase I poison. The
strategy involves iterative palladium-catalyzed borinate ester cross-couplings and should be applicable to the synthesis of analogs
containing heterocycles other than benzimidazole.
© 2003 Elsevier Ltd. All rights reserved.
DNA minor groove-binding ligands Hoechst 33258 (1)
and related terbenzimidazoles such as 2 (Fig. 1) have
been shown to be potent poisons of human topoiso-
merase I (Topo I).1,2 These also possess high levels of
activity against human tumor cell lines in culture, and
thus represent promising lead compounds for the devel-
opment of new anticancer agents. Our interest is in
constructing libraries of analogs of 2 containing 5,6-
fused aromatic heterocycles other than benzimidazole,
with the objective of identifying more effective Topo I
inhibitors. Increased activity could result from altered
DNA sequence selectivity; while compounds such as 1
and 2 bind selectively at runs of AT base pairs, this
preference can be altered by changing the hydrogen
bonding capabilities of individual heterocycles.3–5
Increased activity could also result from more favorable
ligand–protein interactions within a Topo I-DNA-lig-
and complex.
Syntheses of compounds such as 1 and 2 have typically
involved construction of the imidazole portion of benz-
imidazole units by condensation of aryl ortho-diamines
with carboxylic acid derivatives.6 This approach is
problematic with regard to libraries containing a vari-
ety of heterocycles in that an inordinately large number
of synthetic precursors would be required. As illus-
trated in Scheme 1, 1,2,4-trisubstituted benzene deriva-
tives (represented by 3) would serve as precursors.
While the functional group Z in 3 would be determined
by the desired identity of the first heterocycle in 4,
Figure 1. Hoechst 33258 and a phenylterbenzimidazole.
Scheme 1. Generalized synthetic scheme for preparation of analogs of 2 in which formation of the five-membered ring constitutes
the homologation step.
* Corresponding author. Tel.: 1-410-455-2519; fax: 1-410-455-2608; e-mail: pjsmith@umbc.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.007

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B. B. Wang, P. J. Smith / Tetrahedron Letters 44 (2003) 8967–8969
Scheme 2. Generalized synthetic scheme for preparation of analogs of 2 in which palladium-catalyzed addition of an in-tact
heterocycle constitutes the homologation step.
and 7 was then reacted with bis(pinacolato)diboron in
the presence of PdCl2(dppf) to afford 8.13
Coupling of 6 with phenylboronic acid14 followed by
deprotonation with LDA and quenching with
diiodoethane15 provided 9 (Scheme 4). Addition of the
second benzimidazole unit was accomplished by reac-
tion of 9 with 8 in the presence of Pd(PPh3)4;16 subse-
quent iodination gave 10. Coupling of 10 with 8 and
deprotection17 then yielded target compound 2.
Scheme 3. Reagents and conditions: (a) HC(OEt)3, KSF clay,
toluene, reflux, 85%; (b) BnBr, KOH, acetone, 0°C“rt, 90%;
(c) PdCl2(dppf), K2CO3, DMF, 75°C, 85%.
In conclusion, a concise iterative approach for the
synthesis of oligomeric heterocycles has been demon-
strated. Efforts are currently underway to apply this
methodology in the preparation of analogs of 2 con-
taining other heterocycles such as benzoxazole and
indole.
functional groups X% and Y% would be determined by
the desired identity of the second heterocycle in 4. As a
result, a library of 27 of analogs of 2 containing three
different heterocycles could require as many as nine
precursors (and potentially more depending on the
necessary protecting group scheme).7
References
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Lown, J. W.; Rao, K. E.; Bathini, Y. Biochim. Biophys.
Res. Acta 1992, 1131, 53–61; (b) Chen, A. Y.; Yu, C.;
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We now report an alternate approach which involves
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precursor (a metalated heterocycle) per heterocycle in
the final library, and takes advantage of the fact that
iodine can be regiospecifically introduced at the desired
position prior to each subsequent coupling.8,9
To validate this strategy, we now report the synthesis of
2 by iterative palladium-catalyzed borinate ester cou-
plings. Our synthetic approach required key intermedi-
ate 8 (Scheme 3). 5, prepared from 2-nitroaniline10,11
,
4. Lown, J. W. Advances in DNA Sequence-Specific Agents;
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was condensed with triethyl orthoformate12 and benzyl
protected to provide a mixture of 6 and 7 in a 55:45
ratio. These were separated by flash chromatography
Scheme 4. Reagents and conditions: (a) PhB(OH)2, Pd(PPh3)4, aq. 2 M Na2CO3/toluene (1:10), 75°C, 91%; (b) LDA, THF, −78°C;
ICH2CH2I, −78°C“rt, 81%, 83%, respectively; (c) 8, Pd(PPh3)4, K3PO4, DMF, 50°C, 75, 79%, respectively; (d) 60 PSI H2, 10%
Pd/C, Pd black, hexanes/DMF (1:5), 90°C, 75%.

B. B. Wang, P. J. Smith / Tetrahedron Letters 44 (2003) 8967–8969
8969
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