Synthesis of rigid homo- and heteroditopic nucleobase-terminated molecules incorporating adenine and/or thymine

Article abstract of DOI:10.1021/ol071006x

A series of homo- and heteroditopic thymine- and/or adenine-terminated molecules incorporating rigid aryl or oligo(phenylene ethynylene) linkers has been efficiently synthesized. The key steps involved in the synthesis are the construction of the N-arylated nucleobases using the Chan-Lam-Evans-modified Ullman coupling and their further elaboration using the Sonogashira coupling. Furthermore, the synthesis of a rigid tripodal thymine derivative is reported.

Full text of DOI:10.1021/ol071006x

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2851-2854
Synthesis of Rigid Homo- and
Heteroditopic Nucleobase-Terminated
Molecules Incorporating Adenine and/or
Thymine
Mikkel F. Jacobsen, Casper S. Andersen, Martin M. Knudsen, and
Kurt V. Gothelf*
Centre for DNA Nanotechnology, Department of Chemistry, UniVersity of Aarhus,
Langelandsgade 140, 8000 Aarhus C, Denmark
kVg@chem.au.dk
Received April 30, 2007
ABSTRACT
A series of homo- and heteroditopic thymine- and/or adenine-terminated molecules incorporating rigid aryl or oligo(phenylene ethynylene)
linkers has been efficiently synthesized. The key steps involved in the synthesis are the construction of the N-arylated nucleobases using the
Chan−Lam−Evans-modified Ullman coupling and their further elaboration using the Sonogashira coupling. Furthermore, the synthesis of a
rigid tripodal thymine derivative is reported.
The high fidelity observed in the base-pairing between
complementary DNA strands allows for the predetermined
formation of artificial nanostructures.1 In addition, a wide
range of artificial nucleobase derivatives has been employed
in the creation of supramolecular self-assemblies using
molecular recognition via base-pairing.2 Even though the
Watson-Crick mode of bonding is prevalent in natural
systems, e.g., DNA double helices, other hydrogen-bonding
motifs are available and expand the possibility for creation
of different structural networks. In this respect, previous
studies have revealed that simple mixtures of adenine and
thymine can form well-ordered supramolecular nanopatterns
on surfaces featuring a unique hydrogen-bonding setup based
on reverse Hoogsteen A-T-A-T quartets adjacent to
homochiral chains of adenine duplets.3 Furthermore, several
homo- and heteroditopic nucleobase derivatives (bolaam-
phiphiles) have been demonstrated to spontanously homo-
and heteroassemble to form well-defined supramolecular
fibers.4 Therefore, the ability to create artificial polymeric
systems incorporating several nucleobase moieties can serve
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10.1021/ol071006x CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

Scheme 1. Synthesis of Short Thymine-Thymine Derivative 1
Scheme 2. Synthesis of the Tripodal Thymine Derivative 11
and Boronic Acid 7
as a means to study their inter- and intramolecular hydrogen-
bonding properties and gain further insight into the mech-
anisms behind the assembly of complementary DNA strands.
Our continued interest in DNA structures, including its
use for controlling chemical reactivity and creating self-
assembled nanostructures,5 controlling photosensitized pro-
cesses,6 and detection of DNA,7 has driven us to create an
efficient methodology for the synthesis of N-arylated and
N-alkenylated nucleobases employing the Chan-Lam-
Evans-modified Ullmann coupling.8 Thus, the N-arylated and
N-alkenylated nucleobases are obtained via the direct cou-
pling of protected or masked nucleobase derivatives with
alkenyl or aryl boronic acids. We envisaged that such
artificial molecules incorporating both multiple nucleobases
and an extended rigid aromatic system may be suitable for
the controlled formation of supramolecular structures. Such
structures may be formed on surfaces by Watson-Crick and
other types of hydrogen bonding between the bases or in
solution by a combination of hydrogen bonding and π-stack-
ing. In another application such structures may interact with
DNA strands and form extended helices by Watson-Crick
base pairing in analogy with the structures reported by Iwaura
et al.9
As a starting point in this realm, we now report on the
synthesis of a series of novel rigid aryl or oligo(phenylene
ethynylene) structures connected via bisaryl-like linkages to
multiple nucleobase moieties.
(4) (a) Iwaura, R.; Yoshida, K.; Mitsutoshi, M.; Yase, K.; Shimizu, T.
Chem. Mater. 2002, 14, 3047. (b) Shimizu, T.; Iwaura, R.; Masuda, M.;
Hanada, T.; Yase, K. J. Am. Chem. Soc. 2001, 123, 5947. (c) Iwaura, R.;
Minamikawa, H.; Shimizu, T. J. Colloid Interface Sci. 2004, 277, 299. (d)
Shimizu, T.; Masuda, M.; Minamikawa, H. Chem. ReV. 2005, 105, 1401.
(e) Fuhrhop, J.-H.; Wang, T. Chem. ReV. 2004, 104, 2901. (f) Shimizu, T.
Macromol. Rapid Commun. 2002, 23, 311. (g) Shimizu, T.; Masuda, M. J.
Am. Chem. Soc. 1997, 119, 2812. (h) Itojima, Y.; Ogawa, Y.; Tsuno, K.;
Handa, N.; Yanagawa, H. Biochemistry 1992, 31, 4757.
(5) (a) Gothelf, K. V.; Thomsen, A. H.; Nielsen, M.; Clo´, E.; Brown, R.
S. J. Am. Chem. Soc. 2004, 126, 1044. (b) Nielsen, M.; Thomsen, A. H.;
Clo´, E.; Kirpekar, F.; Gothelf, K. V. J. Org. Chem. 2004, 69, 2240. (c)
Brown, R. S.; Nielsen, M.; Gothelf, K. V. Chem. Commun. 2004, 1464.
(d) Gothelf, K. V.; LaBean, T. H. Org. Biol. Chem. 2005, 3, 4023. (e)
Gothelf, K. V.; Brown, R. S. Chem. Eur. J. 2005, 11, 1062. (f) Nielsen,
M.; Dauksaite, V.; Kjems, J.; Gothelf, K. V. Bioconjugate Chem. 2005,
16, 681.
At the outset, we aimed for the synthesis of a short
conjugated T-T derivative 1, in which the two thymine
moieties are separated only by one benzene ring, which was
accomplished by two sequential Chan-Lam-Evans reactions
(Scheme 1). The previously described N3-benzoyl thymine
29 was converted to N-aryl derivative 3 as previously
described.8 By subjecting 3 to the modified Miyuara protocol
the aryl pinacolboronate 4 was obtained in good yield.10 The
efficient hydrolysis of pinacolboronates can be troublesome.
However, the recently described method employing a solid-
(6) Clo´, E.; Snyder, J. W.; Voigt, N. V.; Ogilby, P. R.; Gothelf, K. V. J.
Am. Chem. Soc. 2006, 128, 4200.
(7) Hansen, J. A.; Mukhopadhyay, R.; Hansen, J. Ø.; Gothelf, K. V. J.
Am. Chem. Soc. 2006, 128, 3860.
(8) Jacobsen, M. F.; Knudsen, M. M.; Gothelf, K. V. J. Org. Chem.
2006, 71, 9183.
(9) Frieden, M.; Giraud, M.; Reese, C. B.; Song, Q. J. Chem. Soc., Perkin
Trans. 1 1998, 2827.
(10) Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 1999, 68, 3729.
2852
Org. Lett., Vol. 9, No. 15, 2007

Scheme 3. Synthesis of Oligo(phenylene ethynylene) Linkers
17 and 19
Scheme 4. Completion of T-T (20), A-A (21), and A-T
(24) Derivatives
supported boronic acid in a transesterification reaction
gratifyingly afforded the required boronic acid 5,11 which
was used without further purification in excess in the Chan-
Lam-Evans reaction with 2 to yield the protected T-T
derivative 6. Facile removal of the Bz-protection groups was
accomplished with methanolic hydrazine to yield the desired
T-T derivative 1.
The notorious low solubility of the parent nucleobases in
organic media necessitates the careful design of molecules
incorporating multiple nucleobase moieties. Although 1 has
some solubility in organic solvents (alcohols, DMF, DMSO),
we worried that a longer oligo(phenylene ethynylene) linker
may lower the solubility even further. Therefore, we chose
a design in which either PEG or alkyl side chains are
incorporated. The introduction of alkyl side chains has been
extensively used in the synthesis of large oligo(phenylene
ethynylene) networks in order to improve the solubility in
organic media.12
purposes. With 8 in hand, we aimed for the preperation of a
tripodal thymine derivative 11. To our delight, the triple
Sonogashira reaction of 8 with 1,3,5-triethynylbenzene
provided the star-shaped trimeric derivative 12 in reasonable
yield.14 The deprotection of 12 was accomplished with
methanolic hydrazine to yield 11, which has a considerably
improved solubility profile compared to 1 in organic media
such as CH2Cl2.
A series of nucleobase derivatives incorporating oligo-
(phenylene ethynylene) linkers were now synthesized. The
required linkers for the creation of T-T, A-A, and A-T
derivatives were prepared as outlined in Scheme 3. The
tetrabromo compound 1315 was subjected to reaction with
the in situ prepared sodium alkoxide from 2-methoxyethanol
to afford 14. By the right choice of conditions, 14 could be
converted to either the symmetrical or unsymmetrical oligo-
(phenylene ethynylene) structures 15 or 16, respectively, via
Sonogashira couplings with 2-methylbut-3-yn-2-ol. The
symmetrical oligo(phenylene ethynylene) 15 was deprotected
at both ends by treatment with KOH to yield 17. Bromide
16 was further subjected to a Sonogashira reaction to afford
18 with two orthogonal protection groups, and the 1,1-
dimethylpropargylic alcohol protection was removed using
NaOH providing 19.16
Thus, 2 was reacted with excess of crude boronic acid 7
having two C6-alkyl chains to afford 8 in good yield (Scheme
2). The boronic acid was easily synthesized from the known
symmetrical diiodide 9 by borate trapping of the mono-
organolithium species.13 The boronic acid 7 could be further
converted to the pinacol boronic ester 10 for characterization
(11) Pennington, T. E.; Kardiman, Hutton, C. C. A. Tetrahedron Lett.
2005, 45, 6657.
(12) Tour, J. M. Molecular Electronics: Commercial Insights, Chemistry,
DeVices, Architecture and Programming; World Scientific Publishing:
Singapore, 2003.
(14) (a) Negishi, E.-I. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: New York, 2002. (b) Thorand, S.;
Krause, N. J. Org. Chem. 1998, 63, 8551.
(15) Bonifacio, M. C.; Robertson, C. R.; Jung, J.-Y.; King, B. T. J. Org.
Chem. 2005, 70, 8522.
(13) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
Org. Lett., Vol. 9, No. 15, 2007
2853

The symmetrical oligo(phenylene ethynylene) 17 was
subsequently used in the formation of the symmetrical T-T
and A-A nucleobase derivatives 20 and 21, respectively,
by subjecting it to a double Sonogashira reaction with either
3 or adenine derivative 228 (Scheme 4). The T-T derivative
20 was obtained in good overall yield following a smooth
deprotection step in methanolic hydrazine. On the other hand,
the last deprotection step in the formation of A-A derivative
21 required prolonged heating with methanolic KOH to
remove the four Boc-groups.17 Conventional deprotection by
treatment with TFA was not successful.18
In summary, we have prepared a series of novel rigid
thymine and adenine homo- and heteroditopic nucleobase
derivatives and a tripodal thymine derivative using a
combination of the Chan-Lam-Evans-modified Ullmann
coupling and the Sonogashira reaction. Further efforts in our
laboratories are now directed toward broadening the scope
of the synthetic methodology and studies of the abilities of
such nucleobase derivatives to form homo- and hetero-
assemblies in solution and on surfaces and to interact with
DNA.
In the same vein, the unsymmetrical oligo(phenylene
ethynylene) 19 was subjected to a sequence of Sonogashira
reactions and deprotection steps (Scheme 4). The first
Sonogashira reaction of 19 with N-arylated adenine 22 to
yield 23 was followed by removal of the TIPS-group with
TBAF, a second Sonogashira reaction with thymine deriva-
tive 3, and deprotection with KOH providing the heterodi-
topic A-T derivative 24.
Acknowledgment. Financial support for this work by
Danish Technical Research Council, the Danish National
Research Foundation Centers: Centre for DNA Nanotech-
nology and Center for Catalysis, and the Carlsberg Founda-
tion is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. UV spectra of products 1, 11, 20, 21, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Swindell, C. S.; Fan, W.; Klimko, P. G. Tetrahedron Lett. 1994,
35, 4959.
(17) Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697.
(18) In general, treatment with strong acids may lead to degradation of
any alkyne moieties present.
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