Novel macrocycles derived from nucleosides

Article abstract of DOI:10.1081/NCN-100002552

A novel nucleoside-derived macrocycle formed from three thymidine 5′-carboxylic acid monomer units is described.

Full text of DOI:10.1081/NCN-100002552

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NOVEL MACROCYCLES DERIVED FROM NUCLEOSIDES
Noelia Calcerrada-Muñoz a , Ian O'Neil a & Richard Cosstick b
a Department of Chemistry , University of Liverpool , Crown Street, Liverpool, L69 7ZD,
United Kingdom
b Department of Chemistry , University of Liverpool , Crown Street, Liverpool, L69 7ZD,
United Kingdom
Published online: 07 Feb 2007.
To cite this article: Noelia Calcerrada-Muñoz , Ian O'Neil & Richard Cosstick (2001) NOVEL MACROCYCLES DERIVED FROM
NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1347-1350, DOI: 10.1081/NCN-100002552
To link to this article: http://dx.doi.org/10.1081/NCN-100002552
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1347–1350 (2001)
NOVEL MACROCYCLES DERIVED FROM
NUCLEOSIDES
Noelia Calcerrada-Mun˜oz, Ian O’Neil, and Richard Cosstick∗
Department of Chemistry, University of Liverpool, Crown Street,
Liverpool L69 7ZD, United Kingdom
ABSTRACT
A novel nucleoside-derived macrocycle formed from three thymidine 5ꢀ-car-
boxylic acid monomer units is described.
Although cyclic oligonucleotides had previously been isolated as by-products
in oligonucleotide condensation reactions, the direct synthesis of cyclic oligonu-
cleotides attracted attention in the early 1980s. In particular Hsu et al. described the
synthesis of cyclic diribonucleotides such as r(cUpUp), r(cApAp) and r(cApUp)
and reported that these cyclic ribonucleotides act as inhibitors of DNA dependent
E. coli RNA polymerase (1,2). The synthesis of longer cyclic nucleotides has been
facilitated by the use of polyethylene glycol (PEG) as soluble polymer support (3)
and new approaches to solid-phase synthesis (4). More recently circular oligonu-
cleotides have been shown to bind very strongly to single-stranded nucleic acids
through formation of a triple helical complex (5).
We now describe our first efforts towards the synthesis of a nucleoside-derived
macrocycle (1, Fig. 1) formed from three thymidine 5ꢀ-carboxylic acid monomer
units (2).
Modelling studies have shown that this 12-membered lactone ring forms a rel-
atively strain free system with the carbonyl groups of the ester bonds well disposed
to co-ordinate metal ions. Additionally, hydrogen bonding interactions between the
complementary nucleobases potentially allows for the formation of supramolecular
complexes.
∗Corresponding author. E-mail: rcosstic@liverpool.ac.uk
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Copyright 2001 by Marcel Dekker, Inc.
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CALCERRADA-MUNOZ, O’NEIL, AND COSSTICK
Figure 1.
For the synthesis of the hydroxy acid monomers, oxidation of 3ꢀ-O-t-but-
yldimethylsilylthymidine was accomplished in two steps. An initial Moffat oxida-
tion to give the aldehyde was followed by treatment with NaClO2 in the presence of
KH2PO4 and2-methyl-2-buteneinaqueoust-butanol, togivethehydroxy-protected
acid (3), which would serve as one of the building blocks for synthesis of the linear
trimer (Fig. 2). The benzhydryl protected monomer (4) was prepared by alkyla-
tion with diphenyldiazomethane and subsequent desilylation with triethylamine
trihydrogen fluoride.
Figure 2. Reagents and Conditions i) Dicyclohexylcarbodiimide, dichloroacetic acid, dimethylsul-
foxide; ii) NaClO2, H2O, t-butanol, iii) diphenyldiazomethane in acetone; iv) NEt3 · 3HF in THF;
v) HBTU, hydroxybenzotriazole, diisopropyldiethylamine in CH3CN.

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MACROCYCLES DERIVED FROM NUCLEOSIDES
1349
Figure 3.
In the key ester-forming reaction between the monomers 3 and 4 to gener-
ate the fully protected dimer (5), an extensive range of condensing agents was
investigated. Most success was achieved using O-benzotriazol-1-yl-N,N,Nꢀ,Nꢀ-
tetramethyluronium hexaflurophosphate (HBTU) (6). This commercially available
condensing reagent, originally developed for peptide synthesis, gave the dimer in
95% yield. The linear trimer (6) was obtained by removal of the benzhydryl group
from the dimer followed by a further condensation reaction with monomer (4) and
subsequent deprotection (NEt3 · 3HF, H2/Pd). Although this linear trimer was fully
characterised it was found to be unexpectedly susceptible to hydrolysis/transester-
ification, which greatly hindered its isolation.
Our attempts to perform the cyclisation step (Fig. 3) with HBTU, which
had proved very effective in the synthesis of the linear esters, were unsuccessful.
However, activation with 2,4,6-trichlorobenzoyl chloride (7) (Yamaguchi’s reagent)
in THF followed by dilution into a solution of N,N-dimethylaminopyridine in
toluene gave a mixture of products, from which the cyclic trimer (1) was identified
by LC/MS. A pseudomolecular ion of 713.3 was observed in the electrospray
spectrum corresponding to M−.
In conclusion, an efficient synthesis of the thymidine-derived hydroxy acid
monomers has been developed and HBTU has proved very effective in condensing
these monomer units. Cyclisation has been achieved using Yamaguchi’s reagent
although the macrolactonisation procedure requires further optimisation.
ACKNOWLEDGMENTS
We would like to thank Bridget Stein at the EPSRC service at Swansea for
obtaining mass spectra.

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CALCERRADA-MUNOZ, O’NEIL, AND COSSTICK
REFERENCES
1. Hsu, C.J.; Dennis, D.; Jones, R.A. Nucleosides and Nucelotides, 1985, 4, 377.
2. Hsu, C.J.; Dennis, D, Nucleic acids Res., 1982, 10, 5637.
3. De Napoli, L.; Messere, A.; Montesarichio, D.; Picciali, G.; Santaccroe Nucleosides
and Nucelotides, 1993, 12, 21.
4. Frienden, M.; Grandas, A.; Pedroso E. J. Chem. Soc. Chem. Commun., 1999, 1593.
5. Kool, E.T. Acc. Chem. Res., 1998, 502.
6. Albericio, F.; Carpino, L.A. Methods in Enzymology, 1997, 289, 104.
7. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jap.,
1979, 52, 1989; Hikota, M.; Horita, K.; Yonemitsu, O. J. Org. Chem., 1990, 55, 7.

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