Synthesis of carbocyclic analogues of thymidine

Article abstract of DOI:10.1081/NCN-120022700

A new route towards an enantiomerically pure carbocyclic 2′-deoxyribonucleoside precursor was developed. After coupling with a nucleobase the product is easily accessible for further modifications at the 3′-hydroxy group.

Full text of DOI:10.1081/NCN-120022700

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Nucleosides, Nucleotides and Nucleic Acids
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Synthesis of Carbocyclic Analogues of Thymidine
O. R. Ludek a & C. Meier a b
a Institute of Organic Chemistry , University of Hamburg , Hamburg, Germany
b Universität Hamburg, Institut für Organische Chemie , Martin-Luther-King-Platz 6, D-20146,
Hamburg, Germany
Published online: 31 Aug 2006.
To cite this article: O. R. Ludek & C. Meier (2003) Synthesis of Carbocyclic Analogues of Thymidine, Nucleosides, Nucleotides
and Nucleic Acids, 22:5-8, 683-685, DOI: 10.1081/NCN-120022700
To link to this article: http://dx.doi.org/10.1081/NCN-120022700
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 683–685, 2003
Synthesis of Carbocyclic Analogues of Thymidine
*
O. R. Ludek and C. Meier
Institute of Organic Chemistry, University of Hamburg,
Hamburg, Germany
ABSTRACT
A new route towards an enantiomerically pure carbocyclic 20-deoxyribonucleo-
side precursor was developed. After coupling with a nucleobase the product is
easily accessible for further modifications at the 30-hydroxy group.
INTRODUCTION
Nucleoside-based inhibitors of reverse transcriptase (RT) were the first drugs to
be used in the chemotherapy of AIDS. After entering the cell, these substances
should be activated to their triphosphates by cellular kinases. Thus, for the most
extensively used drug, 30-azido-30-deoxythymidine (AZT), whereas phosphorylation
is facile, the product (AZTMP) is a very poor substrate for the second kinase,
thymidylate kinase (TmpK). Due to the steric demand of the azido group in the
30-position of AZTMP compared to the 30-hydroxyl group of the natural substrate,
20-deoxythymidine monophosphate (dTMP), the structure of the enzyme changes,
which causes a 200-fold decrease in the rate of phosphorylation.[1] Docking
experiments, performed on the basis of molecular modelling, led to the assumption
that carbocyclic nucleotide analogues of AZTMP should still bind well to the active
*Correspondence: C. Meier, Universita¨t Hamburg, Institut fur Organische Chemie,
¨
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany; Fax: +49 404 2838 2495; E-mail:
chris.meier@chemie.uni-hamburg.de.
683
DOI: 10.1081/NCN-120022700
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

684
Ludek and Meier
site of TmpK. Due to the increased flexibility these nucleotides should not cause a
structural change of the enzyme. Here, we will present the enantioselective synthesis
of carbocyclic analogues of thymidine as well as the corresponding monophosphates
by using a convergent synthetic strategy. The carbocyclic moiety is coupled to the
heterocyclic base to obtain carbocyclic thymidine (carba-dT) 6 as a key intermediate
for further variations in the 30-position.
RESULTS
In our search for a short and efficient convergent synthesis towards carbocyclic
20-deoxythymidine 6, we were attracted by the simplicity of forming the carbocyclic
moiety in two stages using the method of Biggadike et al.[2]. The two stereogenic
centers in 1 are introduced by an asymmetric hydroboration of a substituted cyclo-
pentadiene, prepared from cyclopentadiene. After protecting the free hydroxygroup
in 1 with the benzyl group, the chiral olefin 2 can be hydroborated regio- and stereo-
selective using 9-BBN in THF affording the b-alcohol 3 in 87% yield. The b-alcohol
3 can easily be transferred into the desired a-alcohol 4 by a Mitsunobu reaction.
The coupling of the carbocyclic precursor 4 and the nucleobase was also achieved
by a Mitsunobu reaction, using N3-benzoylthymidine as the nucleophile.[3] Removal
of the protection groups afforded enantiomerically pure carbocyclic thymidine 6 in
15% overall yield.

Carbocyclic Analogues of Thymidine
685
The free hydroxy groups in carba-dT 6 can now be replaced by groups isoster to
the azido group in order to investigate the sterical and=or electronical influence of
the substituent in this position on the substrate properties towards thymidylate
kinase.
REFERENCES
1. Lavie, A.; Schlichting, I.; Vetter, I.R.; Konrad, M.; Reinstein, J.; Goody, R.S.
Nature Med. 1997, 3, 922.
2. Biggadike, K.; Borthwick, A.D.; Evans, D.; Exall, A.M.; Kirk, B.E.; Roberts,
S.M.; Stephenson, L.; Youds, P. J. Chem. Soc., Perkin Trans. 1 1988, 549.
3. Bonnal, C.; Chavis, C.C.; Lucas, M. J. Chem. Soc., Perkin Trans. 1 1994, 1401.