1,2-Disubstituted cyclohexane carbocyclic analogues of nucleosides

Article abstract of DOI:10.1081/NCN-100002556

Several compounds of a new series of cyclohexane-based 1,2-disubstituted carbonucleoside analogues, were synthesized. The adenine and uridine derivatives, were prepared by construction of the heterocyclic base on the primary amino group of 2-aminocyclohexylmethanol, and the thymine derivative by condensation of 2-hydroxycyclohexylmethanol with thymine using the Mitsunobu reaction.

Full text of DOI:10.1081/NCN-100002556

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1,2-DISUBSTITUTED CYCLOHEXANE CARBOCYCLIC
ANALOGUES OF NUCLEOSIDES
a
a
a
D. Viña , L. Santana & E. Uriarte
a
Universidad de Santiago de Compostela , Facultad de Farmacia, Spain
Published online: 07 Feb 2007.
To cite this article: D. Viña , L. Santana & E. Uriarte (2001) 1,2-DISUBSTITUTED CYCLOHEXANE CARBOCYCLIC ANALOGUES
OF NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1363-1365
To link to this article: http://dx.doi.org/10.1081/NCN-100002556
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1363–1365 (2001)
1,2-DISUBSTITUTED CYCLOHEXANE
CARBOCYCLIC ANALOGUES OF NUCLEOSIDES
∗
D. Vi n˜ a, L. Santana, and E. Uriarte
Facultad de Farmacia, Universidad de Santiago de Compostela, Spain
ABSTRACT
Several compounds of a new series of cyclohexane-based 1,2-disubstituted car-
bonucleoside analogues, were synthesized. The adenine and uridine derivatives,
were prepared by construction of the heterocyclic base on the primary amino
group of 2-aminocyclohexylmethanol, and the thymine derivative by conden-
sation of 2-hydroxycyclohexylmethanol with thymine using the Mitsunobu
reaction.
We previously reported on the synthesis of a series of 1,2-disubstituted cyclo-
pentane-based carbocyclic nucleosides (OTCs). For further evaluation of the phar-
macological effects of 1,2-disubstitution in nucleoside analogues, we have now
obtained the adenine (1), uracil (2), and thymine (3) members of the homologous
cyclohexane series. These compounds were synthesized using the two most useful
methods for preparing nucleoside analogues: either by constructing the heterocyclic
base on the appropriate substrate, or by condensation of the heterocyclic base with
the sugar or the ring taking its place.
The adenine and uracil derivatives (1 and 2) were prepared in racemic cis form
in 42% and 25% overall yields respectively starting from (± )-cis-2-aminocyclohe-
xylmethanol and constructing the purine (1) or pyrimidine (2) base on the primary
amino group asshown inScheme1. Thestarting aminoalcohol was prepared in three
steps from cyclohexene by treatment with chlorosulfonylisocyanate, hydrolysis of
the resulting lactam, and final reduction (3) (overall yield 25%).
∗
Corresponding author.
1
363
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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VINA, SANTANA, AND URIARTE
1
364
Scheme 1.
Scheme 2.

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CYCLOHEXANE CARBOCYCLIC ANALOGUES OF NUCLEOSIDES
1365
The thymine derivative (3) was synthesized in a moderate 20% unoptimized
yieldbydirectMitsunobucondensation(4)ofthymineand(± )-cis-2-hydroxycyclo-
hexylmethanolfollowingbenzoylationoftheprimaryhydroxylgroupusingbenzoyl
chloride, as shown in Scheme 2. The diol was prepared by NaBH reduction of ethyl
4
2-oxocyclohexanecarboxylate (5).
An extensive series of cyclohexane-based OTCs is currently being synthesized
for pharmacological evaluation.
ACKNOWLEDGMENT
We thank the Spanish Ministry of Science and Tecnology (PM990125) and
the Xunta de Galicia (PGIDT00PX120317PR) for financial support.
REFERENCES
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Katagiri, N.; Nomura, M.; Sato, H.; Kaneko, C.; Yusa, K.; and Tsuro, T. J. Med. Chem.,
992, 35, 1882–1886.
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Hronowski, L. J. J. and Szarek, W. A. Can. J. Chem., 1985, 63, 2787–2797.
Bernath, G.; Lang, K. L.; Gondos, G. Y.; Marai, P.; Kovacs, K. Acta Chim. Hung., 1972,
74, 479–497.
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Girard, F.; Lee, M. G.; Agrofogio, L. A. J. Heterocyclic Chem., 1998, 35, 911–913.
Theil, F.; and Ballschuh, S. Tetrahedron Asymetry, 1996, 7, 3565–3572.

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