ORGANIC
LETTERS
2001
Vol. 3, No. 20
3209-3210
“Fleximers”. Design and Synthesis of
Two Novel Split Nucleosides
Katherine L. Seley,* Liang Zhang, and Asmerom Hagos
School of Chemistry and Biochemistry, Georgia Institute of Technology,
Atlanta, Georgia
Received August 7, 2001
ABSTRACT
A new class of shape-modified nucleosides is introduced. The purine heterobases of adenosine and guanosine have been split into their
imidazole and pyrimidine components, thereby introducing flexibility while retaining the elements necessary for recognition. As a consequence,
these novel “fleximers” should find use as bioprobes for investigating enzyme−coenzyme binding sites as well as nucleic acid and protein
interactions. Their design and synthesis is described.
Purines are one of the most ubiquitous heterocyclic ring
systems found in nature; they are components in numerous
biologically significant molecules and thus present an excel-
lent scaffold for the construction of bioprobes. Pioneering
work in this area by Leonard employed expanded purines
such as his lin-, prox-, and dist-benzo nucleosides.1,2 In some
cases the analogues showed biological activity, however, not
significant enough for the compounds to serve as prototypes
for drug design based solely on enzyme inhibition. This
limitation may have been due to their inherent rigidity;
enzyme/substrate recognition is a “lock and key” relationship,
thus the more flexible the “key”, the more adaptable it can
be at fitting into a variety of “locks”.
One focus for our research involves the design and
synthesis of novel shape-modified nucleosides for studies
into the fundamental aspects of nucleic acid structure,
function, and recognition. As an extension of Leonard’s
work, we have designed a series of innovative nucleoside
“fleximers” (as in 1 and 2), which possess a purine ring split
into the imidazole and pyrimidine components. Analogous
to Leonard’s dist-benzo analogues, the rings remain con-
nected by a single 1.5 Å carbon-carbon bond at the C-5 of
the imidazole and the C-6 of the pyrimidine rings.3,4 As a
result, these novel “fleximers” will provide a unique perspec-
tive in studies of nucleic acid interactions.
Synthesis of the fleximers was envisioned from a tricyclic
nucleoside containing a thiophene spacer ring.5 As shown
in Scheme 1, 4,5-dibromoimidazole (3) was coupled6 to the
commercially available tetraacetate-protected ribose using
bis(trimethylsilyl)acetamide (BSA) and trimethylsilyltriflate
(TMSOTf). Removal of the labile acetate groups and
subsequent conversion to more stable benzyl ethers was
accomplished with a modified benzylation procedure7 to give
4 in a 60% overall yield from 3. Grignard treatment of 4
with ethylmagnesium bromide and dimethylformamide pro-
duced aldehyde 5, which was then converted to oxime 6
(80% from 4). Dehydration of 6 provided nitrile 7 (90%).
(3) Synthesis of the prox-benzo isomers is presently underway.
(4) For the closest nucleoside structure, see: Van Calenbergh, S.; De
Bruyn, A.; Schraml, J.; Blaton, N.; Peeters, O.; De Keukeleire, D.; Busson,
R.; Herdewijn, P. Nucleosides Nucleotides 1997, 16, 291.
(5) Seley, K. L.; Januszczyk, P.; Hagos, A.; Zhang, L.; Dransfield, D. J.
Med. Chem. 2000, 43, 4877.
(6) Koshkin, A. A.; Singh, S. K.; Nielsen, P.; Rajwanshi, V. K.; Kumar,
R.; Meldgaard, M.; Olsen, C. E.; Wengel, J. Tetrahedron 1998, 54, 3607.
(7) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett.
1976, 17, 3535.
(1) Leonard, N. J. Acc. Chem. Res. 1982, 15, 128.
(2) Leonard, N. J.; Hiremath, S. P. Tetrahedron 1986, 42, 1917.
10.1021/ol0165443 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/13/2001
Seley
