Synthesis and structural study of pyrimidyl carbocyclic analogues of nucleosides based on cyclopentene rings

Article abstract of DOI:10.1081/NCN-100002477

A series of 1,2-disubstituted carbonucleoside analogues of pyrimidine and 5-halopyrimidines with the unsaturated carbocycle cyclopentene was synthesized. AIM theory was applied to analyse the conformational and electronic effects of 5-halogenation.

Full text of DOI:10.1081/NCN-100002477

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SYNTHESIS AND STRUCTURAL STUDY OF PYRIMIDYL
CARBOCYCLIC ANALOGUES OF NUCLEOSIDES BASED
ON CYCLOPENTENE RINGS
C. Terán a , M. J. González Moa a , R. Mosquera a & L. Santana b
a Vigo University , Vigo, Spain
b University of Santiago de Compostela , Santiago de Compostela, Spain
Published online: 07 Feb 2007.
To cite this article: C. Terán , M. J. González Moa , R. Mosquera & L. Santana (2001) SYNTHESIS AND STRUCTURAL STUDY
OF PYRIMIDYL CARBOCYCLIC ANALOGUES OF NUCLEOSIDES BASED ON CYCLOPENTENE RINGS, Nucleosides, Nucleotides and
Nucleic Acids, 20:4-7, 999-1002, DOI: 10.1081/NCN-100002477
To link to this article: http://dx.doi.org/10.1081/NCN-100002477
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 999–1002 (2001)
SYNTHESIS AND STRUCTURAL STUDY OF
PYRIMIDYL CARBOCYCLIC ANALOGUES
OF NUCLEOSIDES BASED ON
CYCLOPENTENE RINGS
C. Tera´n,1,∗ M. J. Gonza´lez Moa,1 R. Mosquera,1 and L. Santana2
1Vigo University, Vigo, Spain
2University of Santiago de Compostela, Santiago de Compostela, Spain
ABSTRACT
A series of 1,2-disubstituted carbonucleoside analogues of pyrimidine and
5-halopyrimidines with the unsaturated carbocycle cyclopentene was synthe-
sized. AIM theory was applied to analyse the conformational and electronic
effects of 5-halogenation.
In continuance with our study of carbocyclic analogues of nucleosides (CANs)
having a five-membered carbocycle bearing the base and hydroxymethyl group at
adjacent positions (1), we have prepared racemic mixtures of cis-pyrimidyl and
cis-5-halopyrimidyl derivatives with a double bond between positions 2 and 3 of
the carbocycle (Scheme 1).
The starting material ( )-6-azabicyclo[3.2.0]hept-3-en-7-one (1) was ob-
tained by 2 + 2 cycloaddition of cyclopentadiene (2 mol) to chlorosulfonyl
isocyanate (1 mol) in dry ethyl ether at −60◦C. Transformation of 1 into the uri-
dine analogue 4 was achieved in three steps with an overall yield of 31%, the
key step being the reductive opening of the amide bond of 1 using an open-chain
uracil precursor as the requisite electron-withdrawing N substituent (2). Treatment
of 1 with 3-methoxyacryloyl isocyanate in dry benzene afforded the correspond-
ing carbamoyl derivative 3. Reduction of 3 with excess NaBH4 in methanol and
∗Corresponding author.
999
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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TERAN ET AL.
1000
Scheme 1. a: 3-methoxyacryloyl isocyanate, benzene, 60◦C, 3 h (60%); b: NaBH4, MeOH, r.t.
20 min (74%); c: H2SO4 2 M, reflux, 3 h (68%); d: NCS, DMF, r.t. 24 h (41%); NBS, DMF, r.t. 1 h
(52%); NIS, AcOH, 80◦C, 8 h (29%).
subsequent acidic ring closure afforded the desired pyrimidyl CAN 4. Position 5 of
the uracil ring was then halogenated with NXS (X = Cl, Br, I). Chlorination (to 5,
41%) and bromination (to 6, 52%) being carried out at room temperature in DMF
and iodination (to 7, 29%) at 80◦C in acetic acid.
Computations carried out to compare the structures of the unhalogenated com-
pound 4 and the 5-fluoro derivative afforded very similar results for both molecules
at both AM1 and HF/6–31G∗ levels. In all cases essentially the same 18 con-
formers were found ranked in the same order by energy. In all these conformers
the cyclopentene ring adopts the envelope form, thus maximizing the distance be-
tween the base and the carbon bearing the hydroxymethyl group (C2ꢁ). In the most
stable conformer (Fig. 1) the hydroxyl group is hydrogen-bonded to the uracil
O2 oxygen; the most significant dihedral angles are 267,0◦ for C2-N1-C1ꢁ-C2ꢁ,
197,7◦ for O6ꢁ-C6ꢁ-C2ꢁ-C3ꢁ and 295,8◦ for H-O6ꢁ-C6ꢁ-C2ꢁ. The electronic effects of

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PYRIMIDYL CARBOCYCLIC ANALOGUES
1001
Figure 1.
5-halogenation were examined by applying AIM theory (3), using HF/6–31 ++ G∗∗
wave functions of the most stable conformer of compound 4 and their 5-fluoro and
5-chloro derivatives. The computed bond and integrated atomic properties indicate
that 5-halogenation does not give rise to any significant modification of the elec-
tronic properties of the cyclopentene ring. Main changes in electron distribution
are localized on atoms C4, C5 and C6; whereas H6, O4 and N1 exhibit smaller,
though significant, variations (Table 1).
The electron population in the C5 region is depleted ( ꢀN (ꢁ) negative values)
andmorespace-localized(negativerelativevaluesofthefirstmomentoftheelectron
population, r (1), volume, v; and Shannon entropy (4), Sh) upon 5-halogenation.
The positive ꢀN (C5) value obtained for the chlorinated compound can be inter-
preted as due to the reorganization of the interatomic surfaces after halogenation
which results in an electron charge transfer to C5 from the remaining neighboring
Table 1. Most Important Varitation of the Atomic Properties Due to 5-Halogenation of Compound
4. Clꢁ is Included Because it is the Most Affected Atom of the Cyclopentene Ring
103ꢀN(ꢁ)/a.u. 102ꢀr1(ꢁ)/a.u. ꢀv(ꢁ)/cm3mol−1
ꢀSh(ꢁ)
f-h cl-h
ꢀE(ꢁ)/Kcalmol−1
ꢁ
f-h
cl-h
f-h
cl-h
f-h
cl-h
f-h
cl-h
O4
C4
−24
−79
−13
−68
23
−6
−15
−86
−24
−4
−4
−12
−4
−24
−4
−1
2
−2.5
−1.8
−21.8
−2.6
−1.0
−0.4
0.3
−2.5
−1.7
−12.5
−5.0
−1.3
−0.2
0.3
−0.01 −0.01
−0.06 −0.05
15.8
27.0
33.1
40.5
11.4
40.5
7.5
C5 −485
−0.28 −0.02 181.7
C6 −119 −120
−0.06 −0.07
−0.02 −0.04
27.0
10.3
3.0
H6
N1
C1ꢁ
−28
−11
5
−26
−6
11
−2
0.00
0.00
0.00
0.01 −4.7
13.9
4.9
1

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1002
atoms. It has been also found as on important destabilization of C5, C6, C4 and H6
atoms.
ACKNOWLEDGMENT
We thank the DGESIC (PM 99-0125) for financial support.
REFERENCES
1. Besada P.; Tera´n C.; Santana L.; Teijeira M.; Uriarte E. Nucleosides & Nucleotides,
1999, 18 (4&5), 725–726.
2. Katagiri, N.; Muto, M.; Nomura, M.; Higashikawa, T.; Kaneko, Ch. Chem. Pharm.
Bull., 1991, 39 (5), 1112–1122.
3. Bader, R. F. W. Atoms in Molecules-A Quantum Theory; International series of
monographs on Chemistry, n◦ 22, Oxford University Press, Oxford 1990. Bader
R. F. W. Chem. Rev., 1991, 893–928.
4. Hoˆ, M.; Smith, V. H.; Gatti, D. F.; Sagor R. P.; Esquivel R. O. J. Chem. Phys., 1998,
108, 5469–5475.

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