Regioselective modification of the sugar moiety in pyrimidine nucleosides via a 4',5'-dehydro-2',3'-anhydrouridine intermediate

Article abstract of DOI:10.1039/a905608d

3'-Substituted pyrimidine nucleoside derivatives are obtained in moderate to high yields by the reaction of 1-(2',3'-anhydro-5'-deoxy -4',5'-didehydro-α-L-erythro-pentofuranosyl)uracil with nucleophiles without the formation of the corresponding 2'-adduct

Full text of DOI:10.1039/a905608d

Regioselective modification of the sugar moiety in pyrimidine nucleosides via a
4A,5A-dehydro-2A,3A-anhydrouridine intermediate
Kosaku Hirota,* Hideki Takasu, Yoshie Tsuji and Hironao Sajiki
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585, Japan.
E-mail: hirota@gifu-pu.ac.jp
Received (in Cambridge, UK) 12th July 1999, Accepted 9th August 1999
3A-Substituted pyrimidine nucleoside derivatives are ob-
tained in moderate to high yields by the reaction
of 1-(2A,3A-anhydro-5A-deoxy-4A,5A-didehydro-a-l-erythro-
pentofuranosyl)uracil with nucleophiles without the forma-
tion of the corresponding 2A-adduct.
4A,5A-didehydro-a-l-erythro-pentofuranosyl)uracil 6 and 5A-
iodo-3A-methoxy derivative 7, were prepared. The epoxide 6
reacted regioselectively with MeONa to give the corresponding
3A-adduct 5a in 80% yield via regiospecific nucleophilic attack
of the methoxide anion at the highly reactive allylic 3A-position
of 6. On the other hand, only 2A,5A-anhydro derivative 8 was
accessible from 5A-iodo-3A-methoxy derivative 7 without the
formation of 5a (Scheme 1).
Nucleosides modified in the sugar moiety have become
important components of both chemotherapeutic agents, as
potential antimetabolites,1 and synthetic oligonucleotide
probes.2 From a synthetic point of view, it is desirable to
develop a common key intermediate. 2A,3A-Anhydro-b-d-lyxo-
We have now worked out an efficient synthetic method for
the epoxide 6, possessing contiguous enol ether and epoxide
moieties in the molecule, which acts as a prominent precursor
for a variety of 3A-adducts 5 and that can be incorporated into 3A-
modified pyrimidine nucleosides. The synthesis of 2A,3A-
anhydrouridine 6 was achieved in 92% yield by the reaction of
4 with LiHMDS (2.2 equiv.) in dry DMF (0 °C, 4 h). The
efficiency of 6 as the precursor of the modified sugar moiety
was demonstrated in the nucleophilic addition using various
nucleophiles (Table 1). With the exception of two examples
(Table 1, entries 1 and 2), which needed reflux temperatures for
the completion of the reaction, all other additions were achieved
at room temperature, and the yields of the 3A-adduct 5 were in
the range of 52–81%. In the reaction with NaN3 or PhSH as a
comparatively soft nucleophile, 5A-adduct (9g or 9h)5 was also
formed as a side product (3 or 11% yield) via SN2A addition6
together with a major product, the 3A-adduct (5g or 5h).
In addition, when Et2AlCN was used as a nucleophile,
isomerized product 11 was obtained in 58% yield due to the
activation of 3A-hydrogen of intermediate 10 by the strong
electron-withdrawing cyano group (Scheme 2).
furanosyl pyrimidine nucleosides 1 first synthesized by Fox
et al.3 are versatile building blocks, which through a nucleo-
philic ring-opening reaction can function as precursors of
enantiomerically pure and biologically interesting pyrimidine
nucleoside derivatives, and a number of reports for the
application of 1 have appeared in the literature.4 However, it is
well known that the nucleophilic addition of 1 gave a mixture of
2A- and 3A-adducts (2 and 3) in most cases.
During our studies on the nucleophilic modification of 2A,3A-
epoxy derivatives 1 and related compounds, we have discovered
that the treatment of 2A,3A-epoxy-5A-iodouridine 43c with
MeONa afforded 4A,5A-dehydro-5A-deoxy-3A-methoxy deriva-
tive 5a in 96% yield as the sole product (Scheme 1). The
possible reaction intermediates, 1-(2A,3A-anhydro-5A-deoxy-
Next, we examined the hydroboration reaction of 5a, aiming
to convert it into the 5A-hydroxy derivatives 12 and 13. When 5a
was refluxed with 18 equiv. of BH3–THF in dry THF and then
subsequently treated with H2O2–NaOH, the a-isomer 12 was
obtained as the major product (53%) together with the b-isomer
Table 1 Nucleophilic addition to 6
Yield (%)b
Entry
Nucleophile
Solventa
MeOHc
t/h
R
Product
5
9
1
2
3
4
5
6
7
8
MeONa
Me3Al
BnNH2
NaCH(CO2Me)2
BzOHe
BzSHe
2
12
24
12
1
48
3
1
OMe
Me
NHBn
CH(CO2Me)2
OBz
SBz
N3
SPh
a
b
c
d
e
f
80
81
81
69
61
52
63
80
NDd
NDd
NDd
NDd
NDd
NDd
3
c
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
DMF
NaN3
PhSH
g
h
Et3N
11
a Unless otherwise noted, the reactions were carried out at room temperature. b Isolated yields after chromatographic separation; all the reaction products were
fully characterized by elemental analysis and spectroscopic data. c The reactions were carried out under reflux conditions. d Not detectable. e Reactions were
performed in the presence of Et3N as base.
Chem. Commun., 1999, 1827–1828
1827

mediate without the formation of the corresponding 2A-adduct.
The results presented herein provide a novel entry into a variety
of sugar-modified pyrimidine nucleosides.
Notes and references
1 C. Perigaud, G. Gosselin and J.-L. Imbach, Nucleosides Nucleotides,
1992, 11, 903; L. R. Townsend, Chemistry of Nucleosides and
Nucleotides, Plenum, New York, 1988; A. Matsuda, J. Synth. Org. Chem.
Jpn., 1990, 48, 907; H. Maag, R. M. Rydzewski, M. J. McRoberts, D.
Crawford-Ruth, J. P. H. Verheyden and E. J. Prisbe, J. Med. Chem., 1992,
35, 1440; M.-J. Camarasa, M.-J. Perez-Perez, A. San-Felix, J. Balzarini
and E. De Clercq, J. Med. Chem., 1992, 35, 2721; M.-J. Perez-Perez, A.
San-Felix, J. Balzarini, E. De Clercq and M.-J. Camarasa, J. Med. Chem.,
1992, 35, 2988.
2 T. L. Ruth, Oligonucleotides and Their Analogues, IRL Press, London,
1991; B. Giese, P. Imwinkelried and M. Petretta, Synlett, 1994, 1003 and
references therein.
3 (a) J. F. Cordington, R. Fecher and J. J. Fox, J. Am. Chem. Soc., 1960, 82,
2794; (b) N. C. Chang, J. H. Burchanel, R. Fecher, R. Duschinsky and
J. J. Fox, J. Am. Chem. Soc., 1961, 83, 4060; (c) J. F. Cordington, R.
Fecher and J. J. Fox, J. Org. Chem., 1962, 27, 163.
Scheme 1
4 K. Minamoto, Y. Yamano, Y. Matsuoka, K. Watanabe, T. Hirata and S.
Eguchi, Nucleosides Nucleotides, 1992, 11, 457; J. P. Horwits, J. Chua,
M. A. D. Rooge, M. Noel and I. L. Klundt, J. Org. Chem., 1966, 31, 205;
T. Sasaki, K. Minamoto and K. Hattori, Tetrahedron, 1974, 30, 2689;
D. H. Hollenberg, K. A. Watanabe and J. J. Fox, J. Med. Chem., 1977, 20,
113; G. Kowollik and P. Z. Langen, Z. Chem., 1975, 15, 147; P.
Herdewijin, A. Van Aerschot and L. Kerremans, Nucleosides Nucleo-
tides, 1989, 8, 65; H. M. Misra, W. P. Gati, E. E. Kraus and L. I. Wiebe,
J. Heterocycl. Chem., 1984, 21, 773; J.-T. Haung, L.-C. Chen, L. Wang,
M.-H. Kim, J. A. Warshaw, D. Armstrong, Q.-Y. Zhu, T.-C. Chou, K. A.
Watanabe and J. J. Fox, J. Med. Chem., 1991, 34, 1640; U. Reichman,
D. H. Hollenberg, C. K. Chu, K. A. Watanabe and J. J. Fox, J. Org.
Chem., 1976, 41, 2042; C. F. Hunnel and R. P. Carty, Nucleosides
Nucleotides, 1983, 2, 249; M. E. Perlman and K. A. Watanabe,
Nucleosides Nucleotides, 1989, 8, 145; D. Habich and W. Barth,
Synthesis, 1988, 943; A. Mate, J. B. Hobbs, D. C. Scopes and R. F.
Newton, Tetrahedron Lett., 1985, 26, 97; M. Ashwell, A. S. Jones and R.
T. Walker, Nucleic Acids Res., 1987, 15, 2157; T. R. Webb, H. Mitsuya
and S. Broder, J. Med. Chem., 1988, 31, 1475; M. J. Bamford, P. L. Coe
and R. T. Walker, J. Med. Chem., 1990, 33, 2494; K. Hamaguchi, H.
Tanaka, H. Maeda, Y. Itoh, S. Saito and T. Miyasaka, J. Org. Chem.,
1991, 56, 5401; P. Wigerinck, A. V. Aerschot, G. Janssen, P. Claes, J.
Balzarini, E. De Clercq and P. Herdewijin, J. Med. Chem., 1990, 33, 868;
X. Ariza, J. Garces and J. Vilarrasa, Tetrahedron Lett., 1992, 33, 4069; I.
L. Doerr, J. F. Cordington and J. J. Fox, J. Org. Chem., 1965, 30, 467.
5 V. Dalla and P. Pale, Tetrahedron Lett., 1996, 37, 2781.
Scheme 2
Scheme 3
13 as a minor product (17%) (Scheme 3). This isomer ratio may
be interpreted by invoking the steric hindrance effects of the
methoxy group at the 3A-position.
In conclusion, we have developed a regioselective method for
the synthesis of 3A-substituted pyrimidine nucleoside deriva-
tives 5, 11, 12 and 13 using 1-(2A,3A-anhydro-5A-deoxy-4A,5A-
didehydro-a-l-erythro-pentofuranosyl)uracil 6 as a key inter-
6 J. A. Marshall, Chem. Rev., 1989, 89, 1503.
Communication 9/05608D
1828
Chem. Commun., 1999, 1827–1828