Asymmetric synthesis of both enantiomers of two acyclic nucleoside analogues related to d4T and acyclovir

Article abstract of DOI:10.1016/S0040-4039(01)02298-5

The enantiomers of 1-{[(2-hydroxy-1-phenyl)ethoxy]methyl}thymine and 9-{[(2-hydroxy-1-phenyl)ethoxy]methyl}guanine have been obtained in high yield in five steps from (R)- and (S)-1-phenylethan-1,2-diol. These chiral compounds are acyclic nucleoside analo

Full text of DOI:10.1016/S0040-4039(01)02298-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 989–991
Asymmetric synthesis of both enantiomers of two acyclic
nucleoside analogues related to d4T and acyclovir
David F. Ewing,a Virginie Glac¸on,a Grahame Mackenziea and Christophe Lenb,*
aCentre for Organic and Biological Chemistry, Department of Chemistry, University of Hull, Hull HU6 7RX, UK
bLaboratoire des Glucides, Universite´ de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
Received 2 November 2001; accepted 3 December 2001
Abstract—The enantiomers of 1-{[(2-hydroxy-1-phenyl)ethoxy]methyl}thymine and 9-{[(2-hydroxy-1-phenyl)ethoxy]methyl}-
guanine have been obtained in high yield in five steps from (R)- and (S)-1-phenylethan-1,2-diol. These chiral compounds are
acyclic nucleoside analogues of d4T and acyclovir, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
In recent years there has been significant interest in
nucleosides as potential antiviral agents against Human
Immunodeficiency Virus (HIV) and Herpes Simplex
Virus (HSV). Compounds approved by the US Food
and Drug Administration for the treatment of AIDS
include nucleoside analogues AZT,1 ddC,2 ddI,3 3TC,4
d4T5 and ABC.6 Acyclovir7 is an acyclic nucleoside
which is effective in treatment of HSV infection.
efficient asymmetric synthesis of both enantiomers of
nucleoside analogues based on the acyclic glycone [(2-
hydroxy-1-phenyl)ethoxy]methanol. These compounds
which can be viewed as seco-benzo[c]furan species but,
more importantly, compounds 1-{[(2-hydroxy-1-
phenyl)ethoxy]methyl}thymine (1) and 9-{[(2-hydroxy-
1-phenyl)ethoxy]methyl}guanine (2) are analogues of
d4T and acyclovir, respectively, and hence have inter-
esting therapeutic potential. Furthermore, the presence
of a phenyl group may increase the ease of phosphoryl-
ation as has been observed for some imidazole
ribonucleosides12 and will certainly enhance the
lipophilicity relative to these established drugs.
In the search for new compounds with a higher thera-
peutic index attention has focused mainly upon the
transformation of the sugar moiety of nucleosides. As
part of our continuing efforts to study the structure–
activity relationships of various nucleosides as antiviral
agents convenient methods have been developed8–11 in
our laboratory for the synthesis of analogues of d4T
based on a benzo[c]furan core, e.g. compounds such as
the thymine derivative bfT (Fig. 1). We now report an
Compound 1 and the analogous uracil derivative were
obtained in racemic form by Chu and co-workers13 as
intermediates in a preparation of HEPT14 and EBPU15
analogues. A much more efficient route is shown in
O
O
O
O
N
N
O
NH
NH
NH
N
N
NH
NH
HO
HO
HO
HO
N
NH2
HO
O
O
O
N
O
N
O
O
O
N
O
N
NH2
acyclovir
d4T
1
2
bfT
Figure 1.
Keywords: acyclic nucleosides; d4T; acyclovir; asymmetric dihydroxylation.
* Corresponding author. Tel.: 33(0)3 22 82 74 76; fax: 33(0)3 22 82 75 68; e-mail: christophe.len@sc.u-picardie.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02298-5

990
D. F. Ewing et al. / Tetrahedron Letters 43 (2002) 989–991
OMe
OAc
BzO
O
HO
OH
BzO
OH
BzO
O
ii
iii
iv
i
3
(S)-4
(S)-5
(S)-6
(S)-7
v
v
vii
O
N
O
N
HO
OH
N
NH
NH
N
O
NH2
RO
O
RO
O
(R)-4
ii - vi
(R)-1
(S)-9
(S)-2
(S)-8
(S)-1
R = Bz
R = H
R = Bz
R = H
and
vi
vi
(R)-2
Scheme 1. (i) AD-mix a, t-BuOH, H2O; (ii) BzCl, pyridine; (iii) dimethoxymethane, P2O5, chloroform; (iv) acetic anhydride,
BF3–Et2O; (v) silylated base, dibenzo-18-crown-6-ether, KI, acetonitrile, toluene; (vi) K2CO3, MeOH; (vii) AD-mix b, t-BuOH,
H2O.
It is notable that the convenient high yield synthesis of
these novel acyclic nucleosides having one asymmetric
carbon atom starts with the asymmetric dihydroxyla-
tion procedure. The biological evaluation of these
acyclic nucleosides for anti-viral activity is underway.
Scheme 1, which gives access to both enantiomers of 1
and 2.
The diols (S)-4 and (R)-4 were obtained in 99% yield
from styrene using the Sharpless Asymmetric Dihy-
droxylation reagents AD-mix a and AD-mix b, respec-
tively. Both enantiomers of 4 were obtained in 97% ee
similar to the value reported by Sharpless and co-
workers.16 After protection of the primary hydroxyl
function of the diol (S)-4 with a benzoyl group, the
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1
(CD3OD): l 1.72 (3H, d, J 0.9, Me), 3.50 (1H, dd, J1,2a
2.7, J2a,2b 9.1, H-2a), 3.64 (1H, dd, J1,2b 6.3, J2a,2b 9.1,
H-2b), 4.58 (1H, dd, J1,2a 2.7, J1,2b 6.3, H-1), 4.84 (1H, s,
OH), 5.19 (2H, ABq, CH2), 7.22–7.31 (6H, m, aromatic
H, thymine H-6). For (S)-1 [h]2D2 +79.0° (c 1.82 in
MeOH). For (R)-1 [h]2D2 −79.8° (c 1.76 in MeOH).
1
18. Selected data for compounds (S)-2 and (R)-2; H NMR
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4.58 (1H, dd, J1,2a 3.2, J1,2b 5.5, H-1), 4.88 (1H, t, OH),
5.28 (1H, d, J 8.2, CH2), 5.39 (1H, d, J 8.2, CH2), 6.48
(2H, s, NH2), 7.21–7.32 (5H, m, aromatic H), 7.69 (1H, s,
guanine H-8), 10.60 (1H, s, guanine H-1). For (S)-2 [h]D22
+100.2° (c 0.61 in DMSO). For (R)-2 [h]2D2 −100.3° (c 1.05
in DMSO).
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