A novel approach to unsaturated acyclic nucleoside analogues and the first synthesis of d4T by ring closure metathesis

Article abstract of DOI:10.1016/S0040-4039(02)00572-5

Novel unsaturated acyclic nucleoside analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine have been prepared in good yield from uridine and 5-methyluridine by periodate cleavage followed by a double Wittig reaction which introduces two vinyl groups. The thymine derivative underwent ring closure metathesis to give a novel synthesis of d4T.

Full text of DOI:10.1016/S0040-4039(02)00572-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3503–3505
A novel approach to unsaturated acyclic nucleoside analogues
and the first synthesis of d4T by ring closure metathesis
David Ewing,a Virginie Glac¸on,a Grahame Mackenzie,a Denis Postelb and Christophe Lenb,*
aCentre for Organic and Biological Chemistry, University of Hull, Hull, UK
bLaboratoire des Glucides, Universite´ de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
Accepted 21 March 2002
Abstract—Novel unsaturated acyclic nucleoside analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-
(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine have been
prepared in good yield from uridine and 5-methyluridine by periodate cleavage followed by a double Wittig reaction which
introduces two vinyl groups. The thymine derivative underwent ring closure metathesis to give a novel synthesis of d4T. © 2002
Elsevier Science Ltd. All rights reserved.
Since the discovery that potent inhibition of HIV may
be associated with the conversion of the furanose ring
of normal nucleosides to the corresponding 2%,3%-dide-
hydro-2%,3%-dideoxy analogue, strong interest has cen-
tered round the presence of unsaturation in the sugar
moiety of nucleosides. The archetype of this class of
compounds is d4T (1) which, as its triphosphate,
inhibits HIV reverse transcriptase. Although many
routes to d4T and analogous 2%,3%-pentenfuranose
nucleosides have been found,1 the concept of unsatura-
tion in the nucleoside glycone has also been extended to
many other systems. Recent work includes the forma-
tion of nucleoside analogues in which the base is
attached to a hexenopyranose ring,2 a cyclopentenyl
ring,3 a cyclohexenyl ring,4 a dihydrobenzo[c]furan
ring5 and a range of unsaturated acyclic groups.6 This
diverse range of structures includes the anti-HIV agent
carbovir (2),7 the antibiotic Neplanocin A (3)8 (Fig. 1)
and many other examples of compounds with signifi-
cant antiviral or antibacterial activity.
We are involved in the search for nucleoside analogues
with acyclic glycones which have the potential for a
high therapeutic index9 and we describe here a novel
approach to the preparation of enantiomerically pure
unsaturated acyclic nucleoside analogues. Our method-
ology allows the simultaneous creation of two vinyl
groups to afford species of type 4. This in turn leads to
a new route to 2%,3%-didehydro-2%,3%-dideoxy nucleosides
by ring closure metathesis.
Starting from the readily available nucleoside uridine
(5) or the 5-methyl analogue (6) the primary hydroxyl
group was protected by tritylation (Scheme 1) to give
compounds 7 and 8, respectively. Oxidative cleavage of
the cis vicinal diol grouping was achieved with sodium
NH2
O
O
N
N
N
N
NH
NH
O
N
Base
N
N
O
N
NH2
HO
O
HO
HO
HO
HO
OH
4
1
2
3
Figure 1.
Keywords: unsaturated acyclic nucleosides; ring closure metathesis; d4T.
* 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(02)00572-5

3504
D. Ewing et al. / Tetrahedron Letters 43 (2002) 3503–3505
O
NH2
O
N
O
R
R
O
R
O
NH
N
NH
NH
O
O
N
O
N
O
O
N
O
iii
TrO
ii
i
TrO
HO
TrO
R=H
HO
OH
HO
OH
5 : R = H
7 : R = H
9 : R = H
11
6 : R = CH3
8 : R = CH3
10 : R = CH3
v
iv
iv
R = CH3
O
O
NH2
R
O
NH
NH
N
iv
d4T
O
N
O
N
O
O
N
O
HO
TrO
HO
1
12 : R = H
15
14
13 : R = CH3
Scheme 1. (i) TrCl, pyr.; (ii) (a) NaIO4, EtOH/H2O, (b) Ph3PCH3Br, t-BuOK, toluene; (iii) (a) 1,2,4-triazole, POCl3, CH3CN,
Et3N, (b) aq. 30% NH3 in 1,4-dioxane; (iv) AcOH 80%; (v) Grubbs reagent, CH2Cl2.
periodate in ethanol/water to give the corresponding
dialdehydes. These compounds were not stable and
hence, after isolation, they were subjected directly to a
double Wittig olefination with methyltriphenylphospho-
nium bromide to afford the novel bis alkenes 1-{1-[1-
(trityloxymethyl)prop-2-enyloxy]prop-2-enyl}uracil (9)
1263–1266; (b) Delbederi, Z.; Fossey, C.; Fontaine, G.;
Benzaria, S.; Gavriliu, D.; Ciurea, A.; Lelong, B.;
Laduree, D.; Aubertin, A. M.; Kirn, A. Nucleosides
Nucleotides 2000, 19, 1441–1461; (c) Chiacchio, U.;
Rescifina, A.; Iannazzo, D.; Romeo, G. J. Org. Chem.
1999, 64, 28–36.
and
1-{1-[1-(trityloxymethyl)prop-2-enyloxy]prop-2-
2. Sztaricskai, F.; Csorvasi, A.; Horvath, A.; Batta, G.;
Dinya, Z. J. Carbohydr. Chem. 2000, 19, 1223–1233.
3. (a) Teran, C.; Moa, M. J. G.; Mosquera, R.; Santana, L.
Nucleosides Nucleotides 2001, 20, 999–1002; (b) Song, G.
Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44,
3985–3993.
4. (a) Wang, J.; Herdewijn, P. J. Org. Chem. 1999, 64,
7820–7827; (b) Barral, K.; Halfon, P.; Pepe, G.; Camplo,
M. Tetrahedron Lett. 2002, 43, 81–84.
enyl}thymine (10). It was found that the yield in this
olefination step was strongly dependent on the base
used, t-BuOK in toluene being much more effective
(50% yield) that BuLi in tetrahydofuran (25% yield).
Standard nucleoside methodology was used to convert
the uracil compound 9 to the cytosine analogue 11 in
89% yield.10 The three bis alkene nucleoside analogues
were easily deprotected in very high yield (>88%) to
give compounds 12, 1311 and 14, respectively. These
interesting compounds are clearly capable of further
elaboration by epoxidation or dihydroxylation and may
lead to novel polyhydroxy nucleoside analogues with
therapeutic potential.
5. Ewing, D. F.; Fahmi, N.-E.; Len, C.; Mackenzie, G.;
Pranzo, A. J. Chem. Soc., Perkin Trans. 1 2000, 3561–
3565.
6. (a) Pedersen, D. S.; Boesen, T.; Eldrup, A. B.; Kiaer, B.;
Madsen, C.; Hedriksen, U.; Dahl, O. J. Chem. Soc.,
Perkin Trans. 1 2001, 1656–1661; (b) Redwane, N.;
Lazrek, H. B.; Barascut, J. L.; Imbach, J. L.; Balzarini,
J.; Witvrouw, M.; De Clercq, E. Nucleosides Nucleotides
2001, 20, 1439–1447; (c) Du, J. F.; Wang, G. Y.
Nucleosides Nucleotides 2000, 19, 867–879; (d) Hirota, K.;
Monguchi, Y.; Sajiki, H.; Yatome, C.; Hiraoka, A.;
Kitade, Y. Nucleosides Nucleotides 1998, 17, 1333–1345.
7. Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Chal-
land, R. S.; Earl, R. E.; Guedj, R. Tetrahedron 1994, 50,
10611–10620.
The discovery of convenient catalysts has greatly
increased interest in ring closure metathesis.12 Treat-
ment of the 5-methyluracil derivative 10 with Grubbs
reagent in dichloromethane resulted in clean ring clo-
sure to form the protected d4T species 15. To our
knowledge this is the first example of the formation of
the 2,5-dihydrofuran ring by metathesis. Compound 15
had identical physical data to that reported by
Cosford13 and was easily deprotected to afford d4T (1).
8. Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.;
Tomioka, K. J. Org. Chem. 2001, 66, 8199–8203 and
references cited therein.
References
9. Ewing, D. F.; Glac¸on, V.; Mackenzie, G.; Len, C. Tetra-
hedron Lett. 2001, 43, 989–991.
1. Recent work includes: (a) Guo, Z.; Sanghvi, Y. S.; Bram-
mer, L. E.; Hudlicky, T. Nucleosides Nucleotides 2001, 20,

D. Ewing et al. / Tetrahedron Letters 43 (2002) 3503–3505
3505
10. Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin Trans.
1 1982, 1171–1176.
11. Selected data for compound 13; H NMR (CDCl3): 1.74
79.7 and 80.5 (C-4% and C-1%), 111.8 (C-5), 119.9 and
121.2 (vinyl CH2), 132.8, 133.2 (C-2%, C-3%), 135.9 (C-6),
151.2, 163.7 (C-2 and C-4).
1
12. (a) Frstner, A.; Ackermann, L. Chem. Commun. 1999, 95;
(b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 34,
4413–4450.
13. Cosford, N. D. P.; Schinazi, R. F. J. Org. Chem. 1991,
56, 2161–2165.
(CH3 thymine), 3.63 (2H, m, H-5%a, H-5%b), 4.03 (1H, m,
H-4%), 5.39–5.47 (m, 3 H) and 5.54–5.59 (m, 1H) and
5.68–5.86 (m, 2H) for H-2%, H-3% and vinyl groups CH2,
6.31 (1H, m, H-1%), 7.17 (1H, s, H-6), 8.92 (1H, s, NH).
lC (CDCl3) (77 ppm): 12.5 (CH3 thymine), 64.9 (C-5%),