Synthesis of 4′-C, 3′-O bicyclic thymidine analogues using ring closure metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01926-3

We have developed a route to the synthesis of new six-membered ring bicyclic nucleoside analogues. The synthesis of 4′-C, 3′-O bicyclic thymidine analogues is presented as first examples of this new family. Six-membered ring construction was efficiently achieved by the application of ring closure olefin metathesis on a diene intermediate using Grubbs' catalyst.

Full text of DOI:10.1016/S0040-4039(02)01926-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8091–8094
Synthesis of 4%-C, 3%-O bicyclic thymidine analogues using ring
closure metathesis†
Mickael Montembault,a Nathalie Bourgougnonb and Jacques Lebretona,*
aLaboratoire de Synthe`se Organique, CNRS UMR 6513, Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re,
BP 92208, 44322 Nantes Cedex 3, France
bBLCBM EA 2594, Centre de Recherche et d’Enseignement Yves Coppens, campus de Tohannic, BP573,
Universite´ de Bretagne Sud, 56017 Vannes, France
Received 30 August 2002; accepted 9 September 2002
Abstract—We have developed a route to the synthesis of new six-membered ring bicyclic nucleoside analogues. The synthesis of
4%-C, 3%-O bicyclic thymidine analogues is presented as first examples of this new family. Six-membered ring construction was
efficiently achieved by the application of ring closure olefin metathesis on a diene intermediate using Grubbs’ catalyst. © 2002
Elsevier Science Ltd. All rights reserved.
Since the approval of 3%-azido-3%deoxy-thymidine (AZT,
Zidovudine, Retrovir) as the first drugs for the clinical
treatment of acquired immunodeficiency syndrome
siderable attention has been particularly focused on the
synthesis of C-branched sugar nucleosides,4 carbocyclic
sugar nucleosides,5 acyclic sugar nucleosides,6 and
bicyclic sugar nucleosides.7
(AIDS) by the Food and Drugs Administration,1
a
considerable amount of work has been devoted towards
the synthesis and biological evaluation of nucleoside
analogues. This intensive research was dedicated to the
discovery of more effective, more selective and nontoxic
new therapeutic agents, as well as new agents for other
viral infections.2 These efforts provided a number of
drugs and drug candidates,3 and, in this context, con-
In the course of our ongoing research on the synthesis
and biological evaluation of modified sugar ring
nucleosides, we became interested in an efficient and
flexible strategy for the preparation of 4%,3%-six-mem-
bered ring bicyclic nucleoside analogues, as presented in
Fig. 1, to provide novel analogues for biological
studies.
Surprisingly, although considerable work has been done
in the synthesis of nucleoside analogues, to the best of
our knowledge, no synthetic work has been reported to
provide any member of this family of bicyclic
nucleoside analogues.8,9 This fact prompted us to devise
Figure 1.
Scheme 1. Retrosynthetic scheme.
* Corresponding author. Tel.: +33 2 51 12 54 03; fax: +33 2 51 12 54 02; e-mail: lebreton@chimie.univ-nantes.fr
† The authors wish to dedicate this paper to Dr. Jean Villie´ras, an outstanding chemist and a great teacher, on the occasion of his retirement.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01926-3

8092
M. Montembault et al. / Tetrahedron Letters 43 (2002) 8091–8094
Scheme 2. Reagents and conditions: (a) (i) TBDMSCl, imidazole, DMF, rt, 6 h, 87%; (ii) NaH, allyl bromide, 40°C, ultrasound
bath, 4 h, 80%; (ii) TBAF, THF, rt, 2 h, 96%; (b) (i) DCC, pyridium trifluoacetate, DMSO, rt, 12 h; (ii) HCHO aq., NaOH aq.,
dioxane, rt, 6 h then NaBH4, rt, 30 min, 52%; (c) (i) DMTCl, pyridine, rt, 3 h, 64%; (ii) TBDPSCl, imidazole, DMF, rt, 12 h;
(d) (i) AcOH/THF/H2O (7/3/3), rt, 24 h, 67% for the two steps; (ii) DMP, wet CH2Cl2, rt, 1 h, 98%; (e) Ph3PꢀCH2, THF, −78°C,
30 min then 0°C, 2 h, 89%; (f) Grubbs’ catalyst second generation, CH2Cl2, rt, 4 h, 74%; (g) TBAF, THF, rt, 3 h, 95%; (h) H2,
Pd/C, EtOH, rt, 2 h, 84%.
a synthetic route to reach these compounds and, in this
communication, we wish to describe the feasibility of
our strategy through the synthesis of the 3%-O, 4%-C
bicyclic thymidine analogues 1 and 2 as the first
examples.
the resulting reaction mixture was treated by direct
addition of NaBH4 to afford, after purification, the diol
4 in 52% overall yield from 6.
The 5%a-hydroxyl group of 4 was selectively protected
as 4,4%-dimethoxytrityl (DMT) ether and the 5%b-
hydroxyl group as silyl ether in 64% overall yield to
furnish 7, according to a previously reported proce-
dure.10 Then, the 5%-a-O-DMT group was selectively
removed in 88% yield by treating 7 with AcOH in a
mixture of THF and water to give the 5%-a-hydroxyl
derivative, which was oxidized to the corresponding
aldehyde 8 with Dess–Martin periodinane17 (DMP) in
nearly quantitative yield. The key diene intermediate 9
was prepared from the aldehyde 8 by Wittig reaction
with methylene triphenylphosphorane to afford the
homologated compound in 89% yield after purifica-
tion.18 The key diene 9 was subjected to a RCM
reaction in dichloromethane with Grubbs’ second gen-
eration catalyst at room temperature to give the
cyclized intermediate 10 in 74% yield.19 Previous
attempts to carry out the RCM reaction with
Cl2(Cy3P)2RuCHPh on diene 9 in the same experimen-
tal conditions afforded 10 in lower yield (69%).
Removal of the TBDMS protecting group from 10 with
TBAF afforded the first bicyclic nucleoside analogue
2.20 Reduction of the double bond in 2 was accom-
plished by catalytic hydrogenation on 10% Pd/C in
ethanol to give the nucleoside analogue 1 in 84%.21
Our retrosynthetic analysis is outlined in Scheme 1, and
is centered on a ring closing metathesis (RCM)
reaction10 to provide rapid access into 4%-C, 3%-O
bicyclic thymidine analogues.11 Starting from thymidine
3, the diene intermediate 5 should be readily available
from a known sequence12 described on the 3%-O-
silylether thymidine derivative.
Our synthesis is depicted in Scheme 2. Classical protect-
ing group manipulation on thymidine 3: (i) monosilyla-
tion by tert-butyldimethylsilyl (TBDMS) group under
standard conditions, (ii) O-allylation of the C-3%-
hydroxyl group13 performed with NaH (60% suspension
in oil) and allyl bromide in THF at 40°C in an ultra-
sound bath,14 and (iii) removal of the silyl protecting
group using n-tetrabutylammonium fluoride (TBAF)
furnished the alcohol 6 in 65% overall yield for the
three steps. It should be pointed out that the allyl group
could serve as a protecting group in the first stage of
our synthesis and then as a precursor of the six-mem-
bered ring at this end. We next turned our attention to
the introduction of a vinyl group into the 4%-a-position
as follows.15
Thus, the 5%-hydroxyl group of 6 was oxidized, using
the Moffatt method, to the corresponding aldehyde
which, after purification,16 was reacted with aqueous
NaOH and formaldehyde solutions in dioxane. Then,
As a first biological evaluation, bicyclic thymidine ana-
logues 1 and 2 were tested in an in vitro assay for
Herpes simplex virus type 1 (HSV-1) inhibition: these
two compounds were found to be inactive.

M. Montembault et al. / Tetrahedron Letters 43 (2002) 8091–8094
8093
In summary, we have completed a synthesis of two
9. For examples of 3%-O, 4%-C-methylenethymidines, see:
Yang, C. O.; Kurz, W.; Eugui, E. M.; McRoberts, M. J.;
Verheyden, J. P. H.; Kurz, L. J.; Walker, A. M. Tetra-
hedron Lett. 1992, 33, 33–41. For examples of 3%-O,
4%-C-ethylenethymidines, see: Sigimoto, I.; Shuto, S.;
Mori, S.; Shigeta, S.; Matsuda, A. Bioorg. Med. Chem.
Lett. 1999, 9, 385–388.
10. For general reviews, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450; (b) Armstrong, S. K. J.
Chem. Soc., Perkin Trans. 1 1998, (2) 371–388; (c) Furst-
ner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3012–3043
and references cited therein.
novel 3%-O, 4%-C bicyclic thymidine analogues 1 and 2
using
a
ring closure ruthenium-catalyzed olefin
metathesis reaction as the key reaction step, providing a
new strategy for the synthesis of 4%-C, 3%-bicyclic
nucleoside analogues with six-membered carbo- and
heterocyclic rings. We are currently applying this strat-
egy to the synthesis of the nitrogen and sulfur ana-
logues and this work will be reported in due course as
well as the complete biological activities of all these new
nucleoside analogues.
11. For articles concerning the use of the metathesis reaction
in the nucleoside field, see: (a) Borsting, P.; Sorensen, A.
M.; Nielsen, P.; Hoffmann, R. W. Synthesis 2002, 797–
801; (b) Ewing, D., Glac¸on, V.; Mackenzie, G.; Postel,
D.; Len, C. Tetrahedron Lett. 2002, 43, 3503–3505; (c)
Lera, M.; Hayes, C. J. Org. Lett. 2001, 3, 2765–2768; (d)
Batoux, N.; Benhaddon-Zerouki, R.; Bressolier, P.;
Granet, R.; Laumont, G.; Aubertin, A.-M.; Krausz, P.
Tetrahedron Lett. 2001, 42, 1491–1493.
12. (a) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.;
Mori, S.; Shigeta, S.; Matsuda, A. J. Med. Chem. 1999,
42, 32901–32908; (b) Marx, A.; Erdmann, P.; Senn, M.;
Ko¨rner, S.; Jungo, T.; Petretta, M.; Imwinkelried, P.;
Dussy, A.; Kulicke, K. J.; Macko, L.; Zehnder, M.;
Giese, B. Helv. Chim. Acta 1996, 79, 1980–1994.
13. Purification on silica gel column led to the desired com-
pound in 80% yield accompanied by the corresponding
bis-allyl-2-N-, 3%-O-derivative in 10% yield and unreacted
starting material in 10% yield.
14. Chattopadhyaya et al. reported the preparation of a
dozen 2%- or 3%-O-allyl and propargyl ether uracil deriva-
tives under ultrasonic conditions, see: Wu, J.-C.; Xi, Z.;
Gioeli, C.; Chattopadhyaya, J. Tetrahedron 1991, 47,
2237–2254. Under these conditions, the formation of the
2-N-alkylated derivative seems to be minimized.
15. It should be mentioned that another elegant access to
4%-a-vinyl nucleoside analogues using radical chemistry
has been reported, see: Sugimoto, I.; Shuto, S.; Matsuda,
A. J. Org. Chem. 1999, 64, 7153–7157 and references
cited therein.
Acknowledgements
This work was supported by the Centre National de la
Recherche Scientifique (CNRS) with a BDI doctoral
fellowship for M.M. The authors wish to thank Dr.
Christophe Len (Universite´ de Picardie, Amiens) for
fruitful discussions concerning the RCM reaction and
Dr. Andreas Marx (Kekule´-Institut fu¨r Organische
Chemie und Biochemie, Universita¨t Bonn) for the pro-
cedure to prepare the compound 9.
References
1. (a) Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St.
Clair, M. H.; Nusinoff-Lehrman, S.; Gallo, R. C.; Bolog-
nesi, D. P.; Barry, D. W.; Broder, S. Proc. Natl. Acad.
Sci. USA 1985, 82, 7096–7100; (b) Yarchoan, R.; Broder,
S. Pharmacol. Ther. 1989, 40, 329–348.
2. DeClerq, E. J. Med. Chem. 1995, 38, 2491–2517 and
references cited therein.
3. Tan, X.; Chu, C. K.; Boudinot, F. D. Adv. Drug Deliv.
Rev. 1999, 39, 117–151 and references cited therein.
4. Bamford, M. J.; Coe, P. L.; Walker, R. T. J. Med. Chem.
1990, 33, 2488–2494.
5. (a) Gurjar, M. K.; Maheshwar, K. J. Org. Chem. 2001,
66, 7552–7554; (b) Crimmins, M. A. Tetrahedron 1998,
54, 9229–9272; (c) Bisacchi, G. S.; Chao, S. T.; Bachard,
C.; Daris, J. P.; Inaimo, S.; Jacobs, G. A.; Kocy, O.;
Lapointe, P.; Martel, A.; Merchant, Z.; Slusarchyk, W.
A.; Sundeen, J. E.; Young, M. G.; Colonno, R.; Zahler,
R. Bioorg. Med. Chem. Lett. 1997, 7, 127–132.
16. The best overall yields in this sequence 6 to 4 were
obtained when the aldehyde intermediate was purified on
silica gel chromatography.
6. (a) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbo-
17. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4156–4158; (b) Meyer, S. D.; Schreiber, S. L. J. Org.
Chem. 1994, 59, 7549–7552.
cyclic and
L-Nucleosides; Kluwer Academic Published:
Dordrecht, 1998; pp. 174–284; (b) Lin, T. S.; Luo, M. Z.;
Liu, M. C.; Pai, S. B.; Dutschman, G. E.; Cheng, Y. C.
J. Med. Chem. 1994, 37, 798–803.
18. Summerer, D.; Marx, A. Angew. Chem., Int. Ed. Engl.
2001, 40, 3693–3695.
7. (a) Pineda Molas, M.; Matheu, M. I.; Castillo´n, S.;
Isac-Garc´ıa, J.; Herna´ndez-Mateo, F.; Calvo-Flores, F.
G.; Santoyo-Gonza´lez, F. Tetrahedron 1999, 55, 14649–
14664; (b) Chao, Q.; Zhang, J.; Pickering, L.; Jahnke, T.
S.; Nair, V. Tetrahedron 1998, 54, 3113–3124; (c) Bjo¨rsne,
M.; Szabo`, T.; Samuelsson, B.; Classon, B. Bioorg. Med.
Chem. Lett. 1995, 3, 397–402.
8. Many 2%-O, 4%-C- and 3%-O, 4%-C-methylenenucleosides
have been synthesized and incorporated into antisense
and antigene oligonucleotides, for reviews concerning this
point, see: (a) Leumann, C. J. Bioorg. Med. Chem. 2002,
10, 841–854; (b) Meldgaard, M.; Wengel, J. J. Chem.
Soc., Perkin Trans. 1 2000, 3539–3554.
19. Representative procedure for 10: To a solution of com-
pound 9 (100 mg, 0.18 mmol) in CH2Cl2 (12 mL) was
added ruthenium-catalyst (16 mg, 0.019 mmol) in CH2Cl2
(8 mL) via cannula transfer, and the reaction mixture was
stirred under argon for 4 h at 25°C. The reaction mixture
was then diluted with CH2Cl2 (30 mL), washed with brine
solution, dried over MgSO4 and concentrated. The
residue was then purified on a silica gel column, eluting
with 40% ethyl acetate/hexane to give the cyclized com-
pound 10 (70 mg, 74%). 1H NMR (400 MHz, CDCl3,
ppm) l: 8.83 (s, 1H, NH); 7.38–7.73 (m, 10H, Ph2-Si);
7.54 (d, 1H, J=1.2 Hz, H6); 6.41 (dd, 1H, J=5.2 and 8.9
Hz, H1%); 6.08–6.13 (m, 1H, O-CH2-CHꢀ); 5.62–5.67 (m,

8094
M. Montembault et al. / Tetrahedron Letters 43 (2002) 8091–8094
1H, O-CH2-CHꢀCH-C); 4.29 (d, 1H, J=4.5 Hz, H3%);
2.69–2.76 and 2.33–2.38 (m, 2H, H2%); 1.91 (s, 3H,
Me7).13C NMR l: 12.6; 37.4; 62.7; 67.1; 77.6; 81.1; 88.6;
4.11–4.18 and 3.85–3.91 (m, 2H, O-CH2-CHꢀ); 3.58 and
3.83 (AB system, 2H, J=11.2 Hz, H5%); 2.45–2.51 and
2.32–2.41 (m, 2H, H2%); 1.58 (d, 3H, J=1.2 Hz, Me7);
1.10 (s, 9H, tBu-Si).13C NMR l: 158.5; 145.1; 130.3;
130.1; 127.5; 126.9; 125.9; 125.0; 124.9; 122.8; 118.9;
105.8; 79.3; 75.3; 63.0; 57.2; 33.6; 21.8; 14.2; 6.8. HMRS
(EI) calcd for [M−tBuH]+ 461.1533, found 461.1539.
111.3; 124.2; 131.2; 138.2; 150.7; 163.9. HMRS (EI) calcd
+
’
for [M ] 280.1059, found 280.1060.
21. Selected spectral data for compound 1: 1H NMR (400
MHz, CDCl3, ppm) l: 8.98 (br s, 1H, NH); 7.54 (s, 1H,
H6); 6.19 (dd, 1H, J=5.6 and 8.9 Hz, H1%); 4.08–4.14 (m,
1H, H3%); 3.82–3.90 and 3.31–3.40 (m, 2H, O-CH2-CH-);
3.58–3.68 (m, 2H, H5%); 3.00 (br s, 1H, -OH); 2.52–2.60
and 2.29–2.37 (m, 2H, H2%); 1.90 (s, 3H, Me7); 1.46–1.63
and 1.73–1.93 (m, 4H, O-CH2-CH2-CH2-C). 13C NMR l:
20. Selected spectral data for compound 2: 1H NMR (400
MHz, CDCl3, ppm) l: 7.40 (s, 1H, H6); 6.12–6.17 (m,
1H, O-CH2-CHꢀ); 6.07 (dd, 1H, J=5.5 and 9.7 Hz, H1%);
5.70–5.74 (m, 1H, O-CH2-CHꢀCH-C); 4.32 (d, 1H, J=
5.2 Hz, H3%); 3.92–3.99 and 4.12–4.19 (m, 2H, O-CH2-
CHꢀ); 3.57 and 3.72 (AB System, J=11.9 Hz, 2H, H5%);
12.7; 21.0; 28.2; 38.7; 64.9; 68.0; 77.4; 84.3; 88.7; 110.9;
+
’
137.7; 150.7; 164.1. HMRS (EI) calcd for [M ] 282.1216,
found 282.1218.