Acyclonucleoside Phosphonates by Olefin Cross-Metathesis
romethyl isopropyl carbonate (1.10 g, 7.2 mmol) was added anhy-
drous sodium iodide (755 mg, 5.0 mmol). The solution was heated
to reflux with stirring for 72 h under a positive pressure of dry Ar.
After cooling, the solution was added to diethyl ether (100 mL)
and washed with water (20 mL). The organic layer was dried with
magnesium sulfate, evaporated, and purified by silica gel column
[1] a) I. Lefebvre, C. Perigaud, A. Pompom, A.-M. Aubertin, J.-
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chromatography (EtOAc/petroleum ether, 1:3) to give 2.27 g
1
(
4.4 mmol, 91%) of 13 as a slightly yellow oil. H NMR (400 MHz,
1
7, 2452–2455.
3
CDCl ): δ = 5.82–5.68 (m, 1 H), 5.68–5.58 (m, 1 H), 5.26–5.17 (m,
[
2] H. Schmidinger, R. Birner-Gruenberger, G. Riesenhuber, R.
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2
6
2
1
H), 4.91 (m, J = 6.3 Hz, 2 H), 4.24–4.07 (m, 2 H), 3.47 (t, J =
.2 Hz, 2 H), 3.37 (t, J = 6.7 Hz, 2 H), 2.67 (dd, J = 22.4, 7.4 Hz,
H), 1.91 (m, J = 6.3 Hz, 2 H), 1.57–1.49 (m, J = 6.9 Hz, 2 H),
[3] A. A. Reszka, G. A. Rodan, Curr. Rheumatol. Rep. 2003, 5, 65–
1
3
74.
.33–1.20 (m, 32 H), 0.86 (t, J = 6. 7 Hz, 3 H) ppm. C NMR
): δ = 153.2, 126.6, 126.5, 120.6, 120.5, 84.4, 84.3,
[
4] M. Etminan, K. Aminzadeh, I. R. Matthew, J. M. Brophy, J.
(100 MHz, CDCl
3
Rheumatol. 2008, 35, 691–695.
7
2
2
3.0, 71.2, 66.5, 63.3, 32.7, 31.9, 31.3, 30.7, 29.7, 29.6, 29.5, 29.3,
6.1, 22.7, 21.6, 14.1 ppm. 3 P NMR (162 MHz, CDCl
1
[5] For recent reviews on phosphonate prodrugs, see: a) S. J.
Hecker, M. D. Erion, J. Med. Chem. 2008, 51, 2328–2345; b)
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3
): δ =
+
6.7 ppm. HRMS: calcd. for C27
H
53
O
7
PNa [M + Na] 543.3427;
found 543.3435.
Typical Procedure for Cross-Metathesis with 4: To a CH
(
(
2
Cl
25 mL/mmol) solution of a 5-substituted N -crotyluracil 6a–e
1 equiv.) and 4 (1.3 equiv.) was added 1b (5 mol-%). The solution
2
1
[6] a) K. Parang, L. I. Wiebe, E. E. Knaus, Curr. Med. Chem.
2
000, 7, 995–1039; b) L. Naesens, N. Bischofberger, P. Augus-
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was heated to reflux gently under a positive pressure of dry Ar,
and the reaction was monitored by TLC. After evaporation of all
volatiles, the residue was purified by silica gel column chromatog-
raphy (EtOAc in hexanes) and the desired compounds were isolated
as (E)-7a–e and (Z)-8a–e.
Kim, E. De Clercq, Antimicrob. Agents Chemother. 1998, 42,
1
568–1573; c) J. Fung, C. L. Lai, M. F. Yuen, Expert Opin.
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Mol. Ther. 2006, 8, 352–357.
General Procedure for Cross-Metathesis with 5: To a CH
2 2
Cl
(25 mL/mmol) solution of 6a–e (1 equiv.) and 5 (1.3 equiv.) was
added 3e (2 mol-%). The solution was stirred at r.t. under a positive
pressure of dry Ar, and the reaction was monitored by TLC. After
evaporation of all volatiles, the residue was purified by silica gel
column chromatography (EtOAc in hexanes) and the desired com-
pounds were isolated as (E)-9a–e and (Z)-10a–e.
[
9] For a recent review on prodrugs bearing HDP, see: a) K. Y.
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[
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Tanaka, Eur. J. Pharmacol. 2001, 431, 345–352.
General Procedure for Cross-Metathesis with 13: To a CH
2
Cl
2
(8 mL) solution of 6a–e (0.30 mmol) and 13 (0.39 mmol) was added
[
[
[
11] H. Hiyoshi, M. Yanagimachi, M. Ito, I. Ohtsuka, I. Yoshida,
T. Saeki, H. Tanaka, J. Lipid Res. 2000, 41, 1136–1144.
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3e (15.7 mg, 0.015 mmol). The solution was stirred at r.t. for 1 h
under a positive pressure of dry Ar. After evaporation of all vola-
tiles, the residue was purified by silica gel column chromatography
2007, 340, 667–669.
(pure EtOAc) to obtain pure (E)-14a–e and the respective Z iso-
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see: a) A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H.
Grubbs, J. Am. Chem. Soc. 2003, 125, 11360–11370; b) S. J.
Connon, S. Blechert, Angew. Chem. 2003, 115, 1944; Angew.
Chem. Int. Ed. 2003, 42, 1900–1923; c) A. Deiters, S. F. Martin,
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mers.
General Procedure for Selective POC Deprotection of HDP/POC
Nucleosides 14a–e: One of the (HDP/POC) acyclic nucleotide ana-
log 14a–e was added to a 0.1 m solution of sodium hydroxide in
deionized water (70 mL/mmol). The solution was stirred vigorously
at r.t. for 4 h. The basic solution was neutralized with acidic
DOWEX resin 50W8 and washed twice with CH Cl (20 mL/
2 2
mmol). The desired pure products 16a–e were directly obtained af-
ter evaporation of the volatiles.
[
[
14] P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew.
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Hoveyda, J. Am. Chem. Soc. 1999, 121, 791–799; b) S. B.
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Blechert, Tetrahedron Lett. 2000, 41, 9973–9976.
Supporting Information (see footnote on the first page of this arti-
cle): H, C, and P NMR spectra of all new compounds.
1
13
31
Acknowledgments
Work for this project performed at the University of St Andrews
was funded by the European Commission (EC) through the seventh
framework program (grant CP-FP 211468-2 EUMET). We thank
Umicore AG for generous gifts of starting materials. We also thank
Prof. Balzarini, Pr. Snoeck, and Prof. Andreï (Rega Institute,
Leuven) for the biological evaluation of these compounds. S. P. N.
is a Royal Society Wolfson Research Merit Award holder.
[
16] For a recent review on Ru–indenylidene complexes, see: a) F.
Boeda, H. Clavier, S. P. Nolan, Chem. Commun. 2008, 2726–
2
1
740; b) A. Fürstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738–
742.
[
17] a) T. Weskamp, W. C. Schattenmann, M. Spiegler, W. A.
Herrmann, Angew. Chem. 1998, 110, 2631; Angew. Chem. Int.
Ed. 1998, 37, 2490–2493; b) L. Ackermann, A. Fürstner, T.
Eur. J. Org. Chem. 2011, 7324–7330
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