Synthesis of 2′,3′-Dideoxy-2′-Fluoro-4′-Thionucleosides from a Fluoroxanthate

Laëtitia Jean-Baptiste; Pierre Lefebvre; Emmanuel Pfund; Thierry Lequeux

doi:10.1055/s-2008-1042904

LETTER

Synthesis of 2′,3′-Dideoxy-2′-Fluoro-4′-Thionucleosides from a Fluoroxanthate

Laëtitia Jean-Baptiste, Pierre Lefebvre, Emmanuel Pfund, Thierry Lequeux*
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Caen Basse-Normandie, CNRS, 6 Boulevard du Maréchal Juin, 14050 Caen, France
Fax: +33(2)31452865; e-Mail: thierry.lequeux@ensicaen.fr;

Abstract

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Abstract

The synthesis of a thiobutyrolactone as precursor of modified nucleosides is reported from a fluoroxanthate and a protected allylic alcohol. This approach opens a new and straightforward route for the synthesis of 2′,3′-dideoxy-2′-fluoro-4′-thiothymidine derivatives in few steps, including the formation of a fluorothiolactone and a Vorbrüggen thymine base alkylation reaction.

Key words

fluorine - free radical - nucleosides - lactones

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References

References and Notes

<A NAME="RG00508ST-1A">1a</A> Simons C. Nucleoside Mimetics, In Advanced Chemistry Texts Vol. 3: Gordon and Breach Science Publishers; Amsterdam: 2001.

<A NAME="RG00508ST-1B">1b</A> Isanbor C. O’Hagan D. J. Fluorine Chem. 2006, 127: 303

<A NAME="RG00508ST-1C">1c</A> Clark JL. Mason JC. Hollecker L. Stuyver LJ. Tharnish PM. McBrayer TR. Otto MJ. Furman PA. Schinazi RF. Watanabe KA. Bioorg. Med. Chem. Lett. 2006, 16: 1712

<A NAME="RG00508ST-1D">1d</A> Jeannot F. Gosselin G. Mathé C. Org. Biomol. Chem. 2003, 1: 2096

<A NAME="RG00508ST-2">2</A> Yokoyama M. Synthesis 2000, 1637

<A NAME="RG00508ST-3">3</A> Len C. Mackenzie G. Tetrahedron 2006, 62: 9085

<A NAME="RG00508ST-4A">4a</A> Rahim SG. Trivedi N. Bogunovic-Batchelor MV. Hardy GW. Mills G. Selway JWT. Snowden W. Littler E. Coe PL. Basnak I. Whale RF. Walker RT. J. Med. Chem. 1996, 39: 789

<A NAME="RG00508ST-4B">4b</A> Hertel LW. Kroin JS. Misner JW. Tustin JM. J. Org. Chem. 1988, 53: 2406

<A NAME="RG00508ST-5A">5a</A> Otter GP. Elzagheid MI. Jones GD. MacCulloch AC. Walker RT. Oivanen M. Klika KD. J. Chem. Soc., Perkin Trans. 2 1998, 2343

<A NAME="RG00508ST-5B">5b</A> Tuttle JV. Tisdale M. Krenitsky TA. J. Med. Chem. 1993, 36: 119

<A NAME="RG00508ST-6">6</A> McAtee JJ. Schinazi RF. Liotta DC. J. Org. Chem. 1998, 63: 2161

<A NAME="RG00508ST-7A">7a</A> Gouault S. Pommelet JC. Lequeux T. Synlett 2002, 996

<A NAME="RG00508ST-7B">7b</A> Jean-Baptiste L. Yemets S. Legay R. Lequeux T. J. Org. Chem. 2006, 71: 2352

<A NAME="RG00508ST-8A">8a</A> Jin F. Wang D. Confalone PN. Pierce ME. Wang Z. Xu G. Choudhury A. Nguyen D. Tetrahedron Lett. 2001, 42: 4787

<A NAME="RG00508ST-8B">8b</A> Caille JC. Miel H. Armstrong P. McKervey MA. Tetrahedron Lett. 2004, 45: 863

<A NAME="RG00508ST-8C">8c</A> Huang JT. Chen LC. Wang L. Kim MH. Warshaw JA. Armstrong D. Zhu QY. Chou TC. Watanabe KA. Matulic-Adamic J. Su TL. Fox JJ. Polsky B. Baron PA. Gold JWM. Hardy WD. Zuckerman E. J. Med. Chem. 1991, 34: 1640

<A NAME="RG00508ST-8D">8d</A> Jeong LS. Marquez VE. J. Org. Chem. 1995, 60: 4276

<A NAME="RG00508ST-8E">8e</A> Watanabe KA. Reichman U. Hirota K. Lopez C. Fox JJ. J. Med. Chem. 1979, 22: 21

<A NAME="RG00508ST-8F">8f</A> Boydell AJ. Vinader V. Linclau B. Angew. Chem. Int. Ed. 2004, 43: 5677

<A NAME="RG00508ST-9A">9a</A> Seaong LS. Marquez VE. Chem. Lett. 1995, 301

<A NAME="RG00508ST-9B">9b</A> Watts JK. Sadalapure K. Choubdar N. Pinto BM. Damha MJ. J. Org. Chem. 2006, 71: 921

<A NAME="RG00508ST-9C">9c</A> Katayama S. Takamatsu S. Naito M. Tanji S. Ineyama T. Izawa K. J. Fluorine Chem. 2006, 127: 524

<A NAME="RG00508ST-9D">9d</A> Takamatsu S. Maruyama T. Katayama S. Hirose N. Naito M. Izawa K. J. Org. Chem. 2001, 66: 7469

<A NAME="RG00508ST-10A">10a</A> Jeong LS. Moon HR. Yoo SJ. Lee SN. Chun MW. Lim YH. Tetrahedron Lett. 1998, 39: 5201

<A NAME="RG00508ST-10B">10b</A> Yoshimura Y. Endo M. Sakata S. Tetrahedron Lett. 1999, 40: 1937

<A NAME="RG00508ST-11A">11a</A> Yoshimura Y. Kitano K. Yamada K. Satoh H. Watanabe M. Miura S. Sakata S. Sasaki T. Matsuda A. J. Org. Chem. 1997, 62: 3140

<A NAME="RG00508ST-11B">11b</A> Zheng F. Zhang XH. Qiu XL. Zhang X. Qing FL. Org. Lett. 2006, 8: 6083

<A NAME="RG00508ST-12">12</A> Boivin J. Ramos L. Zard SZ. Tetrahedron Lett. 1998, 39: 6877

<A NAME="RG00508ST-13">13</A> Syvret RG. Vassilaros DL. Parees DM. Pez GP.
J. Fluorine Chem. 1994, 67: 277

Experimental for 3b A solution of O-benzyl allylic alcohol 2b (1.08 g, 7.28 mmol, 1.1 equiv), and xanthate 1 (1.50 g, 6.62 mmol, 1 equiv) in deoxygenated DCE (80 mL) was heated at 85 °C (oil bath). A solution of lauroyl peroxide (0.79 g, 1.99 mmol, 0.3 equiv) in deoxygenated DCE (20 mL) was added dropwise (over 2 h by using a syringe pump), then the mixture was stirred 30 min. The solution was cooled to r.t., and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (pentane-EtOAc, 95:5) to afford 3b as a mixture of diastereomers (1.54 g, 62%, 1:1) as a light yellow liquid.¹H NMR (250 MHz, CDCl₃): δ = 1.32 [t, 6 H, ³ J _HH = 7.1 Hz, CH₃ (2 dia)], 1.40 [t, ³ J _HH = 7.1 Hz, 6 H, CH₃ (2 dia)], 2.12-2.75 [m, 4 H, CH ₂CHF (2 dia)], 3.80-3.99 [m, 4 H, CH₂O (2 dia)], 4.03-4.16 [m, 2 H, CHS (2 dia)], 4.27 [q, ³ J _HH = 7.1 Hz, 4 H, CH₂ (2 dia)], 4.56 [s, 4 H, PhCH₂O (2 dia)], 4.59 [q, ³ J _HH = 7.1 Hz, 2 H, CH₂ (dia 1)], 4.60 [q, ³ J _HH = 7.1 Hz, 2 H, CH₂ (dia 2)], 5.00 [ddd, ² J _HF = 49.0 Hz, ³ J _HH = 8.4 Hz, ³ J _HH = 4.1 Hz, 1 H, CHF (dia 1)], 5.08 [ddd, ² J _HF = 49.0 Hz, ³ J _HH = 10.2 Hz, ³ J _HH = 2.9 Hz, 1 H, CHF (dia 2)], 7.25-7.35 [m, 10 H, Ph (2 dia)]. ¹⁹F NMR (235 MHz, CFCl₃, CDCl₃): δ = -191.46 [ddd, ² J _HF = 49.0 Hz, ³ J _HF = 28.0 Hz, ³ J _HF = 20.0 Hz, 1 F, (dia 1)], -191.42 [ddd, ² J _HF = 49.0 Hz, ³ J _HF = 36.0 Hz, ³ J _HF = 16.0 Hz, 1 F, (dia 2)]. ¹³C NMR (62.5 MHz, CDCl₃): δ = 12.7, 13.1 (s, CH₃), 32.85 [d, ² J _CF = 20.6 Hz, CH₂ (dia 1)], 32.2 [d, ² J _CF = 20.9 Hz, CH₂ (dia 2)], 44.9, 45.4 (s, CHS), 60.7, 69.1, 69.2, 69.6, 70.7, 71.9 (s, OCH₂), 85.8 [d, ¹ J _CF = 184.5 Hz, CF (dia 1)], 85.9 [d, ¹ J _CF = 184.8 Hz, CF (dia 2)], 126.6, 126.7, 127.1, 136.7 (s, Ph), 168.3 [d, ² J _CF = 23.9 Hz, C=O (dia 1)], 168.5 [d, ² J _CF = 23.3 Hz, C=O (dia 2)], 211.7 [C=S (dia 1)], 211.8 [C=S (dia 2)]. MS (ESI, 9 eV): m/z 375 (73) [M + H]⁺, 329 (18), 269 (26), 267 (61), 251 (49), 223 (100), 207 (25), 163 (35), 91 (20). ESI-HRMS: m/z [M + H]⁺ calcd for C₁₇H₂₄FO₄S₂: 375.1100; found: 375.1099.

<A NAME="RG00508ST-15A">15a</A> Annedi SC. Li W. Samson S. Kotra LP. J. Org. Chem. 2003, 68: 1043

<A NAME="RG00508ST-15B">15b</A> Gouault S. Guérin C. Lemoucheux L. Lequeux T. Pommelet JC. Tetrahedron Lett. 2003, 44: 5061

The ¹⁹F NMR spectra of the crude mixture revealed two multiplets: -188.2 (dddd, ² J _FH = 49.4 Hz, ³ J _FH = 25.9 Hz, ³ J _FH = 21.2 Hz, ⁴ J _F-NH = 4.7 Hz) and -191.0 (dddd, ² J _FH = 49.4 Hz, ³ J _FH = 40.0 Hz, ³ J _FH = 16.5 Hz, ⁴ J _F-NH = 4.7 Hz).

<A NAME="RG00508ST-17">17</A> Brown MD. Gillon DW. Meakins GD. Whitham GH. J. Chem. Soc., Perkin Trans. 1 1985, 1623

<A NAME="RG00508ST-18A">18a</A> Choo H. Chong Y. Choi Y. Mathew J. Schinazi RF. Chu CK. J. Med. Chem. 2003, 46: 389

<A NAME="RG00508ST-18B">18b</A> Young RJ, and Miller JA. inventors; EP 514036. ; Chem. Abstr. 1993, 118, 169532

Typical Procedure: Preparation of the γ-Thiobutyro-lactone 6b
Trifluoroacetic acid (1 mL, 13.46 mmol) was added to a solution of thiol 5b (0.20 g, 0.7 mmol) in CH₂Cl₂ (5 mL). The mixture was stirred for 18 h at 20 °C, then poured into a sat. aq NaCl soln (10 mL). The aqueous layer was extracted twice with CH₂Cl₂ (10 mL), and the organic layer was dried (MgSO₄) then the solvent was evaporated. The crude product was purified by flash column chromatography on silica (pentane-EtOAc, 95:5) to afford the less polar isomer 2,4-trans -6b (68 mg, 0.28 mmol, 40%) and the more polar isomer 2,4-cis -6b (52 mg, 0.22 mmol, 31%).
γ-Thiobutyrolactone 2,4-trans -6b: ¹H NMR (250 MHz, CDCl₃): δ = 2.30-2.40 (m, 2 H, H₃), 3.50-3.75 (m, 2 H, H₅), 4.20 (m, 1 H, H₄), 4.50 (s, 2 H, OCH₂Ph), 5.15 (ddd, ² J _HF = 51.2 Hz, ³ J _HH = ³ J _HH = 6.8 Hz, 1 H, H₂) 7.15-7.35 (m, 5 H, Ph). ¹⁹F NMR (235 MHz, CFCl₃, CDCl₃): δ = -184.65 (ddd, ² J _HF = 51.2 Hz, ³ J _HF = ³ J _HF = 18.8 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 32.6 (d, ² J _CF = 20.8 Hz, C₃), 42.0 (d, ³ J _CF = 5.9 Hz, C₄), 71.2, 75.0, 93.0 (d, ¹ J _CF = 190.2 Hz, C₂), 127.5, 128.0, 128.9, 137.5 (s, Ph), 200.7 (d, ² J _CF = 17.4 Hz, C₁).
γ-Thiobutyrolactone 2,4-cis -6b: ¹H NMR (250 MHz, CDCl₃): δ = 2.18 (m, 1 H, H₃), 2.71 (m, 1 H, H_3’), 3.62 (m, 1 H, H₅), 3.80 (m, 1 H, H₅ _′), 3.95 (m, 1 H, H₄), 4.57 (s, 2 H, OCH₂Ph), 5.10 (ddd, ² J _HF = 50.4 Hz, ³ J _HH = 9.8 Hz, ³ J _HH = 6.8 Hz, 1 H, H₂), 7.15-7.35 (m, 5 H, Ph). ¹⁹F NMR (235 MHz, CFCl₃, CDCl₃): δ = -183.7 (ddd, ² J _HF = 50.4 Hz, ³ J _HF = 18.8 Hz, ³ J _HF = 9.4 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 33.6 (d, ² J _CF = 19.6 Hz, C₃), 42.6 (d, ³ J _CF = 7.2 Hz, C₄), 71.7, 74.8, 93.3 (d, ¹ J _CF = 196.2 Hz, C₂), 127.5, 127.9, 128.9, 137.6 (s, Ph), 201.7 (d, ² J _CF = 17.6 Hz, C₁). IR (NaCl): ν = 1714 (C=O) cm^-1. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₂H₁₃FNaO₂S: 263.0518; found: 263.0525.

Selected Analytical Data for the Four Isomers of 9b
¹H NMR (250 MHz, CDCl₃): δ = 1.79 [s, 3 H, CH₃ (dia 1)], 1.86 ]s, 3 H, CH₃ (dia 2)], 1.93 [s, 3 H, CH₃ (dia 3)], 1.97 [s, 3 H, CH₃ (dia 4)], 1.75-2.62 [m, 8 H, CH ₂CHF (4 dia)], 3.58-4.10 (m, 12 H, CHCH₂OBn and CH₂OBn (4 dia)], 4.48-4.56 [m, 8 H, CH₂Ph (4 dia)], 5.18 (br d, ² J _HF = 49.4 Hz, 2 H, H₂ _′ (2 dia)], 5.20 (br d, ² J _HF = 54.1 Hz, 2 H, H₂ _′ (2 dia)], 6.17 (dd, ³ J _HF = 12.5 Hz, ³ J _HH = 4.0 Hz, 1 H, H₁ _′ (dia 1)], 6.19 (dd, ³ J _HF = 10.6 Hz, ³ J _HH = 1.4 Hz, 1 H, H₁ _′ (dia 2)], 6.40 (dd, ³ J _HF = 19.9 Hz, ³ J _HH = 4.2 Hz, 1 H, H₁ _′ (dia 3)], 6.44 (dd, ³ J _HF = 12.5 Hz, ³ J _HH = 3.7 Hz, 1 H, H₁ _′ (dia 4)], 7.19-7.34 [m, 20 H, Ph (4 dia)], 7.59 [s, 2 H, CHCH₃ (2 dia)], 7.93 [s, 2 H, CHCH₃ (2 dia)] 9.40-9.70 (br s, 4 H, NH). ¹⁹F NMR (235 MHz, CFCl₃, CDCl₃): δ = -171.54 [m (dia 1)], -175.88 [dddd, ² J _HF = 49.4 Hz, ³ J _HF = 40.0 Hz, ³ J _HF = 14.1 Hz, ³ J _HF = 10.6 Hz (dia 2)], -187.00 [m (dia 3)], -190.75 [ddddd,² J _HF = 54.1 Hz, ³ J _HF = 42.4 Hz, ³ J _HF = 23.5 Hz, ³ J _HF = 12.5 Hz, ⁴ J _HF = 2.4 Hz (dia 4)]. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₇H₂₀FN₂O₃S: 351.1179 [M + H]⁺; found: 351.1180 [M + H]⁺.

<A NAME="RG00508ST-21">21</A> Van Steenis JH. van der Gen A. J. Chem. Soc., Perkin Trans. 1 2002, 2117

<A NAME="RG00508ST-22A">22a</A> Zard SZ. Angew. Chem., Int. Ed. Engl. 1997, 36: 672

<A NAME="RG00508ST-22B">22b</A> Quiclet-Sire B. Zard SZ. Chem. Eur. J. 2006, 12: 6002