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Synlett 2008(6): 817-820  
DOI: 10.1055/s-2008-1042904
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publication History

Received 8 January 2008
Publication Date:
11 March 2008 (online)

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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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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 2 CHF (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.

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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).

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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, H3’), 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.

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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]+.