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

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.

fluorine - free radical - nucleosides - lactones

References and Notes

1a Simons C. Nucleoside Mimetics, In Advanced Chemistry Texts   Vol. 3:  Gordon and Breach Science Publishers; Amsterdam: 2001. 

1b Isanbor C. O’Hagan D. J. Fluorine Chem.  2006,  127:  303 

1c 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 

1d Jeannot F. Gosselin G. Mathé C. Org. Biomol. Chem.  2003,  1:  2096 

2 Yokoyama M. Synthesis  2000,  1637 

3 Len C. Mackenzie G. Tetrahedron  2006,  62:  9085 

4a 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 

4b Hertel LW. Kroin JS. Misner JW. Tustin JM. J. Org. Chem.  1988,  53:  2406 

5a Otter GP. Elzagheid MI. Jones GD. MacCulloch AC. Walker RT. Oivanen M. Klika KD. J. Chem. Soc., Perkin Trans. 2  1998,  2343 

5b Tuttle JV. Tisdale M. Krenitsky TA. J. Med. Chem.  1993,  36:  119 

6 McAtee JJ. Schinazi RF. Liotta DC. J. Org. Chem.  1998,  63:  2161 

7a Gouault S. Pommelet JC. Lequeux T. Synlett  2002,  996 

7b Jean-Baptiste L. Yemets S. Legay R. Lequeux T. J. Org. Chem.  2006,  71:  2352 

8a Jin F. Wang D. Confalone PN. Pierce ME. Wang Z. Xu G. Choudhury A. Nguyen D. Tetrahedron Lett.  2001,  42:  4787 

8b Caille JC. Miel H. Armstrong P. McKervey MA. Tetrahedron Lett.  2004,  45:  863 

8c 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 

8d Jeong LS. Marquez VE. J. Org. Chem.  1995,  60:  4276 

8e Watanabe KA. Reichman U. Hirota K. Lopez C. Fox JJ. J. Med. Chem.  1979,  22:  21 

8f Boydell AJ. Vinader V. Linclau B. Angew. Chem. Int. Ed.  2004,  43:  5677 

9a Seaong LS. Marquez VE. Chem. Lett.  1995,  301 

9b Watts JK. Sadalapure K. Choubdar N. Pinto BM. Damha MJ. J. Org. Chem.  2006,  71:  921 

9c Katayama S. Takamatsu S. Naito M. Tanji S. Ineyama T. Izawa K. J. Fluorine Chem.  2006,  127:  524 

9d Takamatsu S. Maruyama T. Katayama S. Hirose N. Naito M. Izawa K. J. Org. Chem.  2001,  66:  7469 

10a Jeong LS. Moon HR. Yoo SJ. Lee SN. Chun MW. Lim YH. Tetrahedron Lett.  1998,  39:  5201 

10b Yoshimura Y. Endo M. Sakata S. Tetrahedron Lett.  1999,  40:  1937 

11a Yoshimura Y. Kitano K. Yamada K. Satoh H. Watanabe M. Miura S. Sakata S. Sasaki T. Matsuda A. J. Org. Chem.  1997,  62:  3140 

11b Zheng F. Zhang XH. Qiu XL. Zhang X. Qing FL. Org. Lett.  2006,  8:  6083 

12 Boivin J. Ramos L. Zard SZ. Tetrahedron Lett.  1998,  39:  6877 

13 Syvret RG. Vassilaros DL. Parees DM. Pez GP.
J. Fluorine Chem.  1994,  67:  277 

14

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.

15a Annedi SC. Li W. Samson S. Kotra LP. J. Org. Chem.  2003,  68:  1043 

15b Gouault S. Guérin C. Lemoucheux L. Lequeux T. Pommelet JC. Tetrahedron Lett.  2003,  44:  5061 

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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).

17 Brown MD. Gillon DW. Meakins GD. Whitham GH. J. Chem. Soc., Perkin Trans. 1  1985,  1623 

18a Choo H. Chong Y. Choi Y. Mathew J. Schinazi RF. Chu CK. J. Med. Chem.  2003,  46:  389 

18b Young RJ, and Miller JA. inventors; EP  514036.  ; Chem. Abstr. 1993, 118, 169532

19

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, H_{5 ′}), 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.

20

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, H_{2 ′} (2 dia)], 5.20 (br d, ² J _HF = 54.1 Hz, 2 H, H_{2 ′} (2 dia)], 6.17 (dd, ³ J _HF = 12.5 Hz, ³ J _HH = 4.0 Hz, 1 H, H_{1 ′} (dia 1)], 6.19 (dd, ³ J _HF = 10.6 Hz, ³ J _HH = 1.4 Hz, 1 H, H_{1 ′} (dia 2)], 6.40 (dd, ³ J _HF = 19.9 Hz, ³ J _HH = 4.2 Hz, 1 H, H_{1 ′} (dia 3)], 6.44 (dd, ³ J _HF = 12.5 Hz, ³ J _HH = 3.7 Hz, 1 H, H_{1 ′} (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]⁺.

21 Van Steenis JH. van der Gen A. J. Chem. Soc., Perkin Trans. 1  2002,  2117 

22a Zard SZ. Angew. Chem., Int. Ed. Engl.  1997,  36:  672 

22b Quiclet-Sire B. Zard SZ. Chem. Eur. J.  2006,  12:  6002