Synthesis of Fluorinated Homo-C-Nucleoside Analogues from New Carbo­hydrate-Derived Acylsilanes

Abstract

The stereocontrolled synthesis of new carbohydrate-derived acylsilanes with the silylcarbonyl moiety linked to the anomeric carbon via a methylene group is described. Reaction of these acylsilanes with perfluoroorganometallic reagents followed by treatment with hydrazines or amidines led to new polyfluorinated homo-C-nucleoside analogues, in a one-pot or two-step transformation, respectively.

acylsilane - carbohydrate - heterocycles - organofluorine - C-nucleoside

References

1a Watanabe KA. The Chemistry of C-Nucleosides, In Chemistry of Nucleosides and Nucleotides   Vol. 3:  Townsend LB. Plenum Press; New York: 1994.  p.421-535  

1b Postema MHD. In C-Glycoside Synthesis   Rees CW. CRC Press; Boca Raton: 1995.  Chap. 11. p.303-344  

2 Hanessian S. Pernet AG. Adv. Carbohydr. Chem. Biochem.  1976,  33:  111 

3a Sallam MAE. Townsend LB. Nucleosides Nucleotides  1998,  17:  1215 

3b Doboszewski B. Nucleosides Nucleotides  1997,  16:  1049 

3c Van Calenbergh S. De Bruyn A. Schraml J. Blaton N. Peeters O. De Keukeleire D. Busson R. Herdewijn P. Nucleosides Nucleotides  1997,  16:  291 

3d Pino Gonzalez MS. Lopez Herrera FJ. Pabon Aguas R. Uraga Baelo C. Nucleosides Nucleotides  1990,  9:  51 ; and references cited therein

4 Welsh JT. Eswarakrishnan S. Fluorine in Bioorganic Chemistry   Wiley; New York: 1991. 

5a Portella C. Dondy B. Tetrahedron Lett.  1991,  32:  83 

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5c Dondy B. Portella C. J. Org. Chem.  1993,  58:  6671 

5d Doussot P. Portella C. J. Org. Chem.  1993,  58:  6675 

6 Dondy B. Doussot P. Iznaden M. Muzard M. Portella C. Tetrahedron Lett.  1994,  35:  4357 

7

Chanteau, F.; Didier, B.; Dondy, B.; Plantier-Royon, R.; Portella, C. Eur. J. Org. Chem., accepted for publication.

8 Bouillon J.-P. Didier B. Dondy B. Doussot P. Plantier-Royon R. Portella C. Eur. J. Org. Chem.  2001,  187 

9a Dondoni A. Scherrmann M.-C. Tetrahedron Lett.  1993,  34:  7319 

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12 Yoshida J. Matsunaga S. Ishichi Y. Isoe S. J. Org. Chem.  1991,  56:  1307 

13a Plantier-Royon R. Portella C. Synlett  1994,  527 

13b Plantier-Royon R. Portella C. Tetrahedron Lett.  1996,  37:  6113 

14

Selected data for the acylsilanes 6 and 7. Compound 6: yellow syrup. ¹H NMR (250 MHz, CDCl₃): δ = 7.37-7.20 (m, 20 H, H-aromatic), 4.96-4.85 (m, 4 H, H-benzyl), 3.88 (ddd, 1 H, J _{1 ′ ,2 ′} = 9.2 Hz, J _{1 ′ ,2} = 7.6 Hz, J _{1 ′ ,2} = 3.6 Hz, H-1′), 3.79-3.63 (m, 4 H, H-3′, H-4′, H-6′, H-6′), 3.47 (m, 1 H, H-5′), 3.37 (t, 1 H, J _{2 ′ ,1 ′} = J _{2 ′ ,3 ′} = 9.2 Hz, H-2′), 2.87 (dd, 1 H, J _2,2 = 15.6 Hz, J _{2,1 ′} = 7.6 Hz, H-2), 2.79 (dd, 1 H, J _2,2 = 15.6 Hz, J _{2,1 ′} = 3.6 Hz, H-2), 0.31 (s, 9 H, SiMe₃) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 247.0 (C=O), 138.4-137.9 (C-q aromatic), 128.4-127.5 (CH aromatic), 87.2 (C-3′), 81.0 (C-2′), 78.7 (C-5′), 78.2 (C-4′), 75.5 (CH₂ benzyl), 74.9 (CH₂ benzyl), 74.8 (CH₂ benzyl), 74.6 (C-1′), 73.3 (CH₂ benzyl), 68.6 (C-6′), 49.5 (C-2), -3.4 (SiMe₃) ppm. MS (EI): m/z
(%) = 638 (16) [M⁺], 623 (32) [M - 15], 522, 517, 439 (100), 372, 279. Compound 7: yellow syrup. ¹H NMR (250 MHz, CDCl₃): δ = 7.27-7.10 (m, 15 H, H-aromatic), 4.51-4.32 (m, 7 H, 6 H-benzyl, H-1′), 4.05 (dt, 1 H, J _{4 ′ ,3 ′} = 5.2 Hz, J _{4 ′ ,5 ′} = J _{4 ′ ,5 ′} = 3.9 Hz, H-4′), 3.77 (t, 1 H, J _{3 ′ ,2 ′} = J _{3 ′ ,4 ′} = 5.2 Hz, H-3′), 3.49 (t, 1 H, J _{2 ′ ,3 ′} = J _{2 ′ ,1 ′} = 5.2 Hz, H-3′), 3.40 (dd, 1 H, J _{5 ′ ,5 ′} = 10.5 Hz, J _{5 ′ ,4 ′} = 3.9 Hz, H-5′), 3.35 (dd, 1 H, J _{5 ′ ,5 ′} = 10.5 Hz, J _{5 ′ ,4 ′} = 3.9 Hz, H-5′), 2.71 (dd, 1 H, J _2,2 = 16.5 Hz, J _{2,1 ′} = 7.0 Hz, H-2), 2.56 (dd, 1 H, J _2,2 = 16.5 Hz, J _{2,1 ′} = 5.5 Hz, H-2), 0.20 (s, 9 H, SiMe₃) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 247.2 (C=O), 138.7-138.3 (C-q aromatic), 128.8-128.0 (CH aromatic), 81.5 (C-4′), 80.8 (C-2′), 77.2 (C-3′), 76.7 (C-1′), 73.8 (CH₂ benzyl), 72.2 (CH₂ benzyl), 72.1 (CH₂ benzyl), 70.5 (C-5′), 52.2 (C-2), -2.8 (SiMe₃) ppm. MS (EI): m/z (%) = 518 (26) [M⁺], 427 (100), 337, 261, 179.

15

Experimental Procedure for the Synthesis of Enone 8. To a solution, under Ar, of the acylsilane 6 (100 mg, 0.16 mmol) and perfluorobutyl iodide (32 µL, 0.19 mmol) in anhydrous Et₂O (10 mL) was added dropwise, at -78 °C, a solution of MeLi 1 M in Et₂O (190 µL, 0.19 mmol). After 30 min at
-78 °C, the resulting mixture was stirred at r.t. for 3 d. The reaction was then washed with a sat. NaCl solution and the aqueous layer extracted twice with Et₂O. The organic layer was dried over MgSO₄, filtered and Et₂O was evaporated. The residue was purified by a silica gel column chromatography (petroleum ether/EtOAc: 95:5) to afford 99 mg (84%) of an unseparable mixture of enone 8 (75%) and the corresponding hydroperfluoroketone 9 (25%). Selected data of the mixture of enone 8 and the corresponding hydroperfluoroketone 9. Enone 8: ¹H NMR (250 MHz, CDCl₃): δ = 7.43-7.16 (m, 20 H, H-aromatic), 5.03 (d, 1 H, J = 12.5 Hz, H-benzyl), 4.97 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.91 (d, 1 H, J = 11.0 Hz, H-benzyl), 4.84 (d, 1 H, J = 11.0 Hz, H-benzyl), 4.64 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.63 (d, 1 H, J = 12.0 Hz, H-benzyl), 4.54 (d, 1 H, J = 12.5 Hz, H-benzyl), 4.48 (d, 1 H, J = 12.0 Hz, H-benzyl), 3.88 (ddd, 1 H, J _{1 ′ ,2 ′} = 9.3 Hz, J _{1 ′ ,1} = 7.9 Hz, J _{1 ′ ,1} = 4.4 Hz, H-1′), 3.79-3.66 (m, 4 H, H-3′, H-4′, H-6′, H-6′), 3.50 (m, 1 H, H-5′), 3.38 (t, 1 H, J _{2 ′ ,3 ′} = J _{2 ′ ,1 ′} = 9.3 Hz, H-2′), 2.93 (ddd, 1 H, J _1,2 = 17.1 Hz, J _{1,1 ′} = 4.4 Hz, ⁴ J _1,F = 2.0 Hz, H-1), 2.85 (ddd, 1 H, J _1,2 = 17.1 Hz, J _{1,1 ′} = 7.9 Hz, ⁴ J _1,F = 2.0 Hz, H-1) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 188.7 (dd, ² J _C,F = 17.7 Hz, ³ J _C,F = 3.2 Hz, C=O), 138.7-138.1 (C-q aromatic), 129.0-128.2 (CH aromatic), 87.7 (C-3′), 80.7 (C-2′), 79.4 (C-5′), 78.6 (C-4′), 76.1 (CH₂ benzyl), 75.4 (CH₂ benzyl), 75.3 (CH₂ benzyl), 74.5 (C-1′), 73.9 (CH₂ benzyl), 68.9 (C-6′); 42.7 (d, ³ J _C,F = 1.6 Hz, C-1) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -84.6 (m, 3 F, CF₃), -121.6 (dm, 2 F, ³ J _F,F = 14.7 Hz, CF₂), -151.8 (dm, 1 F, ³ J _F,F = 134.5 Hz, CF₂-CF), -152.6 (dm, 1 F, ³ J _F,F = 134.5 Hz, CO-CF) ppm. Hydroperfluoroketone 9 (50:50 mixture of two diastereomers): ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -81.2 (m, 3 F, CF₃), -120.3 (dm, 2 F, ² J _F,F = 282.0 Hz, CHF-CF₂), -126.7 (m, 2 F, CF₂-CF₂), -205.3 (dm, 1 F, ² J _H,F = 45.7 Hz, CHF) ppm.

16 Dawe RD. Fraser-Reid B. J. Org. Chem.  1984,  49:  522 

17

Selected data for the mixture of enones 10. Enone β-10: ¹H NMR (250 MHz, CDCl₃): δ = 7.41-7.26 (m, 15 H, H-aromatic), 4.79 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.67 (d, 1 H, J = 11.8 Hz, H-benzyl), 4.63 (d, 1 H, J = 11.8 Hz, H-benzyl), 4.58 (d, 1 H, J = 11.8 Hz, H-benzyl), 4.54-4.43 (m, 2 H, H-1′, H-benzyl), 4.39 (d, 1 H, J = 11.5 Hz, H-benzyl), 4.24 (ddd, 1 H, J _{4 ′ ,5 ′} = 4.1 Hz, J _{1 ′ ,1} = 3.5 Hz, J _{1 ′ ,1} = 3.4 Hz, H-4′), 3.96 (dd, 1 H, J _{3 ′ ,2 ′} = 5.3 Hz, J _{3 ′ ,4 ′} = 3.4 Hz, H-3′), 3.71 (dd, 1 H, J _{2 ′ ,1 ′} = 6.9 Hz, J _{2 ′ ,3 ′} = 5.3 Hz, H-2′), 3.59 (dd, 1 H, J _{5 ′ ,5 ′} = 10.6 Hz, J _{5 ′ ,4 ′} = 3.5 Hz, H-5′), 3.49 (dd, 1 H, J _{5 ′ ,5 ′} = 10.6 Hz, J _{5 ′ ,4 ′} = 4.1 Hz, H-5′), 2.96 (dm, 1 H, J _1,1 = 17.9 Hz, H-1), 2.87 (dm, 1 H, J _1,1 = 17.9 Hz, H-1) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 188.5 (dd, ² J _C,F = 17.2 Hz, ³ J _C,F = 2.7 Hz, C=O), 137.9-137.5 (C-q aromatic), 128.4-127.6 (CH aromatic), 82.2 (C-4′), 80.4 (C-2′), 77.2 (C-3′), 75.5 (C-1′), 73.4 (CH₂ benzyl), 72.1 (CH₂ benzyl), 71.7 (CH₂ benzyl), 70.0 (C-5′), 44.2 (C-1) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -84.6 (m, 3 F, CF₃), -121.6 (dm, 2 F, ³ J _F,F = 15.3 Hz, CF₂), -151.7 (dm, 1 F, ³ J _F,F = 137.3 Hz, CO-CF), -152.4 (dm, 1 F, ³ J _F,F = 137.3 Hz, CF₂-CF) ppm. Enone α-10: ¹³C NMR (62.5 MHz, CDCl₃): δ = 188.4 (dd, ² J _C,F = 17.2 Hz, ³ J _C,F = 2.7 Hz, C=O), 138.0-137.7 (C-q aromatic), 128.4-127.6 (CH aromatic), 80.1 (C-4′), 79.3 (C-2′), 77.2 (C-3′), 75.4 (C-1′), 73.6 (CH₂ benzyl), 72.7 (CH₂ benzyl), 71.7 (CH₂ benzyl), 69.9 (C-5′), 41.6 (C-1) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -84.6 (m, 3 F, CF₃) ppm.

18a Lopez Herrera FJ. Uraga Baelo C. Carbohydr. Res.  1985,  139:  95 

18b Lopez Herrera FJ. Uraga Baelo C. Carbohydr. Res.  1985,  143:  161 

18c Lopez Herrera FJ. Pino Gonzalez MS. Pabon Aguas R. J. Chem. Soc., Perkin Trans. 1  1989,  2401 

19

Experimental Procedure for the Synthesis of the Pyrimidines 11 and 12. To a suspension of acetamidinium chloride (5 equiv) and KOH (3 equiv) in CH₂Cl₂ (15 mL) stirred for 1 h, was added a solution of the mixture of enone 8 and the corresponding hydroperfluoroketone 9 or the mixture of enones 10 (1 equiv) in CH₂Cl₂ (2 mL). After 24 h at r. t., the reaction was washed with a sat. NaCl solution and the aqueous layer extracted twice with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered and the solvent was evaporated. The residue was purified by a silica gel column chromatography (petroleum ether/EtOAc: 90:10). Selected data of pyrimidine 11: yellow syrup (79%). ¹H NMR (250 MHz, CDCl₃): δ = 7.35-7.00 (m, 20 H, H-aromatic), 4.95-4.35 (m, 8 H, H-benzyl), 3.70-3.40 (m, 6 H, H-1′, H-3′, H-4′, H-5′, H-6′, H-6′), 3.33 (t, 1 H, J _{2 ′ ,3 ′} = J _{2 ′ ,1 ′} = 9.3 Hz, H-2′), 3.00 (dd, 1 H, J _1,1 = 15.1 Hz, J _{1,1 ′} = 3.0 Hz, H-1), 2.80 (dd, 1 H, J _1,1 = 15.1 Hz, J _{1,1 ′} = 6.9 Hz, H-1), 2.68 (s, 3 H, CH₃) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -83.9 (m, 3 F, CF₃), -117.4 (dm, 2 F, ⁴ J _F,F = 19.0 Hz, CF₂), -139.8 (m, 1 F, CF) ppm. Selected data of pyrimidine 12: yellow syrup (99%, α/β = 20:80), β-anomer 12: ¹H NMR (250 MHz, CDCl₃): δ = 7.38-7.23 (m, 15 H, H-aromatic), 4.63-4.45 (m, 7 H, 6 H-benzyl, H-1′), 4.20 (ddd, 1 H, J _{4 ′ ,3 ′} = 4.2 Hz, J _{4 ′ ,5 ′} = 4.1 Hz, J _{4 ′ ,5 ′} = 3.5 Hz, H-4′), 3.95 (t, 1 H, J _{3 ′ ,2 ′} = J _{3 ′ ,4 ′} = 4.2 Hz, H-3′), 3.81 (dd, 1 H, J _{2 ′ ,1 ′} = 5.9 Hz, J _{2 ′ ,3 ′} = 4.2 Hz, H-2′), 3.56 (dd, 1 H, J _{5 ′ ,5 ′} = 10.7 Hz, J _{5 ′ ,4 ′} = 3.5 Hz, H-5′), 3.51 (dd, 1 H, J _{5 ′ ,5 ′} = 10.7 Hz, J _{5 ′ ,4 ′} = 4.1 Hz, H-5′), 3.16 (dd, 1 H, J _1,1 = 14.0 Hz, J _{1,1 ′} = 7.1 Hz, H-1), 3.11 (dd, 1 H, J _1,1 = 14.0 Hz, J _{1,1 ′} = 5.4 Hz, H-1), 2.70 (s, 3 H, CH₃) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 163.4 (d, ² J _C,F = 9.9 Hz, C-4), 158.5 (d, ² J _C,F = 15.3 Hz, C-6), 153.2 (d, ¹ J _C,F = 273.8 Hz, C-5), 138.0-137.8 (C-q aromatic), 128.3-127.5 (CH aromatic), 118.1 (tq, ¹ J _C,F = 287.4 Hz, ² J _C,F = 35.6 Hz, CF₃), 82.0 (C-4′), 80.6 (C-2′), 78.3 (C-1′), 77.0 (C-3′), 73.3 (CH₂ benzyl), 72.0 (CH₂ benzyl), 71.8 (CH₂ benzyl), 70.2 (C-5′), 35.2 (CH₂), 25.0 (CH₃) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -83.5 (m, 3 F, CF₃), -117.4 (d, 2 F, ⁴ J _F,F = 21.5 Hz, CF₂), -139.4 (m, 1 F, CF) ppm. α-Anomer 12: ¹³C NMR (62.5 MHz, CDCl₃): δ = 163.2 (d, ² J _C,F = 9.2 Hz, C-4), 160.0 (d, ² J _C,F = 14.5 Hz, C-6), 80.5 (C-4′), 79.1 (C-3′), 77.9 (C-1′), 77.8 (C-2′), 73.0 (CH₂ benzyl), 72.6 (CH₂ benzyl), 72.0 (CH₂ benzyl), 70.0 (C-5′), 25.1 (CH₃) ppm.¹⁹F NMR (235.4 MHz, CDCl₃): δ = -117.5 (dm, 2 F, ⁴ J _F,F = 21.5 Hz, CF₂), -139.2 (m, 1 F, CF) ppm.

20

Experimental Procedure for the Synthesis of the Pyrazoles 13 and 14. To a solution, under Ar, of the acylsilane 6 or 7 (1 mmol) and perfluorobutyl iodide (1.2 mmol) in anhydrous Et₂O (15 mL) was added dropwise, at
-78 °C, a solution of MeLi 2.2 M in Et₂O (1.2 mmol). After 30 min at -78 °C, the resulting mixture was stirred at r.t. for 3 d. Methylhydrazine (5 mmol) was then added and the reaction was monitored by TLC (petroleum ether/EtOAc 85:15). After 18 h at r.t., the reaction was washed with a sat. NaCl solution and the aqueous layer extracted twice with Et₂O. The organic layer was dried over MgSO₄, filtered and ether was evaporated. The residue was purified by a silica gel column chromatography (petroleum ether/EtOAc: 90:10). Selected data of pyrazole 13: yellow syrup (83%). ¹H NMR (250 MHz, CDCl₃): δ = 7.33-7.04 (m, 20 H, H-aromatic), 4.92-4.67 (m, 4 H, H-benzyl), 4.59-4.35 (m, 4 H, H-benzyl), 3.72 (s, 3 H, NCH₃), 3.70-3.45 (m, 6 H, H-1′, H-3′, H-4′, H-5′, H-6′, H-6′), 3.32 (t, 1 H, J _{2 ′,3 ′} = J _{2 ′,1 ′} = 8.7 Hz, H-2′), 3.04 (dd, 1 H, J _1,1 = 14.8 Hz, J _{1,1 ′} = 3.3 Hz, H-1), 2.77 (dd, 1 H, J _1,1 = 14.8 Hz, J _{1,1 ′} = 7.3 Hz, H-1) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 146.9 (d, ¹ J _C,F = 260.6 Hz, C-4), 138.4-138.1 (C-q aromatic), 137.9 (d, ² J _C,F = 9.7 Hz, C-5), 135.2 (d, ² J _C,F = 9.7 Hz, C-3), 128.5-127.9 (CH aromatic), 117.5 (tq, ¹ J _C,F = 287.4 Hz, ² J _C,F = 35.6 Hz, CF₃), 87.2 (C-3′), 81.3 (C-2′), 79.2 (C-5′), 78.5 (C-4′), 77.4 (C-1′), 75.6 (CH₂ benzyl), 75.0 (CH₂ benzyl), 74.9 (CH₂ benzyl), 73.4 (CH₂ benzyl), 68.8 (C-6′), 39.7 (CH₂), 29.7 (NCH₃) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -85.5 (m, 3 F, CF₃), -113.3 (dm, 2 F, ⁴ J _F,F = 11.7 Hz, CF₂), -166.9 (m, 1 F, CF) ppm. Selected data of pyrazole 14: yellow syrup (100%, α/β = 25:75). β-Anomer: ¹H NMR (250 MHz, CDCl₃): δ = 7.42-7.20 (m, 15 H, H-aromatic), 4.65-4.42 (m, 7 H, 6 H-benzyl, H-1′), 4.23 (m, 1 H, H-4′), 3.90 (t, 1 H, J _{3 ′,2 ′} = J _{3 ′,4 ′} = 5.6 Hz, H-3′), 3.73 (t, 1 H, J _{2 ′,3 ′}= J _{2 ′,1 ′} = 5.6 Hz, H-2′), 3.70 (s, 3 H, NCH₃), 3.56 (dd, 1 H, J _{5 ′,5 ′} = 10.9 Hz, J _{5 ′,4 ′} = 3.4 Hz, H-5′), 3.48 (dd, 1 H, J _{5 ′,5 ′} = 10.9 Hz, J _{5 ′,4 ′} = 5.3 Hz, H-5′), 2.92 (dm, 1 H, J _1,1 = 14.9 Hz, H-1), 2.85 (dm, 1 H, J _1,1 = 14.9 Hz, H-1) ppm. ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -85.4 (m, 3 F, CF₃), -113.2 (dm, 2 F, ⁴ J _F,F = 12.5 Hz, CF₂), -167.3 (m, 1 F, CF) ppm. α-Anomer: ¹⁹F NMR (235.4 MHz, CDCl₃): δ = -85.1 (m, 3 F, CF₃), -113.1 (dm, 2 F, ⁴ J _F,F = 12.5 Hz, CF₂), -167.7 (m, 1 F, CF) ppm.