Synthesis of 1′-C-Fluoromethyl-ddC by Selectfluor-Induced Glycosylation of exo-Glycals

Abstract

1′-C-fluoromethyl-ddC has been synthesized from 4-pentene-1,2-diol which is easily obtained from glycidol. The key steps are the synthesis of an exo-glycal by a 5-exo iodo-cyclization of a 4-pentene-1,2-diol and elimination, and a fluoro-glycosylation using an exo-glycal as glycosyl donor.

Key words

nucleosides - fluorine - glycosylation - electrophilic addition - cyclization

References

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23

Compound 11: t-BuOK (165 mg, 1.35 mmol) was added to a solution of 6 (220 mg, 0.52 mmol) in dry CH₂Cl₂ (10 mL). The mixture was kept at r.t. for 2.5 h, poured into 10% Na₂S₂O₃ and extracted with CH₂Cl₂. The organic phase was dried with MgSO₄ and concentrated to obtain 9. To a solution of the previously obtained exo-glycal 9 in CH₂Cl₂ (2.5 mL) N⁴-Acetyl-bis(trimethylsilyl)cytosine (0.68 mmol) and NIS (155 mg, 0.68 mmol) were added, and the reaction was kept at r.t. for 2 h, diluted with NaHCO₃ and extracted with CH₂Cl₂. The combined organic layers were dried with MgSO₄ and concentrated. Purification by column chromatography (Merck silica gel 60, 0.040-0.063 mm, eluent: EtOAc-hexane, 5:3) and radial chromatography (Merck silica gel 60 F₂₅₄) gave 11 (40 mg, 14% yield).
¹H NMR (300 MHz, CDCl₃): δ (ppm) = 9.79 (s, 1 H, NH), 8.13 (d, 1 H, J _6,5 = 7.5 Hz, H-6), 7.50-7.46, 7.36-7.24 (2 m, 16 H, H-Ar, H-5), 4.50 (d, 1 H, J _gem = 10.8 Hz, H-1′a), 4.30-4.25 (m, 1 H, H-5′), 3.71 (d, 1 H, H-1′b), 3.30-3.22 (m, 2 H, H-6′), 2.97-2.89, 2.75-2.65 (2 m, 2 H, H-3′), 2.27 (s, 3 H, CH₃), 2.00-1.88 (m, 2 H, H-4′).
¹³C NMR (75.4 MHz, CDCl₃): δ(ppm) = 179.0 (CO), 163.0 (C-2), 145.0 (C-6), 143.5 (C-Ar_q), 128.5, 127.8, 127.0 (CH-Ar), 98.2 (C-2′), 95.6 (C-5), 86.7 (C-Ph₃), 80.5 (C-5′), 65.3 (C-6′), 35.3 (C-3′), 27.8 (C-4′), 24.9 (CH₃), 12.1 (C-1′).

29

Compound 13: Following a similar procedure for the synthesis of 9, exo-glycal 10 was prepared starting from 8 (290 mg, 0.52 mmol) in dry CH₂Cl₂ (10 mL) using t-BuOK (176 mg, 1.56 mmol). To a solution of exo-glycal 10 in CH₃NO₂ (4 mL) N⁴-Acetyl-bis(trimethylsilyl)cytosine (1.04 mmol) was added. Selectfluor {1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)} (272 mg, 0.77 mmols) was added and the reaction was kept at r.t. for 25 min. Then, the mixture was diluted with EtOAc, filtered and concentrated to dryness. Purification by radial chromatography (Merck silica gel 60 F₂₅₄, eluent: CH₂Cl₂-CH₃OH, 50:1) gave 191 mg (61% yield) of 13 as an inseparable diastereomeric mixture.
¹H NMR (400 MHz, CDCl₃) diastereomeric mixture: δ (ppm) = 9.90 (br s, 2 H, NH), 8.27 (d, 1 H, J = 7.6 Hz, H-6a), 8.19 (d, 1 H, J = 8.0 Hz, H-6b), 7.46-7.45 (m, 2 H, H-5a, H-5b), 7.38-7.19, 6.84-6.82 (m, 26 H, H-Ar), 5.03-4.59 (m, 4 H, H1′a, H1′b), 4.48-4.47, 4.31-4.27 (2 m, 2 H, H5′a, H5′b), 3.89 [s, 6 H, CH₃(DMTr)], 3.35-3.17 (m, 4 H, H6′a, H6′b), 2.96-2.36 (m, 4 H, H3′a, H3′b), 2.27 [s, 3 H, CH₃(OAc)], 2.24 [s, 3 H, CH₃(OAc)], 1.93-1.75 (m, 4 H, H-4′a, H-4′b).
¹³C NMR (100.6 MHz, CDCl₃): δ (ppm) = 158.5 (C=O), 146.4, 145.0 (C-6), 135.8, 135.6, 135.5, 130.0, 129.9, 128.0, 127.9, 127.7, 126.8 (C-Ar), 113.2, 113.1 (C-2′), 99.2, 96.4 (C-5), 86.3, 86.1 (C-Ph₃), 83.1 (J _C,F = 181.3), 83.3 (J _C,F& nbsp;= 179.3) (C-1′), 80.9 (C-5′), 65.2, 64.1 (C-6′), 55.1 (OCH₃), 32.8, 32.2 (C-3′), 27.1, 26.4 (C-4′), 24.8 (CH₃).
¹⁹F NMR (400 MHz, CDCl₃): δ (ppm) = -228.03 (t, J = 48.9 Hz), -228.73 (t, J = 50.0 Hz).

30

Compound 15: A solution of 13 (64 mg, 0.10 mmol) in 0.1 M 80% HOAc was stirred at r.t. for 15 min, then was neutralized with 1 M NaHCO₃ and extracted with EtOAc. Purification by radial chromatography (Merck silica gel 60 F₂₅₄, eluent: CH₂Cl₂-CH₃OH, 25:1) gave 14 (19 mg, 63% yield). Then, a solution of 10% NH₄OH (1 mL) was added to 14 (10 mg, 0.03 mmol) in MeOH. The mixture was kept at r.t. for 1 h. Purification by preparative chromatography (Merck silica gel 60 F₂₅₄, eluent: CH₂Cl₂-CH₃OH, 10:1) gave 15 as an inseparable α/β mixture (5 mg, 69% yield).
¹H NMR (400 MHz, CDCl₃): δ (ppm) = 8.09 (d, 1 H, J = 7.2 Hz, H-6a), 7.60 (d, 1 H, J = 8.0 Hz, H-6b), 5.78 (d, 1 H, H-5a), 5.74 (d, 1 H, H-5b), 4.81-4.60 (m, 4 H, H-1′a, H-1′b), 4.39-4.33, 4.21-4.18 (2 m, 2 H, H-5′a, H-5′b), 3.76-3.55 (m, 4 H, H-6′a, H-6′b), 2.65-2.63, 2.51-2.48 (2 m, 4 H, H-3′a, H-3′b), 2.01-1.98, 1.86-1.83 (2 m, 4 H, H-4′a, H-4′b).
¹⁹F NMR (400 MHz, CDCl₃): δ (ppm) = -225.40 (t, J = 50.0 Hz), -226.12 (t, J = 50.4 Hz).