Download PDF
Synlett 2003(2): 0207-0210
DOI: 10.1055/s-2003-36792
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Pineda Molas, Yolanda Díaz, M. Isabel Matheu*, Sergio Castillón*
Departament de Química Analítica i Química Orgànica, Facultat de Química, Universitat Rovira i Virgili, Pl. Imperial Tarraco 1, 43005 Tarragona, Spain
Fax: +34(9775)59563; e-Mail: matheu@quimica.urv.es; e-Mail: castillon@quimica.urv.es;
Further Information

Publication History

Received 14 October 2002
Publication Date:
22 January 2003 (online)

    Permissions and Reprints All articles of this category

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

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-Arq), 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).