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Synlett 2005(10): 1586-1590  
DOI: 10.1055/s-2005-869869
LETTER
© Georg Thieme Verlag Stuttgart · New York

Electrophilic Fluorination of 5-(Cyanomethyl)imidazole-4-carboxylate Nucleosides: Facile Entry to 3-Fluoro-3-deazaguanosine Analogues

Kandasamy Sakthivel*, P. Dan Cook
Biota Inc, 2232 Rutherford Rd, Carlsbad, CA, 92008, USA
Fax: +1(858)6252433; e-Mail: sakvel@hotmail.com;
Further Information

Publication History

Received 28 March 2005
Publication Date:
07 June 2005 (online)

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Abstract

A facile and efficient methodology is described for the synthesis of 3-fluoro-3-deazaguanosines based on a novel electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxylate nucleosides. This general methodology can be readily applied to the synthesis of sugar-modified 3-fluoro-3-deazaguanosine analogues.

Key words

nucleosides - 3-deazaguanosine - 3-deazapurine - fluorinated nucleosides - electrophilic fluorination

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New address: 5655 Greenshade Rd, San Diego, CA 92121, USA. Email: sakthi123@earthlink.net.

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Compound 5a (diastereomers 1:1): 1H NMR (300 MHz, CDCl3): δ = 3.92 (s, 3 H, OCH3), 4.66-4.90 (m, 3 H, 4′, 5′,5′′-H), 5.90-6.06 (m, 2 H, 2′,3′-H), 6.48 (d, J = 6.7 Hz, 1 H, 1′-H), 7.31-7.63 (m, 10 H, 9 Ar-H, Imi-2-H), 7.92-8.14 (m, 7 H, 6 × Ar-H, CHFCN). 19F NMR (282 MHz, CDCl3): δ (diastreomers) = -175.76 (d, J F-H = 43.6 Hz), -172.72 (d, J F-H = 43.6 Hz). HRMS: m/z calcd for C33H26FN3O9 [MNa+]: 650.1551; found: 650.1550. ESI-MS: m/z = 650 [MNa+].
Compound 5b (diastereomers 1:1): 1H NMR (300 MHz, CDCl3): δ = 2.15 (s, 3 H, COCH3), 2.20-2.50 (m, 5 H, 3′,3′′-H, Tol-CH3), 3.94 (s, 3 H, OCH3), 4.53-4.75 (m, 3 H, 4′, 5′,5′′-H), 5.40-5.46 (m, 1 H, 2′-H), 6.13-6.16 (m, 1 H, 1′-H), 7.25 (m, 2 H, Ar-H), 7.41 (d, 1 H, J = 43.1 Hz, CHFCN), 7.86-7.98 (m, 3 H, 2 × Ar-H, Imi-2-H). 19F NMR (282 MHz, CDCl3): δ (diastreomers) = -176.41 (d, J F-H = 43.6 Hz),
-174.03 (d, J F-H = 43.6 Hz). HRMS: m/z calcd for C22H22FN3O7 [MNa+]: 482.1334; found: 482.1333. ESI-MS: m/z = 482 [MNa+].
Compound 5c (diastereomers 1:1): 1H NMR (300 MHz, CDCl3): δ = 1.58 (2 × s, 3 H, CH3), 3.98 (2 × s, 3 H, OCH3), 4.78-4.96 (m, 3 H, 4′, 5′,5′′-H), 5.75 (2 × d, 1 H, 3′-H), 6.66 and 6.80 (2 × s, 1 H, 1′-H), 7.26-7.62 (m, 10 H, 9 × Ar-H, Imi-2-H), 7.80-8.19 and 8.20 (m, 7 H, 6 × Ar-H, CHFCN). 19F NMR (282 MHz, CDCl3): δ (diastereomers) = -179.31 (d, J F-H = 41.6 Hz), -170.0 (d, J F-H = 41.6 Hz). HRMS: m/z calcd for C34H28FN3O9 [MNa+]: 664.1707; found: 664.1704. ESI-MS: m/z = 664 [MNa+].

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Compound 12a (diastereomers 1:3): 1H NMR (300 MHz, DMSO-d 6): δ = 3.45-3.70 (m, 5 H, 2′, 3′-H, OCH3), 3.85-3.86 (m, 1 H, 4′-H), 4.04-4.16 (m, 2 H, 5′,5′′-H), 5.08-5.22 (m, 2 H, 3′, 5′′-OH), 5.40 and 5.49 (2 × d, J = 4.1, 4.7 Hz, 1 H, 2′-OH), 5.51 (d, J = 5.56 Hz, 1 H, 1′-H), 7.17 (d, J H-F = 44.8 Hz, 0.3 H, CHF), 7.22 (d, J H-F = 44.8 Hz, 0.7 H, CHF), 7.40 and 7.60 (2 × br s, 2 H, NH2), 8.21 and 8.24 (2 × br s, 1 H, Imi-2H), 8.50 (br s, 1 H, NH). 19F NMR (282 MHz, CDCl3): δ (diastereomers) = -176.84 (d, J F-H = 43.6 Hz),
-173.84 (d, J F-H = 43.6 Hz). HRMS: m/z calcd for C12H17FN4O6 [MNa+] = 355.1030; found: 355.1034. ESI-MS: m/z = 355 [MNa+].

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To our surprise, 5-imidomethoxy imidazole-4-carboxamide riboside analogues similar to 12a have never been detected, or proposed to form, during the cyclization reactions of 4a or 10a in basic alcoholic solutions. See ref. 11 and ref. 20.

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A similar ring-closure was also effected successfully when using 5% Na2CO3 in EtOH, but, because of its high polarity, we had difficulties in isolating the product from the inorganic salt. Although the ring-closure reaction could also be realized using several organic amine bases (DBU, pyridine, N,N-diisopropylethylamine, etc.), we prefer to use less volatile Et3N base.

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Although the conversions of the ring-closure reactions were >80%, the high polarities of products 3a-c restricted their isolated yields to only 60-68%.

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Compound 3b: UV (0.5 N NaOH): λmax = 287 nm (ε 9400). 1H NMR (300 MHz, DMSO-d 6): δ = 1.80-1.88 (m, 1 H, 3′-H), 2.08-2.18 (m, 1 H, 3′′-H), 3.51-3.55 (m, 1 H, 5′-H), 3.64-3.67 (m, 1 H, 5′′-H), 4.28-4.42 (m, 2 H, 4′-H, 2′-OH), 5.01 (t, 1 H, J = 5.3 Hz, 5′-OH), 5.52 (br s, 2 H, NH2), 5.61 (d, J = 4.4 Hz, 1 H, 2′-H), 5.78 (s, 1 H, 1′-H), 8.04 (s, 1 H, 2-H), 10.44 (br s, 1 H, NH). 19F NMR (282 MHz, DMSO-d 6): δ = -186.70. 13C NMR (75 MHz, DMSO-d 6): δ = 34.6, 62.9, 76.4, 81.7, 93.1 (d, J = 5.5 Hz), 122.2 (d, J = 215.0 Hz), 123.2, 132.1 (d, J = 9.0 Hz), 135.9 (d, J = 22.0 Hz), 137.6, 155.0. HRMS: m/z calcd for C11H14FN4O4 [MH+] = 285.0999; found: 285.0991; [MNa+]: 307.0819; found: 307.0809. ESI-MS: m/z = 285 [MH+].
Compound 3c: UV (H2O): λmax = 272 nm (ε 8200), 310 nm (ε 7100). 1H NMR (300 MHz, DMSO-d 6): δ = 0.71 (s, 3 H, CH3), 3.62-3.69 (m, 1 H, 5′-H), 3.82-3.93 (m, 3 H, 3′,4′,5′′-H), 5.15 (s, 1 H, 2′-OH), 5.21-5.27 (m, 2 H, 3′,5′-OH), 5.54 (br s, 2 H, NH2), 5.77 (s, 1 H, 1′-H), 8.24 (s, 1 H, 2-H), 10.46 (br s, 1 H, NH). 19F NMR (282 MHz, DMSO-d 6): δ =
-186.46. 13C NMR (75 MHz, DMSO-d 6): δ = 20.5, 59.7, 71.7, 79.5, 83.0, 93.3 (d, J = 7 Hz), 122.2 (d, J = 214 Hz), 122.9, 132.2 (d, J = 9 Hz), 135.9 (d, J = 22 Hz), 137.5, 155.0. HRMS: m/z calcd for C12H16FN4O5 [MH+]: 315.1105; found: 315.1102; [MNa+]: 337.0924; found: 337.0920. ESI-MS: m/z = 315 [MH+].