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

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.

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

References

<A NAME="RS03705ST-1">1</A>

New address: 5655 Greenshade Rd, San Diego, CA 92121, USA. Email: [e-mail].

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FDA-Approved drugs based upon fluorinated nucleosides include 5F-3TC (AIDS) and Gemcitabine(cancer).

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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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<A NAME="RS03705ST-22">22</A>

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⁺].

<A NAME="RS03705ST-23">23</A>

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.

<A NAME="RS03705ST-24">24</A>

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.

<A NAME="RS03705ST-25">25</A>

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%.

<A NAME="RS03705ST-26">26</A>

Compound 3b: UV (0.5 N NaOH): λ_max = 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): λ_max = 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⁺].