Design and Synthesis of 3′-Deoxy-3′-Fluoro-2′-O,3′-C-Vinylene-Linked ­Bicyclic Purine Nucleoside

Abstract

Starting from d-xylose via a 3-deoxy-3α-C-ethynyl-3-fluoro sugar as a key intermediate, a novel fluorinated bicyclic purine nucleoside has been synthesized. A neighboring-group participation pathway and a mechanism involving an intramolecular cycloaddition induced by fluorine are proposed for the formation of the key intermediate and the bicyclic nucleoside, respectively.

ethynyl group - fluorine - bicyclic nucleoside - neighboring-group participation - intramolecular cyclization

References and Notes

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17

Compound 10: space group P212121 with cell parameters: a = 7.4156(15) nm, b = 20.417(4) nm, c = 23.585(5) nm; CCDC 701133.

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22

Compound 3: white solid, mp 168 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.04-8.00 (m, 4 H, Ar), 7.60-7.57 (m, 1 H, Ar), 7.43-7.36 (m, 4 H, Ar), 6.02 (d, 1 H, J = 3.5 Hz, H-1), 5.31 (d, 1 H, J = 3.5 Hz, H-2), 4.82-4.79 (m, 1 H, H-5), 4.75-4.71 (m, 1 H, H-4), 4.66-4.64 (m, 1 H, H-5), 2.74 (s, 1 H, H-7), 1.51 (s, 3 H, H-9), 1.35 (s, 3 H, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.4, 164.1, 139.7, 133.5, 131.3, 129.9, 129.1, 128.7, 128.4, 128.2, 113.6, 104.7, 82.6, 78.1, 77.9, 77.8, 77.2, 63.8, 26.8, 26.6.

23

Compound 4: light yellow solid, mp 106-107 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.09-8.07 (m, 4 H, Ar), 7.62 (m, 1 H, Ar), 7.43-7.50 (m, 4 H, Ar), 5.61 (d, 1 H, J = 2.0 Hz,
H-1), 5.17 (d, 1 H, J = 2.0 Hz, H-2), 4.74-4.71 (m, 1 H, H-5), 4.64-4.60 (m, 1 H, H-4), 4.47-4.44 (m, 1 H, H-5), 3.47 (s, 3 H, H-8), 2.76 (br s, 1 H, 2-OH), 2.74 (s, 1 H, H-7). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.7, 165.5, 139.6, 133.8, 131.2, 130.0, 128.8, 128.6, 128.4, 107.1, 83.1, 81.4, 80.0, 77.2, 73.7, 65.2, 56.1.

24

Compound 6: light yellow oil. ^¹H NMR (500 MHz, CDCl₃): δ = 8.08-8.04 (m, 4 H, Ar), 7.64-7.61 (m, 1 H, Ar), 7.50-7.42 (m, 4 H, Ar), 5.59 (d, 1 H, J = 12.5 Hz, H-2), 5.13 (s, 1 H, H-1), 4.78-4.64 (3 H, m, H-4 and H-5), 3.50 (s, 3 H,
H-8), 2.79 (d, 1 H, J = 5.5 Hz, H-7). ESI-HRMS: m/z calcd for C₂₂H₁₈ClFO₆ [M + Na⁺]: 455.0674; found: 455.0672.

25

Compound 7: light yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 8.07-8.02 (m, 4 H, Ar), 7.65-7.61 (m, 1 H, Ar), 7.50-7.41 (m, 4 H, Ar), 6.34 (s, 1 H, H-1), 5.72 (d, 1 H, J = 11.6 Hz, H-2), 4.85-4.62 (m, 3 H, H-4 and H-5), 2.81 (d, 1 H, J = 5.2 Hz, H-7), 2.15 (s, 3 H, H-9). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 165.4, 164.4, 140.0, 134.2, 131.4, 130.2, 129.0, 128.8, 128.7, 128.2, 99.3, 93.2, 84.8, 81.1, 80.0, 74.46, 62.1, 21.1. ^¹9F NMR (CDCl₃): δ = -185.7.

26

Compound 9: white solid, mp: 211-212 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.94 (s, 1 H, H-2), 8.67 (s, 1 H, H-8), 8.11-8.09 (m, 2 H, Ar), 8.05-8.03 (m, 2 H, Ar), 7.70-7.67 (m, 1 H, Ar), 7.54-7.51 (m, 2 H, Ar), 7.46-7.44 (m, 2 H, Ar), 6.88 (s, 1 H, H-1′), 5.92 (dd, 1 H, J = 13.5, 1.0 Hz, H-2′), 4.98-4.93 (m, 1 H, H-4′), 4.90-4.82 (m, 2 H, H-5′), 2.94 (d, 1 H, J = 6.0 Hz, H-7′). ^¹³C NMR (125 MHz, CDCl₃): δ = 165.4, 164.2, 162.6, 153.2, 146.7, 142.8, 140.4, 134.7, 131.4, 130.3, 129.1, 128.0, 127.8, 122.0, 93.8, 90.3, 84.0, 83.0, 80.9, 72.7, 60.9.

27

Compound 10: white solid, mp 112-115 ˚C. ^¹H NMR (500 Hz, DMSO-d ₆): δ = 8.86 (s, 1 H), 8.62 (s, 1 H), 7.03 (t, J = 2.5 Hz, 1 H), 5.95 (d, J = 6.0 Hz, 1 H), 5.68 (dd, J = 6.0, 26.5 Hz), 5.62 (d, J = 2.5 Hz, 1 H), 5.01 (t, J = 5.0 Hz, 1 H), 4.25-4.20 (m, 1 H), 4.06 (s, 3 H), 3.82-3.77 (m, 1 H), 3.71-3.66 (m, 1 H). ^¹³C NMR (75 Hz, DMSO-d ₆): δ = 162.86, 157.15, 153.48 (d, J = 9.0 Hz, C-2), 152.88, 147.27, 112.07, 111.17 (d, ^² J _C-F = 202.1 Hz, C-3a), 103.91 (d, ^³ J _C-F = 24.5 Hz, C-3), 91.16 (d, ^³ J _C-F = 25.3 Hz, C-4), 90.63 (d, J = 13.0 Hz, C-6), 86.39 (d, J = 31.3 Hz, C-6a), 60.07 (d, J = 9.0 Hz, CH₂OH), 55.60 (OCH₃). ^¹9F NMR (400 Hz, DMSO-d ₆): δ = -167.61. ESI-HRMS: m/z calcd for C₁₃H₁₃FN₄O₄ [M + Na⁺]: 331.0819; found: 331.0811.