The Synthesis of the New C-Nucleoside 6-Deazaformycin B

Abstract

The synthesis of the 6-deaza analogue of formycin B is described, through the condensation of lithiated 4-methoxy-2-methyl-3-trifluoroacetamidopyridine with a suitably protected ribonolactone, dehydration of the resulting hemiacetal, reduction and subsequent ring closure followed by protecting group manipulation.

Key words

C-nucleosides - heterocycles - pyrazolo[4,3-b]pyridine - lithiation - ring closure

References and Notes

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19

Data for N-(4-Methoxy-2-methylpyridin-3-yl)trifluoro­-acetamide (9). Yield: 96%; mp 164-165 °C (EtOH). ¹H NMR (DMSO-d ₆): δ = 2.31 (s, 3 H, CH₃), 3.86 (s, 3 H, CH₃O), 7.05 (d, J _5,6 = 5.80 Hz, 1 H, H-5), 8.35 (d, J _6,5 = 5.80 Hz, 1 H, H-6), 10.93 (br s, D₂O exch., 1 H, NH). ¹³C NMR (DMSO-d ₆): δ = 20.30 (CH₃), 56.18 (CH₃O), 106.00 (C-5), 107.50, 113.22, 118.96, 124.69 (CF₃CO), 118.23 (C-3), 149.93 (C-6), 154.15, 154.88, 155.60, 156.31 (CF₃ CO), 156.09 (C-2), 160.89 (C-4). Anal. Calcd for C₉H₉F₃N₂O₂: C, 46.16; H, 3.87; N, 11.96. Found: C, 45.87; H, 3.76; N, 12.13.

20

Data for N-[4-Methoxy-2-(2,3,5-tri-O-benzyl-d-ribo­-furanosylidene)methylpyridin-3-yl]trifluoroacetamide (13). Yield: 71%; mp 146-151 °C (EtOH). ¹H NMR (CDCl₃): δ = 3.56 (m, 1 H, H-5′), 3.74 (m, 1 H, H-5′), 3.89 (s, 3 H, CH₃O), 3.97 (m, 1 H, H-3′), 4.40 (m, 2 H, CH₂), 4.43 (m, 1 H, H-2′), 4.47 (m, 2 H, CH₂), 4.56 (m, 2 H, CH₂), 4.70 (m, 1 H, H-4′), 5.85 (s, 1 H, =CH), 6.79 (d, J _5,6 = 5.62 Hz, 1 H, H-5), 7.18-7.42 (m, 15 H, PhH), 8.45 (d, J _6,5 = 5.62 Hz, 1 H, H-6), 8.79 (br s, D₂O exch., 1 H, NH). ¹³C NMR (CDCl₃): δ = 56.10 (CH₃O), 68.52 (C-5′), 71.28 (CH₂), 72.27 (CH₂), 72.52 (=CH), 72.99 (C-2′), 73.20 (CH₂), 75.80 (C-3′), 76.89 (C-1′), 85.18 (C-4′), 105.81 (C-5), 107.52, 113.25, 118.99, 124.73 (CF₃CO), 118.15 (C-3), 127.61, 127.81, 128.10, 128.16, 128.22, 128.31, 128.41, 128.51, 128.56, 137.04, 137.47 (CPh), 147.07 (C-6), 150.04 (C-2), 153.80, 154.52, 155.26, 155.99 (CF₃ CO), 163.17 (C-4). Anal. Calcd for C₃₅H₃₃F₃N₂O₆: C, 66.24; H, 5.24; N, 4.41. Found: C, 66.02; H, 5.31; N, 4.29.

21

Data for (Z)-N-[4-Methoxy-2-(d-ribofuranosyl­-idene)methylpyridin-3-yl]trifluoroacetamide (15): yield: 86%; mp >250 °C (dec.; EtOH). ¹H NMR (DMSO-d ₆): δ = 3.63 (m, 2 H, H-5′), 4.05 (s, 3 H, CH₃O), 4.07 (m, 1 H, H-3′), 4.53 (m, 1 H, H-4′), 4.81 (m, 1 H, H-2′), 5.28-5.46 (br s, D₂O exch., 2 H, 2 × OH), 5.51 (s, 1 H, =CH), 5.77-5.84 (br s, D₂O exch., 1 H, OH), 7.45 (d, J _5,6 = 7.09 Hz, 1 H, H-5), 8.17 (br s, D₂O exch., 1 H, NH), 8.64 (d, J _6,5 = 7.09 Hz, 1 H, H-6). ¹³C NMR (DMSO-d ₆): δ = 57.52 (CH₃O), 60.33 (C-5′), 69.71 (C-3′), 73.46 (C-2′), 74.07 (C-1′), 84.71 (=CH), 93.15 (C-4′), 104.41 (C-5), 107.45, 113.18, 118.91, 124.65 (CF₃CO), 116.28 (C-3), 143.80 (C-6), 148.17 (C-2), 153.94, 154.65, 155.40, 156.12 (CF₃ CO), 166.92 (C-4). Anal. Calcd for C₁₄H₁₅F₃N₂O₆: C, 46.16; H, 4.15; N, 7.69. Found: C, 46.22; H, 3.96; N, 7.51.

22

Data for N-[4-Methoxy-2-(2,3,5-tri-O-acetyl-α-d-ribofuranosyl)methylpyridin-3-yl]trifluoroacetamide (17). Yield: 51%; light yellow oil; [α]_D +33.1° (c = 0.124, CH₂Cl₂). ¹H NMR (CDCl₃): δ = 2.03 (s, 3 H, CH₃CO), 2.05 (s, 3 H, CH₃CO), 2.12 (s, 3 H, CH₃CO), 2.88 (m, 1 H, CH₂), 3.17 (m, 1 H, CH₂), 3.90 (s, 3 H, CH₃O), 4.03 (m, 1 H, H-5′), 4.24 (m, 1 H, H-5′), 4.30 (m, 1 H, H-4′), 4.54 (m, 1 H, H-1′), 5.26 (m, 1 H, H-3′), 5.55 (m, 1 H, H-2′), 6.81 (d, J _5,6 = 5.86 Hz, 1 H, H-5), 8.38 (d, J _6,5 = 5.86 Hz, 1 H, H-6), 8.84 (br s, D₂O exch., 1 H, NH). ¹³C NMR (CDCl₃): δ = 20.57 (2 × CH₃CO), 20.77 (CH₃CO), 35.49 (CH₂), 56.22 (CH₃O), 63.77 (C-5′), 72.17 (C-3′), 72.69 (C-2′), 77.57 (C-4′), 80.48 (C-1′), 106.35 (C-5), 106.51, 112.24, 117.97, 123.71 (CF₃CO), 119.35 (C-3), 150.32 (C-6), 154.98 (C-2), 154.18, 154.91, 155.63, 156.35 (CF₃ CO), 160.92 (C-4), 168.98 (CH₃ CO), 169.82 (CH₃ CO), 170.69 (CH₃ CO). Anal. Calcd for C₂₀H₂₃F₃N₂O₉: C, 48.78; H, 4.71; N, 5.69. Found: C, 48.63; H, 4.67; N, 5.52.

23

Data for N-[4-Methoxy-2-(2,3,5-tri-O-acetyl-β-d-ribo­-furanosyl)methylpyridin-3-yl]trifluoroacetamide (18): yield: 34%; light yellow oil; [α]_D -30.2° (c = 0.227, CH₂Cl₂). ¹H NMR (CDCl₃): δ = 1.98 (s, 3 H, CH₃CO), 2.03 (s, 3 H, CH₃CO), 2.07 (s, 3 H, CH₃CO), 3.03 (m, 1 H, CH₂), 3.22 (m, 1 H, CH₂), 3.89 (s, 3 H, CH₃O), 4.00 (m, 1 H, H-5′), 4.10 (m, 1 H, H-5′), 4.33 (m, 1 H, H-4′), 4.37 (m, 1 H, H-1′), 4.89 (m, 1 H, H-2′), 4.96 (m, 1 H, H-3′), 6.82 (d, J _5,6 = 5.86 Hz, 1 H, H-5), 8.40 (d, J _6,5 = 5.86 Hz, 1 H, H-6), 8.71 (br s, D₂O exch., 1 H, NH). ¹³C NMR (CDCl₃): δ = 20.49 (CH₃CO), 20.58 (CH₃CO), 20.64 (CH₃CO), 36.77 (CH₂), 56.21 (CH₃O), 63.56 (C-5′), 71.32 (C-2′), 72.47 (C-3′), 80.79 (C-1′), 80.98 (C-4′), 106.46 (C-5), 106.60, 112.33, 118.07, 123.82 (CF₃CO), 119.98 (C-3), 150.35 (C-6), 154.40 (C-2), 154.51, 155.22, 155.98, 156.64 (CF₃ CO), 161.11 (C-4), 169.87 (2 × CH₃ CO), 170.62 (CH₃ CO). Anal. Calcd for C₂₀H₂₃F₃N₂O₉: C, 48.78; H, 4.71; N, 5.69. Found: C, 48.92; H, 4.64; N, 5.76.

25

Data for 1,4-Dihydro-3-(β-d-ribofuranosyl)-7H-pyrazo­-lo[4,3-b]pyridin-7-one(21): yield: 78.9%; mp 200 °C (dec.; EtOH); [α]_D -43.0° (c = 0.330, MeOH). ¹H NMR (DMSO-d ₆): δ = 3.61 (m, 2 H, H-5′), 3.86 (m, 1 H, H-4′), 3.94 (m, 1 H, H-3′), 4.11 (m, 1 H, H-2′), 4.87 (m, 1 H, H-1′), 4.93 (br s, D₂O exch., 1 H, OH-3′), 5.11 (br s, D₂O exch., 1 H, OH-2′), 5.76 (br s, D₂O exch., 1 H, OH-5′) 5.88 (d, J _6,5 = 7.14 Hz, 1 H, H-6), 7.59 (d, J _5,6 = 7.14 Hz, 1 H, H-5), 11.66 (br s, D₂O exch., 1 H, NH-4), 13.46 (br s, D₂O exch., 1 H, NH-1). ¹³C NMR (DMSO-d ₆): δ = 61.27 (C-5′), 71.58 (C-3′), 75.33 (C-2′), 79.09 (C-1′), 84.71 (C-4′), 109.10 (C-6), 126.00 (C-3a), 133.50 (C-7a), 137.23 (C-5), 138.20 (C-3), 168.20 (C-7). Anal. Calcd for C₁₁H₁₃N₃O₅: C, 49.44; H, 4.90; N, 15.72. Found: C, 49.27; H, 4.73; N, 15.59.