Synthesis of Pyridine-stretched 2′-Deoxynucleosides

Russell  Clayton; Michael L.  Davis; William  Fraser; Wei  Li; Christopher A.  Ramsden

doi:10.1055/s-2002-33505

LETTER

Synthesis of Pyridine-stretched 2′-Deoxynucleosides

Russell Clayton^a, Michael L. Davis^b, William Fraser*^b, Wei Li^b, Christopher A. Ramsden*^a
Lennard-Jones Laboratories, School of Chemistry and Physics, Keele University, Keele, Staffordshire, ST5 5BG, UK
Fax: +44(1782)712378; e-Mail: c.a.ramsden@chem.keele.ac.uk;
Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham, B4 7ET, UK
Fax: +44(121)3590733; e-Mail: w.fraser@aston.ac.uk;

Abstract

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Abstract

Synthesis of novel pyridine-stretched nucleoside (PSN) analogues of adenine (strA) (1), 2,6-diaminopurine (strD) (15) and hypoxanthine (strH) (17) from 4(5)-nitroimidazole has been achieved. Glycosylation of 4(5)-nitroimidazole was optimized to give consistently good yields (>70%) of the desired analytically pure 5-nitro-1′-β isomer 8 which on hydrogenation, C-addition of ethoxymethylene malononitrile (EMMN) and cyclisation provides the key intermediate 14 for PSN synthesis.

Key words

2′-deoxynucleosides - 5-aminoimidazoles - DNA - lin-pyridoadenosine - glycosylation - nucleoside analogues

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Referenzen

References

1 Humphries MJ. Ramsden CA. Synthesis 1999, 985

2 Leonard NJ. Sprecker MA. Morrice AG. J. Am. Chem. Soc. 1976, 98: 3987

3 Gowers DM. Fox KR. Nucleic Acids Res. 1999, 27: 1569

4 Fox KR. Curr. Med. Chem. 2000, 7: 17

5 Lin K.-Y. Jones RJ. Matteucci M. J. Am. Chem. Soc. 1995, 117: 3873

6 Hoffer M. Chem. Ber. 1960, 93: 2777

7

Compound 8 (70%): Mp 162 °C (colourless solid). IR (KBr): ν_max = 752, 1092, 1111, 1280, 1374, 1466, 1528, 1723, 2938 cm^-1. ¹H NMR (CDCl₃): δ = 2.42 (3 H, s, ArCH ₃), 2.46 (3 H, s, ArCH ₃), 2.52 (1 H, m, 2′-CH), 3.12 (1 H, m, 2′-CH), 4.74 (3 H, m, 5′-CH ₂ and 4′-CH), 5.64 (1 H, m, 3′-CH), 6.74 (1 H, t, 1′-CH), 7.24 (2 H, d, ArH), 7.30 (2 H, d, ArH), 7.84 (2 H, d, ArH), 7.97 (2 H, d, ArH), 8.05 [1 H, s, imidazole(4)-H], 8.11 [1 H, s, imidazole(2)-H]. ¹³C NMR (CDCl₃): δ = 21.70 (q, ArCH₃), 21.77 (q, ArCH₃), 40.86 (t, 2′-CH₂), 63.60 (t, 5′-CH₂), 74.14 (d, 4′-CH), 83.94 (d, 3′-CH), 88.99 (d, 1′-CH), 126.04 [s, Ar(4)-C], 126.18 [s, Ar(4)-C], 129.32 (d, Ar-CH), 129.39 (d, Ar-CH), 129.55 (d, Ar-CH), 129.81 (d, Ar-CH), 134.33 [d, imidazole(4)-CH], 138.05 [v weak s, imidazole(5)-C], 138.13 [d, imidazole(2)-CH], 144.50 [s, Ar(1)-C], 144.70 [s, Ar(1)-C], 165.92 (s, C=O), 166.07 (s, C=O). MS (EI): m/z (%) = 465 (2) [M⁺], 320 (1), 216 (28), 136 (28), 119 (100), 91 (53), 81 (93), 65 (18), 53 (14), 39 (13), 28 (13). Anal. Calcd for C₂₄H₂₃N₃O₇: C, 61.9%; H, 4.98%; N, 9.0%. Found: C, 61.7%; H, 4.89%; N, 8.8%.

8 timac A. Kobe J. Carbohydr. Res. 2000, 329: 317

9 Bergstrom DE. Zhang P. Johnson WT. Nucleic Acids Res. 1997, 25: 1935

10 Kazimierczuk Z. Cottam HB. Revankar GR. Robins RK. J. Am. Chem. Soc. 1984, 106: 6379

11 Hubbard AJ. Jones AS. Walker RT. Nucleic Acids Res. 1984, 12: 6827

12

Compound 13 (43%): Mp 194-196 °C (yellow needles). IR (KBr): ν_max = 752, 1112, 1266, 1283, 1354, 1540, 1586, 1715, 2218, 2924, 3348 cm^-1. ¹H NMR (d ₆-DMSO): δ = 2.39 (3 H, s, ArCH ₃), 2.41 (3 H, s, ArCH ₃), 2.72 (1 H, m, 2′-CH), 2.86 (1 H, m, 2′-CH), 4.53 (3 H, br s, 5′-CH ₂ and 4′-CH), 5.63 (1 H, d, 3′-CH), 6.09 (1 H, dd, 1′-CH), 7.34 (2 H, d, ArH), 7.38 (2 H, d, ArH), 7.72 (2 H, br s, NH ₂), 7.79 (1 H, s, C=CH), 7.83 [1 H, s, imidazole(2)-H], 7.86 (2 H, d, ArH), 7.95 (2 H, d, ArH). ¹³C NMR (d ₆-DMSO): δ = 21.14 (q, ArCH₃), 21.17 (q, ArCH₃), 35.88 (t, 2′-CH₂), 58.63 [s, C(CN)₂], 63.96 (t, 5′-CH₂), 74.72 (d, 4′-CH), 81.69 (d, 3′-CH), 82.81 (d, 1′-CH), 116.20 [s, imidazole(4)-C], 117.99 (s, CN), 118.56 (s, CN), 126.43 [s, 2 × Ar(4)-C], 129.26 (d, 2 × Ar-CH), 129.32 (d, Ar-CH), 129.47 (d, Ar-CH), 134.13 [d, imidazole(2)-CH], 143.53 (d, C=CH), 143.84 [s, Ar(1)-C], 144.08 [s, Ar(1)-C], 150.02 [s, imidazole(5)-C], 165.12 (s, C=O), 165.40 (s, C=O). MS (EI): m/z (%) = 511 (7) [M⁺], 353 (7), 159 (41), 119 (68), 91 (23), 81 (100).

13

Compound 14 (84%): Mp 162 °C (colourless needles). IR (KBr): ν_max = 940, 1099, 1432, 1576, 1630, 2216, 2923, 3223, 3337 cm^-1. ¹H NMR (d ₆-DMSO): δ = 2.23 (1 H, m, 2′-CH), 2.59 (1 H, m, 2′-CH), 3.52 (2 H, m, 5′-CH ₂), 3.83 (1 H, d, 4′-CH), 4.37 (1 H, s, 3′-CH), 4.96 (1 H, t, 5′-OH), 5.32 (1 H, d, 3′-OH), 6.29 (1 H, t, 1′-CH), 6.79 (2 H, br s, NH ₂), 8.24 (1 H, s, pyridine-H), 8.42 [1 H, s, imidazole(2)-H]. ¹³C NMR (d ₆-DMSO): δ = 39.51 (t, 2′-CH₂), 61.89 (t, 5′-CH₂), 70.99 (d, 4′-CH), 82.71 (d, 3′-CH), 86.26 (s, C.CN), 87.89 (d, 1′-CH), 118.02 (s, CN), 127.11 (s, C), 134.37 [d, imidazole(2)-CH], 142.29 (d, pyridine-CH), 148.96 (s, C), 157.84 (s, C). MS (EI): m/z (%) = 275 (84) [M⁺], 186 (100), 160 (10 0), 159 (100), 132 (35), 117 (63), 99 (32), 73 (50), 45 (39), 43 (36), 28 (26). HRMS (EI): m/z = calcd for C₁₂H₁₃N₅O₃: 275.1018. Found: 275.1008 [M⁺].

14

Compound 1 (47%). Mp >280 °C (colourless needles). IR (KBr): ν_max = 812, 916, 1091, 1419, 1507, 1577, 1685, 3086 cm^-1. ¹H NMR (d ₆-DMSO): δ = 2.36 (1 H, m, 2′-CH), 2.83 (1 H, m, 2′-CH), 3.63 (2 H, m, 5′-CH ₂), 3.93 (1 H, m, 4′-CH), 4.49 (1 H, s, 3′-CH), 5.15 (1 H, t, 5′-OH), 5.40 (1 H, d, 3′-OH), 6.74 (1 H, t, 1′-CH), 8.09 (2 H, br s, NH ₂), 8.51 (1 H, s, 2-H), 8.92 (1 H, s, 6-H), 9.07 (1 H, s, 9-H). ¹³C NMR (d ₆-DMSO): δ = 39.44 (t, 2′-CH₂), 61.95 (t, 5′-CH₂), 71.06 (d, 4′-CH), 83.81 (d, 3′-CH), 88.19 (d, 1′-CH), 106.43 (s, C), 123.80 (d, CH), 134.68 (s, C), 148.25 (d, CH), 151.01 (s, C), 155.73 (s, C), 157.87 (d, CH), 164.11 (s, C). MS (FAB): m/z (%) = 303 (53) [M + H), 187 (31), 165 (30), 152 (46), 124 (36), 120 (46), 115 (35), 107 (100), 105 (43). HRMS-FAB: m/z calcd for C₁₃H₁₅N₆O₃: 303.1206. Found: 303.1209 [M⁺ + H].

15

Compound 15 (45%). Mp >280 °C (cream solid). IR (KBr): ν_max = 803, 1057, 1356, 1470, 1621, 1641, 2887, 3110, 3183, 3318, 3434, 3481 cm^-1. ¹H NMR (d ₆-DMSO): δ = 2.23 (1 H, m, 2′-CH), 2.81 (1 H, m, 2′-CH), 3.61 (2 H, m, 5′-CH ₂), 3.88 (1 H, m, 4′-CH), 4.44 (1 H, m, 3′-CH), 5.17 (1 H, t, 5′-OH), 5.37 (1 H, d, 3′-OH), 6.19 (2 H, br s, NH ₂), 6.42 (1 H, t, 1′-CH), 7.44 (2 H, br s, NH ₂), 8.64 (1 H, s, 6-H), 8.83 (1 H, s, 9-H). ¹³C NMR (d ₆-DMSO): δ = 39.17 (t, 2′-CH₂), 62.08 (t, 5′-CH₂), 71.17 (d, 4′-CH), 83.84 (d, 3′-CH), 88.01 (d, 1′-CH), 102.19 (s, C), 123.83 (d, CH), 131.33 (s, C), 145.35 (d, CH), 150.76 (s, C), 158.27 (d, CH), 162.78 (s, C), 164.21 (s, C). MS (FAB): m/z (%) = 318 (91) [M + H], 202 (100), 141 (15), 121 (9). HRMS-FAB: m/z calcd for C₁₃H₁₅N₇NaO₃: 340.1134. Found: 340.1129 [M⁺ + Na].

16

Compound 17 (44%). Mp >280 °C (cream solid). IR (KBr): ν_max = 807, 1086, 1235, 1392, 1605, 1686, 2925, 3214, 3504 cm^-1. ¹H NMR (d ₆-DMSO) δ = 2.34 (1 H, m, 2′-CH), 2.81 (1 H, m, 2′-CH), 3.62 (2 H, m, 5′-CH ₂), 3.93 (1 H, d, 4′-CH), 4.49 (1 H, br s, 3′-CH), 5.10 (1 H, t, 5′-OH), 5.41 (1 H, d, 3′-OH), 6.58 (1 H, t, 1′-CH), 8.32 (1 H, s, 2-H), 8.75 (1 H, s, 6-H), 8.95 (1 H, s, 9-H). ¹³C NMR (d ₆-DMSO): δ = 45.58 (t, 2′-CH₂), 67.94 (t, 5′-CH₂), 77.05 (d, 4′-CH), 89.99 (d, 3′-CH), 94.28 (d, 1′-CH), 120.59 (s, C), 132.26 (d, CH), 140.99 (s, C), 153.83 (d, CH), 156.48 (s, C), 161.15 (s, C), 168.41 (s, C=O). MS (FAB): m/z (%) = 304 (11) [M + H], 216 (16), 119 (43), 114 (22), 87 (41), 82 (100). HRMS-FAB: m/z calcd for C₁₃H₁₃N₅O₄: 304.1046. Found: 304.1041 [M + H].