7162 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Srivastav et al.
30-O-(Methylsulfonyl)-50-O-trityl-20-deoxythymidine (9). Yield
83%, solid,27 mp 120-122 °C. 1H NMR (CDCl3): δ 1.47 (s, 3H,
CH3), 2.43-2.53 (m, 1H, H-20), 2.65-2.72 (m, 1H, H-200), 3.03 (s,
3H, CH3SO2), 3.50 (m, 2H, H-50), 4.32 (m, 1H, H-40), 5.41 (m, 1H,
H-30), 6.43 (m, 1H, H-10), 7.29-7.41 (m, 15 H, 50-O-trityl), 7.54 (s,
1H, H-6), 8.52 (s, 1H, NH).
1H, 30-OH), 6.17 (dt, J = 8.24 Hz, 6.1 Hz, 1H, H-10), 7.23-7.50
(m, 15H, 50-O-trityl), 7.60 (s, 1H, H-6), 11.24 (s, 1H, NH). ES-MS
(þve mode) = 521.2 (M þ Na)þ; ES-MS (-ve mode) = 497.2
(M - 1)þ.
1-(5-O-trityl-2-deoxy-β-D-lyxofuranosyl)-5-fluorouracil (20).
Yield 76%, solid,27 mp 226-229 °C. 1H NMR (DMSO-d6):
δ 1.90 (d, J = 14.65 Hz, 1H, H-20), 2.44-2.59 (m, 1H, H-200),
3.15-3.41 (m, 2H, H-50), 4.09 (m, 1H, H-40), 4.18 (m, 1H, H-30),
5.36 (d, J = 3.66 Hz, 1H, 30-OH), 6.13 (d, J = 8.54 Hz, 1H,
H-10), 7.25-7.46 (m, 15 H, 50-O-trityl), 7.92 (d, J = 7.32 Hz, 1H,
H-6), 11.85 (s, 1H, NH).
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)-5-iodoracil (21). This
compound was synthesized from 5-iodo-30-O-(methylsulfonyl)-50-
O-trityl-20-deoxyuridine (14) in 41% yield as a syrup.30 1H NMR
(DMSO-d6): δ 1.9 (m, 1H, H-20), 2.47-2.60 (m, 1H, H-200),
3.16-3.25 and 3.39-3.58 (2 m, 2H, H-50), 4.09-4.25 (m, 2H,
H-30 and H-40), 5.29 (d, J = 3.36 Hz, 1H, 30-OH), 6.12 (d, J =
7.02 Hz, 1H, H-10), 7.22-7.55 (m, 15H, 50-O-trityl), 8.18 (s, 1H,
H-6), 11.70 (s, 1H, NH). ES-MS (þve mode) = 619.0 (M þ Na)þ;
ES-MS (-ve mode) = 595.1 (M - 1)þ.
Synthesis of 1-(2-Deoxy-β-D-lyxofuranosyl)pyrimidines (22-28).
A full procedure is provided for 1-(2-deoxy-β-D-lyxofuranosyl)-
uracil (22). For other analogues, only yield and spectroscopic
data are presented.
4-Thio-30-O-(methylsulfonyl)-50-O-trityl-20-deoxythymidine (10).
Yield 19%, syrup. 1H NMR (CDCl3): δ 1.65 (s, 3H, CH3),
2.49-2.54 (m, 1H, H-20), 2.71-2.73 (m, 1H, H-200), 3.02 (s, 3H,
CH3SO2), 3.53 (m, 2H, H-50), 4.36 (m, 1H, H-40), 5.40 (m, 1H,
H-30), 6.39 (m, 1H, H-10), 7.28-7.41 (m, 15 H, 50-O-trityl), 7.61 (s,
1H, H-6), 10.12 (s, 1H, NH), ES-MS (þve mode) = 601.1 (M þ
Na)þ; ES-MS (-ve mode) = 577.1 (M - 1)þ.
5-Trifluoromethyl-30-O-(methylsulfonyl)-50-O-trityl-20-deoxyur-
idine (11). Yield 79%, syrup. 1H NMR (DMSO-d6): δ 2.54-2.73
(m, 2H, H-20), 3.20 (s, 3H, CH3SO2), 3.24-3.36 (m, 2H, H-50),
4.25 (m, 1H, H-40), 5.23 (m, 1H, H-30), 6.07 (t, J = 6.71 Hz, 1H,
H-10), 7.24-7.41 (m, 15 H, 50-O-trityl), 8.13 (s, 1H, H-6), 12.0 (s,
1H, NH). ES-MS (þve mode) = 639.1 (M þ Na)þ; ES-MS (-ve
mode) = 615.1 (M - 1)þ.
5-Fluoro-30-O-(methylsulfonyl)-50-O-trityl-20-deoxyuridine (13).
Yield 99%, solid,27 mp 96-98 °C. 1H NMR (CDCl3): δ 2.41 (m,
1H, H-20), 2.77 (m, 1H, H-200), 3.04 (s, 3H, CH3SO2), 3.52 (m, 2H,
H-50), 4.36 (m, 1H, H-40), 5.36 (m, 1H, H-30), 6.32 (m, 1H, H-10),
7.24-7.42 (m, 15 H, 50-O-trityl), 7.78 (d, J = 6.10 Hz, 1H, H-6),
8.71 (br s, 1H, NH).
1-(2-Deoxy-β-D-lyxofuranosyl)uracil (22). The compound 15
(0.82 g, 1.74 mmol) was dissolved in 80% aqueous acetic acid (25
mL) and heated at 90 °C for 0.5 h. Solvent was removed in
vacuo, and the crude product thus obtained was purified on
silica gel column using MeOH/CHCl3 (8:92, v/v) as eluent to
give 26 (0.323 g, 81%) as a solid; mp 168-170 °C; [R]D -27.19
Synthesis of 1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)pyrim-
idines (15-21). A full procedure is provided for 1-(5-O-trityl-
2-deoxy-β-D-threo-pentofuranosyl)uracil (15). For other ana-
logues, only yield and spectroscopic data are presented.
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)uracil (15). NaOH
(1 g, 25 mmol) was added to a solution of compound 8 (1.29 g,
2.35 mmol) in 90% aqueous ethanol (50 mL), and the reaction
mixture was refluxed for 2 h. The reaction mixture was cooled in
an ice bath and neutralized with 80% acetic acid. Solvent was
removed in vacuo, and the crude product thus obtained was
purified on silica gel column using MeOH/CHCl3 (4:96, v/v) as
eluent to give 1528,29 (0.82 g, 74%) as a solid; mp 237-239 °C. 1H
NMR (DMSO-d6): δ 1.85 (d, J = 14.65 Hz, 1H, H-20), 2.47-2.60
(m, 1H, H-200), 3.16-3.39 (m, 2H, H-50), 4.07 (m, 1H, H-40), 4.18
(m, 1H, H-30), 5.26 (d, J = 3.66 Hz, 1H, 30-OH), 5.55 (d, J = 7.93
Hz, 1H, H-5), 6.11 (m, 1H, H-10), 7.24-7.44 (m, 15 H, 50-O-trityl),
7.73 (d, J = 7.93 Hz, 1H, H-6), 11.29 (s, 1H, NH).
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)thymine (16). Yield
67%, solid,27 mp 110-112 °C. 1H NMR (DMSO-d6): δ 1.64 (s,
3H, CH3), 1.84 (d, J = 14.65 Hz, 1H, H-20), 2.49-2.58 (m, 1H,
H-200), 3.16-3.42 (m, 2H, H-50), 4.09 (m, 1H, H-40), 4.18 (m, 1H,
H-30), 5.21 (d, J = 3.36 Hz, 1H, 30-OH), 6.11 (m, 1H, H-10),
7.25-7.44 (m, 15 H, 50-O-trityl), 7.59 (s, 1H, H-6), 11.29 (s, 1H,
NH).
1
(c 0.30, DMSO). H NMR (DMSO-d6): δ 1.86 (m, 1H, H-20),
2.55 (m, 1H, H-200), 3.58-3.75 (m, 2H, H-50), 3.78-3.83 (m, 1H,
H-40), 4.22 (m, 1H, H-30), 4.69 (t, J = 5.49 Hz, 1H, 50-OH), 5.26
(d, J = 3.36 Hz, 1H, 30-OH), 5.65 (d, J = 8.24 Hz, 1H, H-5),
6.02 (dd, J = 8.5 Hz, 2.14 Hz, 1H, H-10), 7.92 (d, J = 8.24 Hz,
1H, H-6), 11.24 (s, 1H, NH). Anal. (C9H12N2O5) C, H, N.
1-(2-Deoxy-β-D-lyxofuranosyl)thymine(23). Yield81%, solid,27
mp 172-174 °C; [R]D þ14.0 (c 0.36, H2O); UV (H2O) λmax 268 nm
(ε 8818). 1H NMR (DMSO-d6): δ 1.76 (s, 3H, CH3), 1.84 (dd, J =
14.95 Hz, 2.14 Hz, 1H, H-20), 2.55-2.59 (m, 1H, H-200), 3.58-3.82
(m, 3H, H-40 and H-50), 4.22 (m, 1H, H-30), 4.69 (t, J = 5.49 Hz,
1H, 50-OH), 5.25 (d, J = 3.35 Hz, 1H, 30-OH), 6.06 (dd, J = 8.54
Hz, 2.44 Hz, 1H, H-10), 7.79 (s, 1H, H-6), 11.25 (s, 1H, NH). Anal.
(C10H14N2O5) C, H, N.
1-(2-Deoxy-β-D-lyxofuranosyl)-4-thiothymine (24). Yield 49%,
solid, mp 69-70 °C; [R]D þ67.52 (c 0.52, MeOH); UV (MeOH)
1
λmax 336 nm (ε 12871). H NMR (DMSO-d6): δ 1.93-1.98 (m,
1H, H-20), 1.96 (s, 3H, CH3), 2.52-2.59 (m, 1H, H-200), 3.63-3.78
(m,2H, H-50), 3.84-3.89 (m, 1H, H-40), 4.24(m,1H, H-30), 4.74(t,
J = 5.49 Hz, 1H, 50-OH), 5.21 (d, J = 3.36 Hz, 1H, 30-OH), 5.99
(dd, J = 7.94 Hz, 1.83 Hz, 1H, H-10), 7.87 (s, 1H, H-6), 12.67 (s,
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)-4-thiothymine (17).
Yield 76%, solid,22 mp 136-138 °C. 1H NMR (DMSO-d6):
δ 1.81 (s, 3H, CH3), 1.95 (d, J = 18.31 Hz, 1H, H-20), 2.44-2.56
(m, 1H, H-200), 3.15-3.45 (m, 2H, H-50), 4.17 (m, 2H, H-30 and
H-40), 5.15 (br s, 1H, 30-OH), 6.05 (d, J = 6.71 Hz, 1H, H-10),
7.25-7.46 (m, 15 H, 50-O-trityl), 7.60 (s, 1H, H-6), 12.62 (br s,
1H, NH).
13
1H, NH). C NMR (CD3OD): δ 19.92 (CH3), 44.99 (C-20),
64.03 (C-50), 73.40 (C-30), 89.05 (C-40), 89.30 (C-10), 122.18 (C-5),
137.34 (C-6), 152.54 (C-2), 194.88 (C-4). Anal. (C10H14N2O4S) C,
H, N, S.
1-(2-Deoxy-β-D-lyxofuranosyl)-5-trifluoromethyluracil (25).
Yield 67%, solid, mp 78-80 °C; [R]D -5.63 (c 0.43, MeOH); UV
1
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)-5-trifluoromethyluracil
(MeOH) λmax 276 nm (ε 7338). H NMR (DMSO-d6): δ 2.01
1
(18). Yield 19%, syrup. H NMR (DMSO-d6): δ 1.97 (m, 1H,
(d, J = 14.35 Hz, 1H, H-20), 2.45-2.50 (m, 1H, H-200),
3.66-3.81 (m, 2H, H-50), 3.91-3.93 (m, 1H, H-40), 4.22 (m,
1H, H-30), 4.79 (m, 1H, 50-OH), 5.18 (m, 1H, 30-OH), 5.99 (d,
J = 7.63 Hz, 1H, H-10), 8.80 (s, 1H, H-6), 11.50 (s, 1H, NH).
Anal. (C10H11F3N2O5) C, H, N.
H-20), 2.47-2.58 (m, 1H, H-200), 3.20-3.52 (m, 2H, H-50),
4.14-4.22 (m, 2H, H-30 and H-40), 5.22 (brs, 1H, 30-OH), 6.12
(m, 1H, H-10), 7.22-7.44 (m, 15 H, 50-O-trityl), 8.69 (s, 1H, H-6),
11.53 (brs, 1H, NH). ES-MS (þve mode) = 561.2 (M þ Na)þ;
ES-MS (-ve mode) = 537.2 (M - 1)þ.
1-(2-Deoxy-β-D-lyxofuranosyl)-5-ethyluracil (26). Yield 72%,
solid,16 mp 148-151 °C; [R]D -12.12 (c 0.50, MeOH); UV
(MeOH) λmax 267 nm (ε 10970). 1H NMR (DMSO-d6): δ 1.02
(t, J = 7.33 Hz, 3H, 5-CH3), 1.85 (dd, J = 14.65 and 2.44 Hz,
1H, H-20), 2.21 (q, J = 6.71 Hz, 2H, 5-CH2), 2.53-2.64 (m, 1H,
H-200), 3.68 (m, 2H, H-50), 3.81 (m, 1H, H-40), 4.25 (m, 1H, H-30),
4.70 (t, J = 5.50 Hz, 1H, 50-OH), 5.28 (d, J = 3.35 Hz, 1H,
1-(5-O-Trityl-2-deoxy-β-D-lyxofuranosyl)-5-ethyluracil (19). This
compound was synthesized from 5-ethyl-30-O-(methylsulfonyl)-50-
O-trityl-20-deoxyuridine (12)26 in 97% yield as a syrup. 1H NMR
(DMSO-d6): δ 0.83 (t, J = 7.63 Hz, 3H, CH3), 1.89 (m, 1H, H-20),
2.08 (q, J = 7.32 Hz, 2H, CH2), 2.53-2.62 (m, 1H, H-200), 3.21 and
3.42 (2 m, 2H, H-50), 4.10-4.24 (m, 2H, H-30 and H-40), 5.26 (m,