Synthesis and Biological Evaluation of Bicyclic Nucleosides
filtered and concentrated under reduced pressure. After purifica-
tion by chromatography on silica gel (petroleum ether/AcOEt,
90:10), the monoprotected alcohol 24 was obtained as white crys-
CH=CH2), 66.3 (CH2-O-Si), 26.8 [(CH3)3C-Si], 26.2 [C(CH3)-
CH3(endo)], 25.8 [C(CH3)-CH3(exo)], 19.3 [(CH3)3C-Si] ppm.
(3ξ)-3,7-Anhydro-5,6-dideoxy-1,2-O-(1-methylethylidene)-4-{[(tert-
butyldiphenylsilyl)oxy]methyl}-β-L-threo-hept-5-enofuranose (25):
To a solution of compound 19 (3.7 g, 7.5 mmol) in dry CH2Cl2
(850 mL) was added Grubbs’ type-II catalyst (670 mg, 0.75 mmol,
0.1 equiv.). The reaction mixture was stirred for 16 h at room temp.,
and then the solvent was evaporated. The crude residue was puri-
fied by chromatography on silica gel (petroleum ether/AcOEt, 95:5)
to give the bicyclic compound 25 as a brown oil (3.4 g, 97 %).
tals (8.3 g, 64%); m.p. 67–69 °C. IR (KBr): ν = 3500, 3133, 2987,
˜
2952, 2857, 1471, 1429, 1385, 1136, 1007 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.68–7.65 (m, 4 H, HAr), 7.43–7.38 (m, 6
H, HAr), 5.99–5.86 (syst. ABMXY, 1 H, H2C=CH-CH2), 5.83 (d,
J = 3.3 Hz, 1 H, H1Ј), 5.30 [syst. ABMXY, J = 17.1, 1.5 Hz, 1 H,
H-(H)C=CH-CH2], 5.24 [syst. ABMXY, J = 10.3, 1.5 Hz, 1 H, H-
(H)C=CH-CH2], 4.70 (dd, J = 5.1, 3.8 Hz, 1 H, H2Ј), 4.43 (d, J =
5.1 Hz, 1 H, H3Ј), 4.22 and 4.02 (syst. ABMXY, J = 12.6, 5.4,
1.5 Hz, 2 H, H2C=CH-CH2), 3.84 and 3.78 (syst. AB, J = 11.9 Hz,
2 H, -CH2OH), 3.82 and 3.75 (syst. AB, J = 9.0 Hz, 2 H, H5Ј), 1.64
{s, 3 H, [C(CH3)-CH3(endo)]}, 1.37 {s, 3 H, [C(CH3)-CH3(exo)]},
1.06 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.6
(CHAr), 134.1 (H2C=CH-), 133.3, 133.0 (CAr-Si), 129.8, 127.7
(CHAr), 118.2 (H2C=CH-), 113.7 [2 ϫO-C(O)CH3], 104.4 (C1Ј),
87.3 (C4Ј), 79.2 (C2Ј), 78.1 (C3Ј), 71.9 (O-CH2-CH=CH2), 65.5
(CH2-O-Si), 63.2 (CH2-OH), 26.8 [(CH3)3C-Si], 26.7 [C(CH3)-
CH3(endo)], 26.3 [C(CH3)-CH3(exo)], 19.3 [(CH3)3C-Si] ppm.
[α]2D5 = –3.1 (c = 1.0, CHCl ). IR (neat): ν = 2931, 2857, 1428, 1381,
˜
3
1372, 1113, 1018 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.63–7.72
(m, 4 H, HAr), 7.35–7.45 (m, 6 H, HAr), 5.97 (d, J = 4.3 Hz, 1 H,
H1Ј), 6.00–5.93 (m, 1 H, H2C=CH-CH2), 5.73 [syst. ABMX, J =
10.6, 2.2 Hz, 1 H, H-(H)C=CH-CH2], 4.94 (dd, J = 5.9, 4.3 Hz, 1
H, H2Ј), 4.50 and 4.04 (syst. ABMX, J = 16.4, 3.0, 2.2 Hz, 2 H,
HC=CH-CH2), 4.39 (d, J = 5.9 Hz, 1 H, H3Ј), 3.65 and 3.43 (syst.
AB, J = 10.8 Hz, 2 H, H5Ј), 1.54 {s, 3 H, [C(CH3)-CH3(endo)]},
1.38 {s, 3 H, [C(CH3)-CH3(exo)]}, 1.05 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.7 (CHAr), 133.0, 132.8 (CAr-Si),
129.8 (CHAr, HC=CH-CH2), 127.8 (CHAr), 124.3 (HC=CH-CH2),
114.1 [O-C(O)(CH3)2], 105.4 (C1Ј), 82.2 (C2Ј), 80.2 (C4Ј), 74.4 (C3Ј),
68.1 (C5Ј), 63.8 (HC=CH-CH2-O), 27.2 [C(CH3)-CH3], 26.8 [(CH3)3-
C-Si], 26.4 [C(CH3)-CH3], 19.2 [(CH3)3C-Si] ppm.
3-O-Allyl-5-(tert-butyldiphenylsilyl)-1,2-O-isopropylidene-4-C-vinyl-
α-D-erythrofuranose (19): To a solution of oxalyl chloride (2.9 mL,
33.1 mmol, 2.0 equiv.) in anhydrous CH2Cl2 (70 mL) at –78 °C was
added a solution of dry DMSO (3.9 mL, 10.3 mmol, 3.3 equiv.) in
anhydrous CH2Cl2 (35 mL). After stirring for 20 min at –78 °C,
alcohol 24 (8.3 g, 16.5 mmol) in anhydrous CH2Cl2 (35 mL) was
added dropwise. The reaction mixture was stirred for 30 min at
–78 °C, Et3N (12.4 mL, 102.5 mmol, 6.2 equiv.) was added, and the
reaction was warmed to room temp. before being cooled to 0 °C
for addition of H2O. After extraction with CH2Cl2, the organic
layer was washed with H2O and brine, dried with MgSO4, filtered
and concentrated under reduced pressure. The aldehyde (8.2 g) was
then used crude for the next reaction. To a suspension of triphenyl-
phosphonium bromide (23.6 g, 66.1 mmol, 4.0 equiv.) in dry THF
(300 mL) at 0 °C was added nBuLi (1.6 m in hexanes, 23.8 mL,
59.5 mmol, 3.6 equiv.). After stirring for 5 min at 0 °C and 1 h at
room temp., the reaction mixture was cooled to –78 °C. A solution
of the previous crude aldehyde (8.2 g, 16.5 mmol) in dry THF
(200 mL) was added dropwise. The reaction was stirred for 30 min
at –78 °C then for 2 h at 0 °C and finally for 1 h at room tempera-
ture before being cooled to 0 °C for the addition of a saturated
aqueous solution of NH4Cl. After extraction with CH2Cl2, the
combined organic layers were washed with brine, dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude residue was purified by chromatography on silica gel (petro-
leum ether/AcOEt, 95:5), and the unsaturated compound 19 was
obtained as a colourless oil (3.7 g, 45% over two steps). [α]2D5 = –1.0
1,2-Di-O-acetyl-3,7-anhydro-5,6-dideoxy-4-{[(tert-butyldiphenylsil-
yl)oxy]methyl}-α/β-L-lyxo-hept-5-enofuranose (20): To a solution of
the bicyclic compound 25 (3.4 g, 7.3 mmol) in acetic acid (95 mL)
was added acetic anhydride (10.2 mL, 87.5 mmol, 12.0 equiv.) and
a concentrated solution of H2SO4 (95 μL, 14 μmol, 0.002 equiv.).
After stirring for 3 h at room temp., an aqueous saturated solution
of NaHCO3 was added, and the aqueous layer was extracted with
CH2Cl2. The organic layer was dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude residue was purified
by chromatography on silica gel (petroleum ether/AcOEt, 80:20) to
give anomer β-20 as a colourless oil (1.7 g, 46%) and anomer α-20
as a colourless oil (1.2 g, 31%). β-Anomer: [α]2D5 = +67.0 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.66 (m, 4 H, HAr),
7.46–7.36 (m, 6 H, HAr), 6.51 (d, J = 5.1 Hz, 1 H, H1Ј), 6.15–6.08
(syst. ABMX, J = 10.4, 4.3, 1.6 Hz, 1 H, HC=CH-CH2), 5.70–5.66
(m, 2 H, HC=CH-CH2, H2Ј), 4.38 (d, J = 5.0 Hz, 1 H, H3Ј), 4.28
and 3.90 (syst. ABMX, J = 16.4, 4.3, 2.0 Hz, 2 H, HC=CH-CH2),
3.59 and 3.38 (syst. AB, J = 11.0 Hz, 2 H, H5Ј), 2.19, 2.11 [s, 3 H,
O-C(=O)-CH3], 1.10 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.6, 170.0 [2ϫO-C(=O)-CH3], 135.6, 132.7 (CHAr),
132.3 (CAr), 130.8 (HC=CH-CH2), 129.9, 127.8 (CHAr), 124.7
(HC=CH-CH2), 94.5 (C1Ј), 81.5 (C4Ј), 74.3 (C3Ј), 72.6 (C2Ј), 68.0
(C5Ј), 62.8 (HC=CH-CH2), 26.8 [(CH3)3C-Si], 21.4, 20.7 [2ϫO-
C(=O)-CH3], 19.1 [(CH3)3C-Si] ppm. α-Anomer: [α]2D5 = –59.0 (c =
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.66 (m, 4 H,
HAr), 7.46–7.36 (m, 6 H, HAr), 6.38 (d, J = 5.4 Hz, 1 H, H1Ј), 6.08
(syst. ABMX, J = 10.4, 4.3, 1.5 Hz, 1 H, HC=CH-CH2), 5.64 (syst.
ABMX, J = 10.4, 2.0 Hz, 1 H, HC=CH-CH2), 5.60 (dd, J = 5.3,
5.0 Hz, 1 H, H2Ј), 4.50 and 4.04 (syst. ABMX, J = 16.4, 4.3, 2.0 Hz,
2 H, HC=CH-CH2), 4.40 (d, J = 5.0 Hz, 1 H, H3Ј), 3.66 and 3.43
(syst. AB, J = 11.0 Hz, 2 H, H5Ј), 2.18, 2.00 [s, 3 H, O-C(=O)-
CH3], 1.10 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.7, 170.1 [2ϫO-C(=O)-CH3], 135.6 (CHAr), 132.6 (CAr), 130.0
(HC=CH-CH2) 129.9, 127.8 (CHAr), 124.1 (HC=CH-CH2), 99.2
(C1Ј), 82.0 (C4Ј), 80.2 (C3Ј), 75.2 (C2Ј), 67.6 (C5Ј), 63.0 (HC=CH-
CH2), 26.7 [(CH3)3C-Si], 21.0 [2ϫO-C(=O)-CH3], 19.2 [(CH3)3C-
Si] ppm.
(c = 1.0, CHCl ). IR (neat): ν = 2980, 2858, 1472, 1428, 1265, 1250,
˜
3
1113, 1028 cm–1. H NMR (300 MHz, CDCl3): δ = 7.75–7.66 (m,
1
4 H, HAr), 7.45–7.35 (m, 6 H, HAr), 6.14 (syst. ABX, J = 17.3,
11.0 Hz, 1 H, HC=CH2 vinyl), 6.08–5.94 (m, 1 H, H2C=CH-CH2
allyl), 5.85 (d, J = 3.8 Hz, 1 H, H1Ј), 5.45 [syst. ABX, J = 17.3,
1.8 Hz, 1 H, HC=C(H)-H vinyl], 5.35 [syst. ABMXY, J = 17.3, 1.4,
1.1 Hz, 1 H, H-(H)C=CH-CH2 allyl], 5.25–5.22 [m, 1 H, H-(H)-
C=CH-CH2 allyl], 5.18 [syst. ABX, J = 11.0, 1.8 Hz, 1 H, H-
C=C(H)-H vinyl], 4.72 (dd, J = 4.9, 3.8 Hz, 1 H, H2Ј), 4.48 (d, J =
4.9 Hz, 1 H, H3Ј), 4.30–4.12 (m, 2 H, H2C=CH-CH2 allyl), 3.57 (s,
2 H, H5Ј), 1.54 {s, 3 H, [C(CH3)-CH3(endo)]}, 1.38 {s, 3 H,
[C(CH3)-CH3(exo)]}, 1.05 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.7, 135.5 (CHAr), 134.8 (H2C=CH- vinyl), 133.9
(H2C=CH- allyl), 133.5, 133.0 (CAr-Si), 129.7, 127.7 (CHAr), 117.9
(H2C=CH- allyl), 116.2 (H2C=CH- vinyl), 113.5 [2ϫO-C(O)CH3],
Uridine Derivative 26: To
a suspension of uracil (203 mg,
103.9 (C1Ј), 87.1 (C4Ј), 79.5 (C2Ј), 77.0 (C3Ј), 72.0 (O-CH2- 0.37 mmol, 1.5 equiv.) in freshly distilled CH3CN (3 mL) was
Eur. J. Org. Chem. 2011, 7390–7399
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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