M. Spadafora et al. / Tetrahedron 65 (2009) 7809–7816
7815
temperature for 1 h. The solution was evaporated in vacuo and the
residue was purified by flash chromatography (methylene chloride/
methanol: 90:10) to give the diol as a foam (630 mg, 98%). The
spectral data of this product are in accordance with those recently
reported by M. Hocek et al. (Ref. 2) (see 1H and 13C spectral data).
HRMS (ESI) calcd for C9H10BrO3S [MꢀH]ꢀ, 276.9539; found,
276.9528.
4.3.8.
ribofuranose 1a
b-1-(5-(3-Hydroxy-chromone-2)-thiophen-2-yl)-2-deoxy-D-
To a solution of MEM-protected nucleoside 16 previously
obtained (140 mg, 0.15 mmol) in dioxane (3 mL) was added HCl 6 N
(1.5 mL). The mixture was stirred at room temperature overnight
then neutralized by saturated aqueous NaHCO3 solution and
extracted with ethyl acetate (3ꢂ10 mL). The organic layers were
evaporated in vacuo and the residue was purified by silica gel col-
umn chromatography (methylene chloride/methanol: 95:5 to
90:10) to give the free 3-HC-nucleoside 1a as a pale resin (46 mg,
85%). Rf¼0.26 (9:1 CH2Cl2/MeOH). 1H NMR (DMSO-d6, 500 MHz)
0
4.3.5.
b-1-(5-Bromothiophen-2-yl)-3,5-di-O-tert-
butyldiphenylsilyl-2-deoxy-
D-ribofuranose 15
To a solution of diol previously obtained (610 mg, 2.19 mmol) in
dry DMF (11 mL) were successively added imidazole (3.5 equiv) and
TBDPSCl (3.5 equiv,1.97 mL) under N2 atmosphere. After stirring for
24 h, the reaction mixture was quenched with a saturated solution
of NH4Cl and then extracted three times with methylene chloride.
The combined organic layers were dried over MgSO4, filtered and
evaporated. The residue was purified by silica gel column (cyclo-
hexane/ethyl acetate: 90:10) to afford 15 as a colourless oil (1.57 g,
95%). Rf¼0.8 (cyclohexane/ethyl acetate: 80:20). 1H NMR (CDCl3,
d
¼1.85 (ddd, 1H, J¼2.1, 11.3 and 13.7 Hz, H2 ), 2.12 (ddd, 1H, J¼2.1
0
0
and 3.8 and 13.7 Hz, H2 ), 3.30–3.62 (m, 1H, H5 ), 3.65–3.67 (m, 2H,
0
0
0
H5 and H4 ), 3.99 (br m, 1H, H3 ), 4.97 (dd, 1H, J¼2.1 Hz and 11.3 Hz,
0
H1 ), 7.15 (d, 1H, J¼3.9 Hz, H-thiophene), 7.47 (t, 1H, J¼7.4 Hz, H-6),
7.71 (d, 1H, J¼8.3 Hz, H-8), 7.81 (m, 1H, H-7), 7.82 (d, 1H, J¼3.9 Hz,
H-thiophene), 8.11 (dd, 1H, J¼1.2 and 7.4 Hz, H-5). 13C NMR (DMSO-
d6, 125 MHz)
d
¼42.4, 67.8, 68.2, 68.7, 71.0, 120.0, 123.7, 126.0, 126.5,
126.7, 129.9, 132.8, 135.5, 138.5, 145.2, 152.8, 156.1, 173.9. MS (ESI,
200 MHz)
d
¼0.85 (s, 9H, t-Bu), 1.01 (s, 9H, t-Bu), 1.81 (ddd, 1H,
MeOH) m/z: 358.9 [MꢀH]ꢀ. HRMS (ESI) calcd for C18H17O6S
J¼12.6, 10.9 and 5.2 Hz, H2’), 1.81 (dd, 1H, J¼11.4 and 5.1 Hz, H2 ),
[MþH]þ, 361.0745; found, 361.0741. IR (KBr)
n .
: 3432, 1651 cmꢀ1
0
0
3.24 (dd, 1H, J¼11.0 and 4.0 Hz, H5 ), 3.40 (dd, 1H, J¼11.0 and 4.0 Hz,
0
0
0
H5 ), 4.00 (dt,1H, J¼3.7 and 1.1 Hz, H4 ), 4.32 (br d,1H, J¼5.0 Hz, H3 ),
4.4. Synthesis of the triazolyl-3-hydroxy-chromone 1b
0
4.96 (dd, 1H, J¼10.9 and 5.1 Hz, 1H, H1 ), 6.64 (dd, 1H, J¼3.7 and
0.6 Hz, H-thiophene), 6.77 (d, 1H, J¼3.7, H-thiophene), 7.115–7.65
4.4.1.
tolouyl-2-deoxy-D
b
-1-(4-(3-Benzyloxy-chromone-2)-triazol-1-yl)-3,5-di-O-
-ribofuranose 17
(m, 20H, Ar). 13C NMR (CDCl3, 50 MHz)
d
¼19.2, 26.9, 27.1, 44.7, 64.3,
75.6, 88.5, 127.7, 127.7, 127.8, 127.9, 129.3, 129.8, 130.0, 133.2, 133.7,
133.8, 135.9, 147.2. MS (ESI, MeOH) m/z: 777.4–779.4 [MþNa]þ.
HRMS (ESI) calcd for C41H46BrO3SSi2 [MꢀH]ꢀ, 753.1895; found,
753.1884.
Method A. To a stirred solution of azido-sugar 4 (1 mmol), alkyne
10 (1.1 equiv) and n-Bu4NF (1.1 equiv) in methylene chloride (5 mL)
were successively added CuI (164 mg, 2 equiv), DIEA (0.37 mL,
5 equiv) and acetic acid (1 equiv). The mixture was stirred 4 h at
room temperature, filtered and the solvent removed in vacuo. The
crude product was purified by flash chromatography (cyclohexane/
ethyl acetate: 80:20) to give 17 (598 mg, 89%).
4.3.6.
b-1-(5-Tributylstannylthiophen-2-yl)-3,5-di-O-tert-
butyldiphenylsilyl-2-deoxy-
D-ribofuranose (intermediate)
To a solution of 15 (2.08 mmol) in dry ether (8 mL) was added
dropwise n-BuLi (1.1 equiv, 1.6 M solution) at 0 ꢁC, under N2 at-
mosphere. After 1 h, the mixture was cooled to ꢀ78 ꢁC and tribu-
tyltin chloride (1.1 equiv) was slowly added and the mixture was
stirred overnight. The reaction mixture was quenched with satu-
rated NH4Cl solution and extracted with ether. The combined or-
ganic layers were dried over MgSO4, filtered and concentrated in
vacuo. The obtained crude product was used in the next step
without further purification.
Method B. A mixture of azido-sugar 4 (1 mmol), alkyne 10
(1.1 equiv), n-Bu4NF (1.1 equiv), CuI (164 mg, 2 equiv), DIEA
(0.37 mL, 5 equiv) was adsorbed on silica gel (1 g) using methylene
chloride. After evaporation, the resulting yellow powder was
placed into a microwave and irradiated for 2 min. The mixture was
eluted twice with ethyl acetate and the solvent evaporated under
reduced pressure to give a crude product, which was subjected to
a simple filtration over silica gel (cyclohexane/ethyl acetate: 80:20)
to give 17 (638 mg, 95%). Mp (methylene chloride/ether)¼183–
185 ꢁC. Rf¼0.56 (cyclohexane/ethyl acetate: 50:50). 1H NMR (CDCl3,
4.3.7.
b-1-(5-(3-Hydroxy-chromone-2)-thiophen-2-yl)-3,5-di-O-
200 MHz)
d¼2.25 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.82–2.92 (m, 1H,
0
0
0
tert-butyldiphenylsilyl-2-deoxy-D-ribofuranose 16
H2 ), 3.11–3.24 (m, 1H, H2 ), 4.50 (d, 2H, J¼4.4 Hz, 2H5 ), 4.63–4.67
0
To a stirred solution of 2-bromo-3-HC 9 (284 mg, 0.86 mmol)
and tin derivative (2 mmol) in toluene (10 mL) under N2 atmo-
sphere were successively added Pd(PPh3)4 (50 mg) and CuI
(16 mg). The mixture was stirred at 120 ꢁC for 2 h, filtered
through Celite and concentrated in vacuo. The crude residue was
then purified by flash chromatography on silica gel (eluting with
cyclohexane/ethyl acetate: 90:10) to afford 16 as a yellow oil
(573 mg, 72%). Rf¼0.30 (cyclohexane/ethyl acetate: 70:30). 1H
(m, 1H, H4 ), 5.21 and 5.32 (2d, 2H, J¼11.0 Hz, CH2), 5.69–5.74 (m,
0
0
1H, H3 ), 6.42 (t, 1H, J¼5.7 Hz, H1 ), 7.13 (d, 2H, J¼8.0 Hz), 7.30–7.47
(m, 8H), 7.75 (m, 2H), 7.90 (d, 2H, J¼8.2 Hz), 7.95 (d, 2H, J¼8.2 Hz),
8.30 (d, 2H, J¼8.0 Hz). 13C NMR (CDCl3, 50 MHz)
¼21.7, 21.9, 38.4,
d
63.7, 74.4, 74.6, 83.9, 89.2, 118.7, 124.5, 125.0, 125.8, 126.5, 128.7,
129.0, 129.3, 129.4, 129.8, 129.9, 133.8, 136.8, 139.2, 144.2, 144.7,
155.3, 165.9, 166.2, 174.4. MS (ESI, MeOH) m/z¼709.8 [MþK]þ.
HRMS (ESI) calcd for C39H33N3O8 [MþH]þ, 672.2345; found,
672.2341.
NMR (acetone-d6, 200 MHz)
d
¼0.87 (s, 9H, t-Bu), 1.02 (s, 9H, t-
0
0
Bu), 1.97 (m, 1H, 2H2 ), 2.29 (dd, 1H, J¼12.6 and 5.0 Hz, H2 ), 3.02
(s, 3H, CH3), 3.19 (t, 2H, J¼4.6 Hz, CH2 MEM), 3.30 (dd, 1H, J¼11.0
4.4.2.
b-1-(4-(3-Benzyloxy-chromone-2)-triazol-1-yl)-2-deoxy-D-
0
0
and 3.7 Hz, H5 ), 3.47 (dd, 1H, J¼11.1 and 3.8 Hz, H5 ), 3.62 (t, 2H,
ribofuranose (intermediate)
0
J¼4.6 Hz, CH2 MEM), 4.05 (dt, 1H, J¼3.5 and 1.3 Hz, H4 ), 4.58 (d,
By the same procedure as described above for the synthesis of
14, compound 17 (100 mg, 0.15 mmol) was deprotected using
K2CO3 in MeOH to afford the pure product (62 mg, 95%). Mp
(methylene chloride/ether)¼94–96 ꢁC. Rf¼0.24 (9:1 CH2Cl2/MeOH).
0
0
1H, J¼5.1 Hz, H3 ), 5.37 (s, 2H, OCH2O), 5.47 (dd, 1H, J¼10.4 and
0
5.0 Hz, H1 ), 7.08 (d, 1H, J¼3.9, H-thiophene), 7.15–7.70 (m, 23H,
Ar), 7.85 (d, 1H, J¼3.9 Hz, H-thiophene), 8.02 (dd, 1H, J¼7.8 and
1.4 Hz, H-chromone). 13C NMR (CDCl3, 50 MHz)
d
¼20.0, 20.1, 27.6,
1H NMR (MeOD, 200 MHz)
d
¼2.47–2.78 (m, 2H, 2H2 ), 3.60 (dd, 1H,
0
0
27.8, 46.2, 59.2, 65.5, 71.0, 72.7, 76.9, 77.7, 89.8, 97.0, 119.1, 125.3,
126.0, 126.0, 126.5, 129.0, 129.1, 129.2, 131.0, 131.1, 131.3, 131.5,
132.0, 134.2, 134.3, 134.8, 134.9, 136.4, 136.7, 136.8, 137.0, 151.7,
154.8, 158.1, 174.0. MS (ESI, MeOH) m/z: 947.4 [MþNa]þ.
J¼4.6 and 11.9 Hz, 1H5 ), 3.70 (dd, 1H, J¼3.8 and 11.9 Hz, 1H5 ), 4.03
0
(dd, 1H, J¼4.2 and 8.2 Hz, H4 ), 4.48–4.56 (dd, 1H, J¼5.5 and 10.0 Hz,
0
0
H3 ), 5.28 (s, 2H, CH2), 6.42 (t, 1H, J¼5.9 Hz, H1 ), 7.20–7.35 (m, 4H),
7.44 (td, 1H, J¼1.1 and 8.1 Hz), 7.64 (d, 1H, J¼8.4 Hz), 7.75 (ddd, 1H,