Doubly Homologated Adenosine Analogues
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1183
1
25.89, 26.44, 26.70, 35.38, 59.38, 74.03, 76.61, 77.36, 104.18,
112.78, 128.41, 129.46, 129.88, 133.31, 165.92; HRMS (CI) m/z
423.2209 (12, MH+ [C22H35O6Si] ) 423.2203).
g, 79%) as white crystals: mp 73-75 °C; H NMR δ 1.20 &
1.45 (2 × s, 2 × 3, 2 × Me), 2.40 (dt, J ) 15.3, 6.8 Hz, 1, H5′),
2.48 (ddd, J ) 15.7, 7.0, 5.0 Hz, 1, H5), 4.25 (dt, J ) 8.6, 6.0
Hz, 1, H4), 4.57 (dd, J ) 9.2, 4.8 Hz, 1, H3), 4.87 (t, J ) 4.4
Hz, 1, H2), 5.77 (d, J ) 3.8 Hz, 1, H1), 6.46 (t, J ) 7.1 Hz, 1
H6), 7.31-7.98 (m, 5, Arom); 13C NMR δ 26.90, 26.94, 35.58
(C5), 75.58 (C4), 76.23 (C3), 77.64 (C2), 92.11 (C7), 104.54 (C1),
113.48, 128.89, 129.56, 130.30, 133.56 (C6), 133.88, 166.20;
HRMS (CI) m/z 464.9565 (44, MH+ [C17H1981Br2O5] ) 464.9559),
HCl/H2O (0.1 M, 17.2 mL) was added to this product (4.14
g, 9.8 mmol) in MeOH (85 mL) and stirring was continued at
ambient temperature for 30 min. Saturated NaHCO3/H2O (6
mL) was added, and the mixture was stirred for 15 min and
was then concentrated. The residue was partitioned (EtOAc//
NaHCO3/H2O), and the organic layer was washed (brine), dried
(Na2SO4), and evaporated. Chromatography of the residue
(20f35% EtOAc/hexanes) gave 2c (2.68 g, 89%) as an oil: 1H
NMR δ 1.34 & 1.54 (2 × s, 2 × 3, 2 × Me), 1.75-2.05 (m, 2,
H5,5′), 2.40 (br s, 1, OH), 3.82 (t, J ) 5.8 Hz, 2, H6,6′), 4.42
(td, J ) 8.8, 3.6 Hz, 1, H4), 4.72 (dd, J ) 9.1, 4.8 Hz, 1, H3),
4.92 (t, J ) 4.4 Hz, 1, H2), 5.88 (d, J ) 3.9 Hz, 1, H1), 7.40-
8.08 (m, 5, Arom); 13C NMR δ 26.46, 26.57, 34.59, 59.80, 75.74,
76.46, 77.15, 104.22, 112.99, 128.47, 129.27, 129.87, 133.44,
165.92; HRMS (CI) m/z ) 309.1341 (100, MH+ [C16H21O6] )
309.1338).
462.9599 (100, MH+ 81/79Br2] ) 462.9579), 460.9594 (51, MH+
[
[79Br2] ) 460.9599). Anal. [C17H18Br2O5 (462.14)] C, H.
Meth od B. Treatment of 2c (1.75 g, 5.68 mmol) by proce-
dure B gave 3b (1.98 g, 75%).
7-Br om o-3-O-(ter t-b u t yld im et h ylsilyl)-5,6,7-t r id eoxy-
7-flu or o-1,2-O-isop r op ylid en e-r-D-r ibo-h ep t-6-en ofu r a n -
ose (3c). Treatment of 2b13c (1.59 g, 5 mmol) by procedure B
(CBr3F was used instead of CBr4; column chromatography,
10f20% EtOAc/hexane) gave 3c (986 mg, 48%; E/ Z, ∼45:55):
1H NMR δ 0.01 (s, 6, 2 × Me), 0.80 (s, 9, t-Bu), 1.20 & 1.40
(2 × s, 2 × 3, 2 × Me), 2.08-2.40 (m, 2, H5,5′), 3.58-3.64 (m,
1, H3), 3.87-3.95 (m, 1, H4), 4.39-4.42 (m, 1, H2), 5.15 (dt,
J ) 31.1, 7.5 Hz, 0.45, H6), 5.62 (dt, J ) 12.9, 7.3 Hz, 0.55,
H6), 5.70-5.72 (m, 1, H1); 13C NMR δ -4.53, -4.43, -4.12,
-4.04, 18.52, 26.09, 26.11, 26.95, 28.04 (J ) 1.4 Hz) & 30.37
(J ) 3.7 Hz, C5), 76.25 & 76.39 (C3), 78.07 & 78.22 (J ) 1.7
Hz, C4), 79.42 (C2), 104.17 & 104.21 (C1), 106.44 (J ) 17.5
Hz, C6Z), 108.39 (J ) 12.4 Hz, C6E), 112.87, 112.89, 132.95
(J ) 320.2 Hz, C7E), 136.56 (J ) 314.3 Hz, C7Z); 19F NMR
7,7-Dibr om o-3-O-(ter t-bu tyldim eth ylsilyl)-5,6,7-tr ideoxy-
1,2-O-isop r op ylid en e-r-D-r ibo-h ep t-6-en ofu r a n ose (3a ).
P r oced u r e B. A solution of 2b13c (3.18 g, 10 mmol) and N,N′-
dicyclohexylcarbodiimide (DCC; 6.11 g, 30 mmol) in dried
Me2SO (25 mL) was cooled (∼5 °C) under argon, Cl2CHCO2H
(0.41 mL, 645 mg, 5 mmol) was added, and stirring was
continued for 90 min at ambient temperature. The brown
solution was injected (syringe) into a mixture containing
(dibromomethylene)triphenylphosphorane [generated in situ
by stirring CBr4 (6.63 g, 20 mmol), Ph3P (5.25 g, 20 mmol),
and activated Zn (dust; 1.30 g, 20 mmol) in dried CH2Cl2 (100
mL) for 5 h at ambient temperature under Ar; sonication was
applied intermittently for a total of 30 min], stirring was
continued for 10 h, and oxalic acid dihydrate (2.52 g, 20 mmol)
in MeOH (20 mL) was added. After 20 min, the reaction
mixture was concentrated (to ∼1/3 volume), dicyclohexylurea
was filtered and washed with cold MeOH, and the combined
filtrates were evaporated (in vacuo). The residue was parti-
tioned (NaHCO3/H2O//CHCl3), and the organic layer was
washed (2 × H2O, brine), dried (MgSO4), and volatiles were
evaporated. Column chromatography of the residue (15%
δ -74.46 (d, J F-6 ) 30.9 Hz, 0.45, F7E), -69.93 (d, J F-6
)
13.2 Hz, 0.55, F7Z); HRMS (CI) m/z 413.0981 (96, MH+
[C16H2981BrFO4Si] ) 413.0983), 411.1009 (100, MH+ [79Br] )
411.1003).
Further elution of the column (20f30% EtOAc/hexane) gave
6-aldehyde-2b (490 mg, 31%; 3-O-tert-butyldimethylsilyl-5-
deoxy-1,2-O-isopropylidene-â-D-ribo-hexodialdofuranose): 1H
NMR δ 9.71 (t, J ) 2.4 Hz, 1, H6); 13C NMR δ 200.28 (C6).
3-O-Ben zoyl-7-br om o-5,6,7-tr id eoxy-7-flu or o-1,2-O-iso-
p r op ylid en e-r-D-r ibo-h ep t-6-en ofu r a n ose (3d ). Meth od A.
Treatment of 3c (822 mg, 2 mmol) by procedure C gave
7-bromo-5,6,7-trideoxy-7-fluoro-1,2-O-isopropylidene-R-D-ribo-
hept-6-enofuranose (481 mg, 81%; E/ Z, ∼45:55): 1H NMR δ
5.16 (dt, J ) 30.9, 7.7 Hz, 0.45, H6), 5.62 (dt, J ) 12.9, 7.5 Hz,
0.55, H6), 5.77 (d, J ) 3.9 Hz, 1, H1); 19F NMR δ -74.25 (d,
J F-6 ) 30.8 Hz, 0.45, F7E), -69.45 (d, J F-6 ) 12.8 Hz, 0.55,
F7Z); HRMS (CI) m/z 299.0117 (97, MH+ [C10H1581BrFO4] )
299.0118), 297.0128 (100, MH+ [79Br] ) 297.0138).
Benzoylation of this product (455 mg, 1.53 mmol) by
procedure A gave 3d (564 mg, 92%; E/ Z, ∼45:55) as a syrup:
1H NMR δ 1.30 & 1.49 (2 × s, 2 × 3, 2 × Me), 2.37-2.64 (m,
2, H5,5′), 4.28-4.38 (m, 1, H4), 4.69 (dd, J ) 9.1, 4.7 Hz, 0.45,
H3), 4.70 (dd, J ) 9.1, 4.8 Hz, 0.55, H3), 4.96 (m, 1, H2), 5.20
(dt, J ) 30.7, 7.7 Hz, 0.45, H6), 5.65 (dt, J ) 12.7, 7.5 Hz,
0.55, H6), 5.88 (d, J ) 3.8 Hz, 1, H1), 7.45-8.10 (m, 5, Arom);
13C NMR δ 26.92, 26.97, 28.43 (J ) 1.6 Hz) & 30.41 (J ) 3.8
Hz, C5), 76.00 & 76.15 (C3), 76.13 & 76.17 (C4), 77.70 & 77.75
(C2), 104.52 & 104.57 (C1), 105.62 (J ) 18.2 Hz, C6Z), 107.58
(J ) 12.4 Hz, C6E), 113.44, 128.93, 129.59, 129.64, 130.27,
130.31, 133.90, 133.77 (J ) 320.9 Hz, C7E), 137.49 (J ) 316.1
Hz, C7Z), 166.21; 19F NMR δ -73.75 (d, J F-6 ) 30.9 Hz, 0.45,
F7E), -68.55 (d, J F-6 ) 12.8 Hz, 0.55, F7Z); HRMS (CI) m/z
403.0365 (96, MH+ [C17H1981BrFO5] ) 403.0379), 401.0399
(100, MH+ [79Br] ) 401.0400). Anal. [C17H18BrFO5 (401.23)]
C, H.
1
EtOAc/hexane) gave 3a (4.22 g, 89%) as a syrup: H NMR δ
0.02 (s, 6, 2 × Me), 0.80 (s, 9, t-Bu), 1.20 & 1.41 (2 × s, 2 × 3,
2 × Me), 2.19 (dt, J ) 15.7, 7.0 Hz, 1, H5′), 2.36 (ddd, J )
15.7, 6.6, 4.6 Hz, 1, H5), 3.47 (dd, J ) 8.8, 4.6 Hz, 1, H3), 3.82
(ddd, J ) 8.7, 6.9, 4.6 Hz, 1, H4), 4.28 (t, J ) 4.2 Hz, 1, H2),
5.59 (d, J ) 3.8 Hz, 1, H1), 6.40 (t, J ) 6.9 Hz, 1 H6);
13C NMR δ -4.81, -4.53, 18.13, 25.72, 26.55, 35.28 (C5),
76.24 (C3), 77.25 (C4), 78.97 (C2), 90.38 (C7), 103.83 (C1),
112.52, 134.17 (C6); HRMS (FAB) m/z 496.9940 (58, MNa+
[C16H2881Br2O4SiNa] ) 496.9981), 494.9986 (100, MNa+
[
81/79Br2]
) 495.0001), 493.0021 (45, MNa+ [79Br2] ) 493.0021).
3-O-Ben zoyl-7,7-d ibr om o-5,6,7-tr id eoxy-1,2-O-isop r op -
ylid en e-r-D-r ibo-h ep t-6-en ofu r a n ose (3b). Meth od A. P r o-
ced u r e C. TBAF/THF (1 M, 10 mL) was added to a stirred
solution of 3a (4.00 g, 8.5 mmol) in dried THF (30 mL) at ∼0
°C under N2. After 2 h, volatiles were evaporated, and the
residue was partitioned (NaHCO3/H2O//EtOAc). The organic
layer was washed (brine), dried (MgSO4), and evaporated.
Column chromatography of the residue (30% EtOAc/hexane)
gave 7,7-dibromo-5,6,7-trideoxy-1,2-O-isopropylidene-R-D-ribo-
hept-6-enofuranose (2.55 g, 84%) as a syrup: 1H NMR δ 1.25
& 1.46 (2 × s, 2 × 3, 2 × Me), 2.33 (dt, J ) 15.6, 7.2 Hz, 1,
H5′), 2.49 (ddd, J ) 15.6, 6.7, 4.4 Hz, 1, H5), 2.65 (d, J ) 10.5
Hz, OH3), 3.54-3.61 (m, 1, H3), 3.73 (ddd, J ) 8.8, 7.1, 4.5
Hz, 1, H4), 4.50 (t, J ) 4.5 Hz, 1, H2), 5.72 (d, J ) 3.9 Hz, 1,
H1), 6.48 (t, J ) 7.0 Hz, 1 H6); 13C NMR δ 26.77, 26.88, 35.46
(C5), 75.40 (C3), 78.25 (C4), 78.74 (C2), 91.26 (C7), 104.09 (C1),
112.94, 134.30 (C6); HRMS (CI) m/z 360.9291 (50, MH+
Meth od B. Treatment of 2c (924 mg, 3 mmol) by procedure
B (CBr3F was used instead of CBr4) gave 3d (493 mg, 41%;
E/ Z, ∼45:55). Further elution of the column (15f30% EtOAc/
hexane) gave 6-aldehyde-2c (321 mg, 35%; 3-O-benzoyl-5-
deoxy-1,2-O-isopropylidene-â-D-ribo-hexodialdofuranose): 1H
NMR δ 9.85 (t, J ) 1.5 Hz, 1, H6); 13C NMR δ 199.56 (C6).
1,2-Di-O-acetyl-3-O-ben zoyl-7,7-dibr om o-5,6,7-tr ideoxy-
D-r ibo-h ep t-6-en ofu r a n ose (4a ). P r oced u r e D. A solution
of 3b (462 mg, 1 mmol) in CF3CO2H/H2O (9:1, 7 mL) was
stirred at ∼0 °C (ice bath) for 1 h. Volatiles were evaporated
under oil-pump vacuum (<10 °C), coevaporated with toluene
[C10H1581Br2O4] ) 360.9298), 358.9307 (100, MH+
[
81/79Br2] )
358.9317), 356.9339 (51, MH+ [79Br2] ) 356.9337).
Treatment of this product (1.38 g, 3.85 mmol) with BzCl
(0.90 mL, 1.08 g, 7.7 mmol) by procedure A [6 h, DMAP (10
mg) added] and column chromatography (10% EtOAc/hexane)
gave 3b (1.73 g, 97%). Crystallization (MeOH) afforded 3b (1.4