Nucleic Acid Related Compounds
J . Org. Chem., Vol. 63, No. 4, 1998 1209
(EtOAc f 10% S2/EtOAc) to give 12a as a brown solid (∼150
8.17 (s, 0.64H), 8.27 (s, 0.36H), 8.34 (s, 0.64H); 19F NMR
(CDCl3) δ -199.79 (ddd, J ) 52.7, 23.6, 18.5 Hz, 0.64F),
-199.38 (ddd, J ) 52.7, 24.0, 21.3, Hz, 0.36F), -160.00 (dd, J
) 53.1, 20.0 Hz, 0.64F), -159.72 (dd, J ) 54.0, 15.6 Hz, 0.36F);
HRMS (CI) m/z 452.1197 (66, MH+ [C19H20F2N5O4S] ) 452.1204.
m-CPBA (299 mg of 78% reagent, 1.35 mmol) in CH2Cl2 (20
mL) was added dropwise to 10b (611 mg, 1.35 mmol) in CH2Cl2
(20 mL) at -78 °C, and stirring was continued for 2 h at -20
°C and 1 h at 0 °C. Workup as in procedure C and chroma-
tography (EtOAc f 5% MeOH/EtOAc) gave recovered 10b (47
mg, 7%) and then 11b (588 mg, 93%) as a solid foam: 19F NMR
(CDCl3) δ -201.59 (ddd, J ) 51.7, 21.5, 15.8 Hz, 0.52F),
-199.38 (dd, J ) 47.4, 8.6 Hz, 0.06F), -198.97 (ddd, J ) 53.1,
23.0, 20.1 Hz, 0.06F), -198.43 (ddd, J ) 51.7, 24.4, 20.8 Hz,
0.28F), -197.08 (ddd, J ) 51.7, 24.5, 19.4 Hz, 0.14F), -194.42
(dd, J ) 47.4, 24.4 Hz, 0.14F), -193.07 (dd, J ) 47.4, 30.2 Hz,
0.52F), -185.68 (dd, J ) 48.1, 15.1, Hz, 0.28F).
1
mg; purity ∼70%, H NMR). This material was stirred with
NH3/MeOH (10 mL) for 2 h at ∼0 °C, volatiles were evapo-
rated, and the brown residue was purified (RP-HPLC, pre-
parative column, 2×; program: 20% MeCN/H2O for 30 min,
20 f 50% MeCN/H2O for 50 min, 2.8 mL/min) to give 13a (Z)
(11 mg, 4% from 10a ; tR ) 70 min) and 13a (E) (22 mg, 8%; tR
) 75 min). 13a (Z): 1H NMR (CD3OD) δ 2.60-2.73 (m, 1H),
3.10-3.25 (m, 1H), 4.90-4.99 (m, 1H), 6.27 (d, J ) 2.3 Hz,
1H), 6.37 (dt, J ) 76.0, 1.8 Hz, 1H), 8.20 (s, 1H), 8.23 (s, 1H);
19F NMR (CD3OD) δ -166.15 (dm, J ) 76.0 Hz); HRMS m/z
251.0813 (100, M+ [C10H10FN5O2] ) 251.0819). 13a (E): 1H
NMR (CD3OD) δ 2.89 (dm, J ) 14.6 Hz, 1H), 3.30-3.45 (m,
1H), 4.91-5.00 (m, 1H), 6.22-6.25 (m, 1H), 7.14 (dt, J ) 78.9,
2.4 Hz, 1H), 8.19 (s, 1H), 8.23 (s, 1H); 19F NMR (CD3OD) δ
-182.56 (dtd, J ) 78.9, 4.0, 1.5 Hz); HRMS m/z 251.0811 (100,
M+ [C10H10FN5O2] ) 251.0819).
9-(3,5-Did eoxy-3,5-d iflu or o-â-D-er yth r o-p en t-4-en ofu r -
a n osyl]a d en in e [13b(Z) a n d 13b(E)]. Acetylation of 7b (785
mg, 2.01 mmol) with Ac2O (0.27 mL, 292 mg, 2.86 mmol) by
procedure B (7.5 h, ice-salt bath, workup only) gave 2′-O-
acetyl-3′-deoxy-3′-fluoro-5′-S-(4-methoxyphenyl)-5′-thioadeno-
sine (8b, 862 mg, 99%): 1H NMR (CDCl3) δ 2.10 (s, 3H), 3.25
(dd, J ) 14.5, 5.6 Hz, 1H), 3.30 (dd, J ) 14.5, 7.8 Hz, 1H),
3.80 (s, 3H), 4.45 (ddd, J ) 24.4, 7.8, 5.6, 1.5 Hz, 1H), 5.43
(ddd, J ) 53.6, 4.4, 1.5 Hz, 1H), 5.74 (br s, 2H), 6.12 (d, J )
7.0 Hz, 1H), 6.16 (ddd, J ) 19.4, 7.0, 4.4 Hz, 1H), 6.82 (d, J )
8.8 Hz, 2H), 7.39 (d, J ) 8.8 Hz, 2H), 7.88 (s, 1H), 8.34 (s,
1H); 19F NMR (CDCl3) δ -197.91 (ddd, J ) 53.6, 24.4, 19.4
Hz); 13C NMR (CDCl3) δ 20.60, 37.27 (d, J ) 8.5 Hz), 55.61,
72.98 (d, J ) 16.0 Hz), 83.06 (d, J ) 24.2 Hz), 86.12, 90.73 (d,
J ) 190.0 Hz), 115.06, 121.5, 124.53, 134.36, 141.06, 149.98,
154.22, 159.84, 169.83; HRMS (FAB) m/z 434.1295 (100, MH+
[C19H21FN5O4S] ) 434.1298).
A solution of isomeric 11b (588 mg, 1.26 mmol; dried in
vacuo at 60 °C for 12 h) and EtN(i-Pr)2 (2.2 mL, 1.6 g, 12.6
mmol) in dried diglyme (20 mL) was purged with argon for
0.5 h and heated at 143 ( 1 °C (oil bath temperature). Stirring
was continued for 24 h, EtN(i-Pr)2 (1.1 mL, 0.82 g, 6.3 mmol)
was added, and heating was continued for 48 h. Volatiles were
evaporated, and the residue was chromatographed (EtOAc f
5% MeOH/EtOAc) to give 12b (E/Z ∼36:64; 283 mg, 72%): 1H
NMR (CDCl3) δ 2.10 (s, 3H), 5.91 (dd, J ) 56.1, 4.2 Hz, 0.64H),
6.18 (dd, J ) 55.1, 4.2 Hz, 0.36H), 6.34 (ddd, J ) 18.3, 6.6, 4.2
Hz, 0.36H), 6.39 (ddd, J ) 20.6, 7.7, 4.2 Hz, 0.64H), 6.64 (d, J
) 6.6 Hz, 0.36H), 6.70 (d, J ) 7.7 Hz, 0.64H), 7.16 (dd, J )
72.8, 8.0 Hz, 0.64H), 7.51 (dd, J ) 77.0, 6.7 Hz, 0.36H), 7.57
(br s, 2H), 8.22 (s, 1H), 8.46 (s, 0.36H), 8.49 (s, 0.64H); 19F
NMR (CDCl3) δ -190.08 (dddd, J ) 55.1, 18.3, 10.3, 6.7 Hz,
0.36F), -183.36 (dddd, J ) 56.1, 20.6, 10.3, 8.0 Hz, 0.64F),
-173.06 (dd, J ) 77.0, 10.3 Hz, 0.36F), -155.80 (dd, J ) 72.8,
10.3 Hz, 0.64F).
Treatment of 8b (869 mg, 2 mmol) by procedure C gave 2′-
O-acetyl-3′,5′-dideoxy-3′-fluoro-5′-[(4-methoxyphenyl)sulfinyl]-
adenosine [9b, (R/S)S ∼48:52; 787 mg, 88%] as an amorphous
solid: HRMS (FAB) m/z 450.1243 (100, MH+ [C19H21FN5O5S]
) 450.1247). Chromatography (EtOAc f 5% MeOH/EtOAc)
gave partial separation. Less polar 9b(RS): 1H NMR (CDCl3)
δ 2.10 (s, 3H), 3.10 (dd, J ) 12.8, 2.6 Hz, 1H), 3.78 (dd, J )
12.8, 10.8 Hz, 1H), 3.85 (s, 3H), 5.00 (dddd, J ) 21.9, 10.8,
2.6, 1.9 Hz, 1H), 5.41 (ddd, J ) 53.6, 4.4, 1.9 Hz, 1H), 6.11 (br
s, 2H), 6.13 (d, J ) 6.9 Hz, 1H), 6.33 (ddd, J ) 19.5, 6.9, 4.4
Hz, 1H), 7.10 (d, J ) 8.8 Hz, 2H), 7.51 (d, J ) 8.8 Hz, 2H),
7.89 (s, 1H), 8.22 (s, 1H); 19F NMR (CDCl3) δ -199.61 (ddd, J
) 53.6, 21.9, 19.5 Hz); 13C NMR (CDCl3) δ 20.51, 55.72, 60.87
(d, J ) 6.9 Hz), 72.30 (d, J ) 15.3 Hz), 77.93 (d, J ) 24.8 Hz),
87.46, 91.55 (d, J ) 193.8 Hz), 115.13, 121.18, 125.92, 134.79,
141.23, 149.56, 153.17, 156.13, 162.51, 169.90. More polar
9b(SS): 1H NMR (CDCl3) δ 2.08 (s, 3H), 3.31 (dd, J ) 13.7,
5.4 Hz, 1H), 3.58 (dd, J ) 13.7, 7.3 Hz, 1H), 3.80 (s, 3H), 4.69
(dddd, J ) 24.2, 7.3, 5.4, 1.5 Hz, 1H), 5.58 (ddd, J ) 53.6, 4.4,
1.5 Hz, 1H), 6.09 (d, J ) 7.3 Hz, 1H), 6.26 (br s, 2H), 6.32
(ddd, J ) 19.2, 7.3, 4.4 Hz, 1H), 6.88 (d, J ) 8.8 Hz, 2H), 7.48
(d, J ) 8.8 Hz, 2H), 7.93 (s, 1H), 8.30 (s, 1H); 19F NMR (CDCl3)
δ -196.82 (ddd, J ) 53.6, 24.2, 19.2 Hz); 13C NMR (CDCl3) δ
20.48, 55.61, 56.84 (d, J ) 6.5 Hz), 72.35 (d, J ) 15.6 Hz),
77.45 (d, J ) 25.9 Hz), 86.32, 91.62 (d, J ) 191.5 Hz), 114.75,
120.71, 126.23, 133.21, 140.32, 149.69, 153.36, 156.13, 162.23,
169.68.
A solution of 9b (788 mg, 1.75 mmol) in CH2Cl2 (15 mL)
was treated with DAST/SbCl3 by procedure D (4 h), and the
residue was flash chromatographed (EtOAc) to give amorphous
2′-O-acetyl-3′-deoxy-3′,5′-difluoro-5′-S-(methoxyphenyl)-5′-thio-
adenosine (10b, 5′R/S ∼36:64; 611 mg, 77%): 1H NMR (CDCl3)
δ 2.11 (s, 1.08H), 2.12 (s, 1.92H), 3.82 (s, 3H), 4.59 (ddd, J )
24.0, 15.6, 4.9 Hz, 0.36H), 4.69 (dddd, J ) 20.0, 18.5, 4.2, 2.0
Hz, 0.64H), 5.51 (dd, J ) 52.7, 4.4 Hz, 0.36H), 5.56 (ddd, J )
52.7, 4.9, 4.2 Hz, 0.64H), 5.77 (ddd, J ) 23.6, 7.3, 4.9 Hz,
0.64H), 5.88 (ddd, J ) 21.3, 7.3, 4.4 Hz, 0.36H), 5.99 (dd, J )
53.1, 4.2 Hz, 0.64H), 6.03 (dd, J ) 54.0, 4.9 Hz, 0.36H), 6.32
(d, J ) 7.3 Hz, 0.36H), 6.36 (d, J ) 7.3 Hz, 0.64H), 6.49 (br s,
0.72H), 6.55 (br s, 1.28H), 6.88 (d, J ) 9.0 Hz, 2H), 7.46 (d, J
) 9.0 Hz, 0.72H), 7.48 (d, J ) 9.0 Hz, 1.28H), 8.04 (s, 0.36H),
A solution of 12b (37 mg, 0.12 mmol) in NH3/MeOH (20 mL)
was stirred for 2 h at ambient temperature. Volatiles were
evaporated, and “diffussion crystallization” (EtOAc/hexane) of
the residue gave 13b (E/Z ∼36:64; 22 mg, 69%). RP-HPLC:
(Z)tR ) 38.3 min, (E)tR ) 41.4 min [preparative column, H2O/
MeOH/MeCN (55:30:15)]. 13b(Z): mp ∼239 °C dec [MeOH/
EtOAc (∼1:1)//hexanes]; UV max 259 nm (ꢀ 14 800); 1H NMR
δ 5.42 (ddd, J ) 24.9, 8.3, 3.4 Hz, 1H), 5.50 (dd, J ) 56.7, 3.4
Hz, 1H), 6.27 (d, J ) 8.3 Hz, 1H), 6.35 (br s, 1H), 7.03 (dd, J
) 73.7, 7.8 Hz, 1H), 7.44 (br s, 2H), 8.17 (s, 1H), 8.48 (s, 1H);
19F NMR δ -184.30 (dddd, J ) 56.7, 24.9, 10.3, 7.8 Hz, F3′),
-156.83 (dd, J ) 73.7, 10.3 Hz, F5′); 13C NMR δ 70.43 (d, J )
19.1 Hz), 87.22, 87.87 (dd, J ) 183.1, 8.0 Hz), 119.5, 133.76
(dd, J ) 254.6, 13.5 Hz), 138.27 (dd, J ) 13.9, 5.2 Hz), 140.59,
149.85, 153.19, 156.40; MS m/z 269 (100, M+), 252 (20), 135
(34). Anal. Calcd for C10H9N5O2F2‚0.25 H2O (273.7): C, 43.88;
H, 3.50; N, 25.59. Found: C, 43.71; H, 3.68; N, 25.68.
1
13b(E): mp 239-240 °C dec; UV max 259 nm (ꢀ 14 500); H
NMR δ 5.38 (dddd, J ) 24.0, 8.3, 6.8, 4.4 Hz, 1H), 5.83 (ddd,
J ) 56.2, 4.4, 2.1 Hz, 1H), 6.21 (d, J ) 8.3 Hz, 1H), 6.33 (d, J
) 6.8 Hz, 1H), 7.38 (dd, J ) 77.7, 7.4 Hz, 1H), 7.42 (br s, 2H),
8.17 (s, 1H), 8.46 (s, 1H); 19F NMR δ -190.06 (dddd, J ) 56.2,
24.0, 11.6, 7.4 Hz, F3′), -172.88 (ddd, J ) 77.7, 11.6, 2.1 Hz,
F5′); 13C NMR δ 70.12 (d, J ) 17.6 Hz), 85.38 (d, J ) 181.8
Hz), 86.87, 119.42, 138.24, (dd, J ) 238.2, 11.1 Hz), 140.45,
143.93 (dd, J ) 29.4, 13.4 Hz), 149.82, 153.15, 156.37; MS m/z
269 (100, M+), 252 (22), 135 (36). Anal. Calcd for C10H9N5O2F2
(269.2): C, 44.62; H, 3.37; N, 26.01. Found: C, 44.44; H, 3.36;
N, 25.83.
RP-HPLC of the mother liquor (preparative column, pro-
gram: 15% MeCN/H2O for 15 min, 15 f 40% MeCN/H2O for
30 min; 2.5 mL/min) gave 13b(Z) (3 mg, 9%; tR ) 36.2 min),
13b(E/Z) (1.5 mg, 5%), and 13b(E) (1.5 mg, 5%, tR ) 39.2 min)
[to give 13b (88% overall)].
9-(3-Ch lor o-3,5-dideoxy-5-flu or o-â-D-er yth r o-pen t-4-en o-
fu r a n osyl)a d en in e [13c(Z) a n d 13c(E)]. Treatment of 7c
(1.29 g, 3.16 mmol) by procedure B (7.5 h, ice-salt bath,
workup only) gave 2′-O-acetyl-3′-chloro-3′-deoxy-5′-S-(4-meth-
oxyphenyl)-5′-thioadenosine (8c, 1.41 g, 99%): 1H NMR (CDCl3)
δ 2.16 (s, 3H), 3.23 (dd, J ) 14.3, 6.5 Hz, 1H), 3.41 (dd, J )