2100 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6
Rapp et al.
brine, dried (Na2SO4), and evaporated. Column chromatography
(0 f 70% EtOAc/hexane) gave 8a (E/Z, 89:11; 74 mg, 86%) as a
white solid powder. Compound 8a (E) had: 1H NMR δ 0.56-
0.62 (m, 2, c-Pr), 0.91-0.96 (m, 2, c-Pr), 1.41 (s, 3, CH3), 1.62 (s,
3, CH3), 3.05 (br s, 1, c-Pr), 4.64 (dd, J ) 3.1, 6.8 Hz, 1, H4′),
5.13 (dd, J ) 3.1, 6.1 Hz, 1, H3′), 5.58 (dd, J ) 1.6, 6.1 Hz, 1,
H2′), 6.04 (br s, 1, NH), 6.08 (d, J ) 1.6 Hz, 1, H1′), 6.36 (d, J )
14.5 Hz, 1, H6′), 6.70 (dd, J ) 6.8, 14.5 Hz, 1, H5′), 7.81 (s, 1,
H2), 8.51 (s, 1, H8). Compound 8a (Z) had: 1H NMR δ 0.56-
0.62 (m, 2, c-Pr), 0.91-0.96 (m, 2, c-Pr), 1.41 (s, 3, CH3), 1.62 (s,
3, CH3), 3.05 (br s, 1, c-Pr), 4.10-4.15 (m, 1, H4′), 5.03 (dd, J )
4.1, 7.7 Hz, 1, H3′), 5.67 (d, J ) 4.1 Hz, 1, H2′), 6.04 (br s, 1,
NH), 6.09 (s, 1, H1′), 6.43 (“t”, J ) 7.8 Hz, 1, H5′), 6.49 (d, J )
7.9 Hz, 1, H6′), 7.81 (s, 1, H2), 8.49 (s, 1, H8); MS m/z 470 (MH+).
6-N-Cyclopropyl-9-[5,6-dideoxy-6-iodo-â-D-ribo-hex-5-(E/Z)-
enofuranosyl]adenine (8b). Deprotection of 8a (62 mg, 0.13
mmol), as described for 4b [column chromatography (0 f 20%
MeOH/EtOAc)] gave crude 8b (42 mg, 75%). RP-HPLC purifica-
tion (preparative C18 column; gradient program 30 f 70% CH3-
CN/H2O for 30 min followed by 70 f 100% CH3CN/H2O for next
10 min at 2.5 mL/min; tR 28.6 min) gave 8b (E/Z, 89:11; 15 mg,
30%) as a white powder: mp 186-192 °C; UV max 269 nm (ꢀ
16 400), min 238 nm (ꢀ 3800). Compound 8b (E) had: 1H NMR
(DMSO-d6) δ 0.58-0.64 (m, 2, c-Pr), 0.69-0.76 (m, 2, c-Pr), 3.01
(br s, 1, c-Pr), 4.16-4.22 (m, 1, H3′), 4.33 (dd, J ) 4.5, 7.5 Hz, 1,
H4′), 4.69 (“q”, J ) 5.1 Hz, 1, H2′), 5.48 (d, J ) 5.4 Hz, 1, OH3′),
5.61 (d, J ) 5.5 Hz, 1, OH2′), 5.91 (d, J ) 5.0 Hz, 1, H1′), 6.67
(d, J ) 14.5 Hz, 1, H6′), 6.85 (dd, J ) 7.5, 14.5 Hz, 1, H5′), 8.00
(br s, 1, NH), 8.22 (s, 1, H2), 8.37 (s, 1, H8); 13C NMR (DMSO-
d6) δ 7.33 (c-Pr, C2/2′), 24.10 (c-Pr, C1), 73.59, 73.82 (C3′/2′),
83.12 (C4′), 86.70 (C6′), 88.68 (C1′), 120.56 (C5), 140.81 (C5′),
144.63 (C8), 149.10 (br s, C4), 153.51 (C2), 156.57 (C6).
Compound 8b (Z) had: 1H NMR (DMSO-d6) δ 0.58-0.64 (m, 2,
c-Pr), 0.69-0.76 (m, 2, c-Pr), 3.01 (br s, 1, c-Pr), 4.13-4.17 (m,
1, H3′), 4.54 (dd, J ) 3.0, 7.8 Hz, 1, H4′), 4.84 (“q”, J ) 5.5 Hz,
1, H2′), 5.57 (d, J ) 5.1 Hz, 1, OH3′), 5.62 (d, J ) 4.8 Hz, 1,
OH2′), 5.94 (d, J ) 6.1 Hz, 1, H1′), 6.72 (d, J ) 7.8 Hz, 1, H6′),
6.80 (t, J ) 7.8 Hz, 1, H5′), 8.00 (br s, 1, NH), 8.22 (s, 1, H2),
8.37 (s, 1, H8); MS m/z 430 (MH+). Anal. C14H16IN5O3‚0.33H2O
(435.22) C, H, N.
6-N-Cyclopropyl-9-[5,6-dideoxy-6-fluoro-6-phenylsulfonyl-
2,3-O-isopropylidene-â-D-ribo-hex-5-(E/Z)-enofuranosyl]ade-
nine (9). LiHMDS (1 M/THF; 0.3 mL, 0.3 mmol) was added
dropwise to the stirred solution of diethyl fluoro(phenylsulfonyl)-
methylephosphonate20b (93 mg, 0.3 mmol) in THF (2.5 mL) at -78
°C. The resulting mixture was stirred for 30 min, and the crude
5′-aldehyde [generated from 3b (92 mg, 0.26 mmol) as described
for 4a (step a)] was added dropwise. After 15 min, the reaction
mixture was allowed to warm to -30 °C over 1.5 h and was
quenched with NH4Cl/H2O (0.5 mL). Oxalic acid dihydrate (98
mg, 0.78 mmol) in MeOH (2 mL) was added, and DCU was filtered
off. The residue was partitioned (NaHCO3/H2O//CHCl3), and the
separated organic layer was washed (NaHCO3/H2O, brine), dried
(Na2SO4), evaporated, and chromatographed [EtOAc/hexane (8:2)
f EtOAc followed by 0 f 40% S1/EtOAc] to give 9 (E/Z, 63:37;
82 mg, 59%) as a white foam. Compound 9 (E) had: 1H NMR δ
0.65-0.73 (m, 2, c-Pr), 0.91-0.97 (m, 2, c-Pr), 1.47 (s, 3, CH3),
1.62 (s, 3, CH3), 3.06 (br s, 1, c-Pr), 5.10 (“d”, J ) 8.2 Hz, 1,
H4′), 5.26 (“d”, J ) 5.9 Hz, 1, H3′), 5.59 (d, J ) 5.6 Hz, 1, H2′),
6.06 (s, 1, H1′), 6.27 (s, 1, NH), 6.55 (dd, J ) 8.2, 32.6 Hz, 1,
H5′), 7.58 (t, J ) 8.1 Hz, 2, Ar), 7.66-7.72 (m, 1, Ar), 7.84 (d, J
) 8.1 Hz, 2, Ar), 7.96 (s, 1, H2), 8.40 (s, 1, H8); 19F NMR δ
-122.46 (d, J ) 32.6 Hz, 0.63F). Compound 9 (Z) had: 1H NMR
δ 0.65-0.73 (m, 2, c-Pr), 0.91-0.97 (m, 2, c-Pr), 1.47 (s, 3, CH3),
1.62 (s, 3, CH3), 3.06 (br s, 1, c-Pr), 5.26 (“d”, J ) 5.9 Hz, 1,
H3′), 5.54 (d, J ) 4.8 Hz, H2′), 6.09 (s, 1, H1′), 6.20-6.30 (m, 3,
H4′,5′ & NH), 7.58-7.84 (m, 5, Ar), 7.99 (s, 1, H2), 8.46 (s, 1,
H8); 19F NMR δ -112.13 (d, J ) 20.5 Hz, 0.37F); MS m/ z 502
(MH+).
nine (10). Reaction of 9 (E/Z, 63:37; 127 mg, 0.25 mmol) with
Bu3SnH, as described for 7 [column chromatography: hexane
followed by elution with 0 f 80% EtOAc/hexane)], gave 10 (E/Z,
75:25; 102 mg, 62%) as a transparent oil. Compound 10 (E) had:
1H NMR δ 0.65-0.68 (m, 2, c-Pr), 0.84-0.96 (m, 11, c-Pr, Bu3-
Sn), 1.24-1.46 (m, 18, Bu3Sn), 1.42 (s, 3, CH3), 1.63 (s, 3, CH3),
3.02 (br s, 1, c-Pr), 5.03 (dd, J ) 2.6, 6.1 Hz, 1, H3′), 5.10 (dd, J
) 8.8, 51.5 Hz, 1, H5′), 5.33 (dd, J ) 2.5, 8.5 Hz, 1, H4′), 5.66 (d,
J ) 1.6, 6.2 Hz, 1, H2′), 6.05 (d, J ) 1.6 Hz, 1, H1′), 6.13 (br s,
1, NH), 7.84 (s, 1, H2), 8.47 (s, 1, H8); 19F NMR δ -95.66 (d, J
) 52.0 Hz, 84% of 0.75F) & (ddd, J ) 4.7, 52.0, 215.0 Hz, 16%
of 0.75F). Compound 10 (Z) had: 1H NMR δ 0.65-0.68 (m, 2,
c-Pr), 0.84-0.96 (m, 11, c-Pr, Bu3Sn), 1.24-1.46 (m, 18, Bu3Sn),
1.42 (s, 3, CH3), 1.63 (s, 3, CH3), 3.02 (br s, 1, c-Pr), 4.49 (“dt”,
J ) 2.9, 10.7 Hz, 1, H4′), 5.01 (dd, J ) 3.3, 6.3 Hz, 1, H3′), 5.48
(dd, J ) 1.6, 6.3 Hz, 1, H2′), 6.03 (d, J ) 1.6 Hz, 1, H1′), 6.04
(dd, J ) 10.1, 34.0 Hz, 1, H5′), 6.13 (br s, 1, NH), 7.82 (s, 1, H2),
8.49 (s, 1, H8); 19F NMR δ -89.07 (“d”, J ) 34.0 Hz, 0.25F); MS
m/z 652 (100, M + 1, 120Sn), 650 (75, MH+, 118Sn), 648 (38, MH+,
116Sn).
6-N-Cyclopropyl-9-[5,6-dideoxy-6-fluoro-â-D-ribo-hex-5-
(E/Z)-enofuranosyl]adenine (11). A solution of 10 (E/Z, 75:25;
90 mg, 0.14 mmol) in TFA/H2O (9:1, 3 mL) was stirred at ∼0 °C
(ice bath) for 50 min. Volatiles were evaporated (<15 °C) and
coevaporated with toluene (2×) and ethanol under vacuum. The
residue was chromatographed (hexane followed by elution with 0
f 20% S1/EtOAc) to give 11 (E/Z, 26:74; 41 mg, 61%) as a white
powder: mp 184-187 °C; UV max 269 nm (ꢀ 17 400), min 231
nm (ꢀ 3000). Compound 11 (E) had: 1H NMR (MeOH-d4) δ 0.63-
0.69 (m, 2, c-Pr), 0.87-0.93 (m, 2, c-Pr), 2.96 (br s, 1, c-Pr), 4.30
(t, J ) 4.9 Hz, 1, H3′), 4.44 (dd, J ) 4.7, 8.8 Hz, 1, H4′), 4.78 (t,
J ) 4.6 Hz, 1, H2′), 5.73 (ddd, J ) 8.8, 11.1, 19.9 Hz, 1, H5′),
6.00 (d, J ) 4.0 Hz, 1, H1′), 6.95 (dd, J ) 11.1, 83.7 Hz, 1, H6′),
8.22 (s, 1, H2), 8.32 (s, 1, H8); 19F NMR (MeOH-d4) δ -126.53
(dd, J ) 19.9, 83.7 Hz, 0.26F); 13C NMR (MeOH-d4) δ 8.97 (c-Pr,
C2/2′), 25.95 (c-Pr, C1), 76.31 (C2′), 77.05 (C3′), 82.62 (d, J )
14.8 Hz, C4′), 91.84 (C1′), 113.09 (d, J ) 11.6 Hz, C5′), 122.42
(C5), 142.47 (C8), 151.31 (br s, C4), 153.93 (d, J ) 260.6 Hz,
C6′), 155.19 (C2), 158.53 (C6). Compound 11 (Z) had: 1H NMR
(MeOH-d4) δ 0.63-0.69 (m, 2, c-Pr), 0.87-0.93 (m, 2, c-Pr), 2.96
(br s, 1, c-Pr), 4.29 (t, J ) 5.1 Hz, 1, H3′), 4.85 (t, J ) 5.0 Hz, 1,
H2′), 5.01 (dd, J ) 4.6, 9.1 Hz, 1, H4′), 5.36 (ddd, J ) 4.8, 9.1,
41.3 Hz, 1, H5′), 6.01 (d, J ) 4.9 Hz, 1, H1′), 6.73 (ddd, J ) 1.0,
4.8, 83.7 Hz, 1, H6′), 8.22 (s, 1, H2), 8.32 (s, 1, H8); 19F NMR
(MeOH-d4) δ -127.15 (dd, J ) 41.3, 83.7 Hz, 0.74F); 13C NMR
(MeOH-d4) δ 8.97 (c-Pr, C2/2′), 25.95 (c-Pr, C1), 76.27 (C2′), 77.59
(C3′), 79.65 (d, J ) 6.6 Hz, C4′), 91.80 (C1′), 112.48 (C5′), 122.68
(C5), 142.69 (C8), 151.31 (br s, C4), 155.20 (C2), 155.22 (d, J )
263.3 Hz, C6′), 158.53 (C6); MS m/z 322 (MH+). Anal. C14H16-
FN5O3 (321.31) C, H, N.
6-N-Cyclopropyl-9-(6,6-dibromo-5,6-dideoxy-2,3-O-isoprop-
ylidene-â-D-ribo-hex-5-enofuranosyl)adenine (13a). A mixture of
CBr4 (299 mg, 0.9 mmol) and PPh3 (236 mg, 0.9 mmol) and zinc
dust (59 mg, 0.9 mmol) in CH2Cl2 (3 mL) was stirred for 3 h at
ambient temperature. A solution of crude 5′-aldehyde [generated
from 3b (92 mg, 0.26 mmol) as described for 4a (step a)] was
added dropwise to the brown reaction mixture of ylide, and stirring
was continued for 14 h [TLC (CHCl3/MeOH, 95:5) showed less
polar 13a comigrated with Ph3PO]. Oxalic acid dihydrate (98 mg,
0.78 mmol) in MeOH (2 mL) was added, and DCU was filtered
off. The mother liquor was partitioned (NaHCO3/H2O//CHCl3), and
the separated organic layer was washed (brine), dried (Na2SO4),
evaporated, and chromatographed (50 f 90% EtOAc/hexane) to
give 13a (97 mg, 74%) as a white foam: 1H NMR δ 0.63-0.69
(m, 2, c-Pr), 0.91-0.96 (m, 2, c-Pr), 1.40 (s, 3, CH3), 1.63 (s, 3,
CH3), 3.04 (br s, 1, c-Pr), 4.96 (dd, J ) 2.4, 8.1 Hz, 1, H4′), 5.21
(dd, J ) 2.4, 4.1 Hz, 1, H3′), 5.58 (d, J ) 4.1 Hz, 1, H2′), 6.07 (s,
1, H1′), 6.18 (br s, 1, NH), 6.70 (d, J ) 8.1 Hz, 1, H5′), 7.81 (s,
1, H2), 8.47 (s, 1, H8); MS m/z 502 (MH+).
6-N-Cyclopropyl-9-[5,6-dideoxy-6-fluoro-6-(tributylstannyl)-
2,3-O-isopropylidene-â-D-ribo-hex-5-(E/Z)-enofuranosyl]ade-
6-N-Cyclopropyl-9-(6,6-dibromo-5,6-dideoxy-â-D-ribo-hex-5-
enofuranosyl)adenine (13b). Treatment of 13a (90 mg, 0.18 mmol)