1616 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Wnuk et al.
CN/H2O for 30 min at 3 mL/min; tR 35-39 min) of the mother
liquor gave 12 mg (9%) of 20b (E/ Z ∼4.5:1).
n osin e-5′-ca r boxa ld eh yd e) (23e). Hydrolysis of oximes 5a
(56 mg, 0.2 mmol) in Me2CO/H2O/TFA and RP-HPLC purifica-
tion (as described for 23a , method A) gave 23e hydrate (29
mg, 51%; white solid with data as reported7).
2′,5′-Did eoxy-5′,5′-(N,N′-d ip h en ylet h ylen ed ia m in o)-
a d en osin e (22b). Oxidation (1 h at 0 °C, 2 h at ambient
temperature) of 18d (147 mg, 0.5 mmol) with the Dess-Martin
periodinane reagent (as described for 20b, method B) was
followed by stirring the crude 5′-carboxaldehyde with 1,2-
dianilinoethane (159 mg, 0.75 mmol) for 1 h at ambient
temperature and for 15 h at ∼5 °C. Volatiles were evaporated,
and the residue was worked up by procedure D [unreacted 18d
was present (TLC, S3) in the water layer] and chromato-
graphed (CHCl3 f 2% MeOH/CHCl3) to give 22d (87 mg,
9-(2,3:5,6-Di-O-isop r op ylid en e-â-D-gu lofu r a n osyl)a d e-
n in e (26). Adenine (594 mg, 4.4 mmol) was added to a
solution of 25b [1.21 g, 4 mmol; prepared from D-gulonic
γ-lactone via 24 and 25a as described27 and acetylation (Ac2O/
DMAP/pyridine)] in dried CH3CN (150 mL). SnCl4 (2.29 g,
1.03 mL, 8.8 mmol) was added dropwise to the stirred
suspension at ambient temperature. After 1 h, the resulting
solution was heated (∼35 °C) for 2 h, stirred at ambient
temperature for 14 h, refluxed for 3 h [TLC (S1, S2) showed
two products with higher Rf values than adenine], and
concentrated (∼10 mL). NaHCO3 (∼3 g) and water (∼15 mL)
were added (vigorous evolution of CO2), and the emulsion was
partitioned (NaHCO3/H2O//CHCl3). The aqueous layer was
extracted (3 × CHCl3), and the combined organic phase was
washed (NaCl/H2O, brine), dried (MgSO4), concentrated, and
chromatographed (EtOAc f 30% S1/EtOAc) to give 26 (450
mg, 30%; off-white solid): 1H NMR δ 1.26, 1.28, 1.35, 1.51 (4
× s, 4 × 3, Me’s), 3.75-3.82 (m, 1, H5′), 4.06-4.38 (m, 3,
H4′,6′,6′′), 5.22 (dd, J 3′-4′ ) 3.5 Hz, J 3′-2′ ) 5.8 Hz, 1, H3′),
5.43 (d, 1, H2′), 6.25 (s, 1, H1′), 7.38 (br s, 2, NH2), 8.19 (s, 1,
H2), 8.28 (s, 1, H8); MS m/ z 377 (18, M+), 362 (84, M - 15),
302 (61), 218 (100), 164 (72), 136 (86, BH2); HRMS (CI) m/z
378.1767 (100), calcd for MH+ (C17H24N5O5) 378.1777. Also
eluted was 9-(2,3:5,6-di-O-isopropylidene-R-D-gulofuranosyl)-
adenine (135 mg, 9%; off-white solid): 1H NMR δ 1.25, 1.30,
1.38, 1.50 (4 × s, 4 × 3, Me’s), 3.79-3.93 (m, 2, H6′,6′′), 4.08-
4.16 (m, 1, H4′), 4.31-4.43 (m, 1, H5′), 4.85 (dd, J 3′-4′ ) 3.5
Hz, J 3′-2′ ) 6.0 Hz, 1, H3′), 4.93 (dd, J 2′-1′ ) 3.4 Hz, 1, H2′),
6.15 (d, 1, H1′), 7.33 (br s, 2, NH2), 8.18 (s, 1, H2), 8.19 (s, 1,
H8); MS m/ z 377 (12, M+), 362 (83, M - 15), 319 (100), 164
(84), 136 (50, BH2).
9-(r-L-lyxo-P en tod ia ld o-1,4-fu r a n osyl)a d en in e Oxim es
[28(E/Z)]. The aqueous eluent containing 29 [prepared as
described for 32 from 27 (68 mg, 0.2 mmol)] was concentrated
in vacuo (<30 °C), coevaporated (CH3CN, 2 × 5 mL), and
dissolved in dried pyridine (5 mL). NH2OH‚HCl (139 mg, 2
mmol) was added, and stirring was continued overnight at
ambient temperature [TLC (S1) showed less polar products].
Evaporation and deprotection (2 h, procedure B and RP-HPLC
as for 20b; precipitation from MeOH with CH3CN) gave 28
(E/ Z ∼7:3; 18 mg, 32%): mp 102-105 °C dec; UV max 258 (ꢀ
12 800), min 230 nm (ꢀ 3000); MS m/ z 280 (12, M+), 135 (100,
BH); HRMS (CI) m/z 281.0995 (16), calcd for MH+ (C10H13N6O4)
281.0998. Treatment of crude 30 with NH2OH‚HCl/pyridine
gave 28 (∼15%), but treatment of the aqueous eluent contain-
ing 29 with NH2OH‚HCl/NaHCO3/MeOH gave traces of oximes.
9-(r-L-lyxo-P en todialdo-1,4-fu r an osyl)aden in e (30). The
aqueous eluent containing 29 [prepared as described for 32
from 27 (169 mg, 0.5 mmol)] was concentrated in vacuo (<30
°C) and treated with TFA/H2O (4:1, 5 mL) at 0 °C (ice bath)
for 2 h. Evaporation, coevaporation (EtOH), and RP-HPLC
(as described for 20b) gave 30 (43 mg, 33%; white solid with
data as reported7).
36%): 1H NMR (CDCl3) δ 2.05 (s, 3, Ac), 2.36 (ddd, J 2′′-3′
)
2.4 Hz, J 2′′-2′ ) 13.7 Hz, J 2′′-1′ ) 5.4 Hz, 1, H2′′), 2.57 (ddd,
J 2′-3′ ) 6.5 Hz, J 2′-1′ ) 8.7 Hz, 1, H2′), 3.56-3.85 (m, 4, CH2-
CH2), 4.58-4.62 (m, 1, H4′), 5.55-5.62 (m, 1, H3′), 5.88 (s, 1,
H5′), 6.11 (br s, 2, NH2), 6.37 (dd, 1, H1′), 6.71-7.32 (m, 10,
Arom), 7.49 (s, 1, H2), 8.32 (s, 1, H8); MS m/ z 485 (2, M+),
290 (21), 223 (100), 135 (40, BH). [Oxidation of 18d (88 mg,
0.3 mmol) by procedure C, treatment with oxalic acid dihy-
drate, filtration of DCU,16a and analogous treatment of the
mother liquor with 1,2-dianilinoethane gave 22d (45 mg,
31%).]
Deacetylation (NH3/MeOH, 10 mL; 2 h, ∼0 °C) of 22d (97
mg, 0.2 mmol) and crystallization (MeOH) of the residue gave
1
22b (60 mg, 67%): mp 128-132 °C dec; H NMR (CDCl3) δ
2.10 (br s, 1, OH3′), 2.37-2.64 (m, 2, H2′,2′′), 3.53-3.80 (m, 4,
CH2CH2), 4.47 (dd, J 4′-3′ ) 4.8 Hz, J 4′-5′ ) 2.1 Hz, 1, H4′), 4.72-
4.92 (m, 1, H3′), 5.61 (br s, 2, NH2), 5.77 (d, 1, H5′), 6.38 (t,
J 1′-2′,2′′ ) 6.1 Hz, 1, H1′), 6.74-7.28 (m, 10, Arom), 7.48 (s, 1,
H2), 8.28 (s, 1, H8); MS (CI) m/ z 444 (20, MH+), 223 (100),
135 (40, BH); HRMS (CI) m/z 444.2140 (100), calcd for MH+
(C24H26N7O2) 444.2148.
9-(3-De oxy-â-D-er yt h r o-p e n t od ia ld o-1,4-fu r a n osyl)-
a d en in e (23a ). Meth od A. Oximes 20a (40 mg, 0.15 mmol)
were dissolved in Me2CO/H2O (5:1, 6 mL), TFA (0.115 mL, 171
mg, 1.5 mmol) was added dropwise at ambient temperature,
and stirring was continued overnight. TLC (S1) showed that
20a had been converted into more polar products that mi-
grated faster than adenine. Evaporation of volatiles and
purification of the residue by RP-HPLC (10% CH3CN/H2O for
30 min followed by a gradient of 10% f 30% CH3CN/H2O for
40 min at a flow rate of 2.7 mL/min; tR 31-36 min) gave 23a
hydrate (16 mg, 40%). Trituration with Et2O gave a white
solid: mp 135-143 °C dec; UV max 260 (ꢀ 10 600), min 227
nm (ꢀ 1600); MS (CI) m/ z 268 (14, MH+ - hydrate), 250 (22,
MH+), 178 (81), 135 (100, BH).
Meth od B. Oxidation of 17c (100 mg, 0.3 mmol) with the
Dess-Martin periodinane reagent,26 treatment of the 5′-
carboxaldehyde with 1,2-dianilinoethane, deacetylation (NH3/
MeOH; 14 h, ∼0 °C), and chromatography (EtOAc f 4%
MeOH/EtOAc) (as described for 22b) gave 22a (58 mg, 44%):
1H NMR (CDCl3) δ 1.95 (br s, 1, OH2′), 2.01-2.45 (m, 2,
H3′,3′′), 3.60-3.83 (m, 4, CH2CH2), 4.44-4.50 (m, 1, H4′),
4.96-5.05 (m, 1, H2′), 5.70 (br s, 2, NH2), 5.80 (s, 1, H1′), 5.88
(s, 1, H5′), 6.72-7.38 (m, 10, Arom), 7.70 (s, 1, H2), 8.20 (s, 1,
H8); MS (CI) m/ z 444 (10, MH+), 223 (100), 135 (15, BH).
Treatment of 22a (88 mg, 0.2 mmol) with TsOH‚H2O (as
described for 23b) and RP-HPLC purification gave 23a hydrate
(16 mg, 28%; white solid).
9-(2-De oxy-â-D-er yt h r o-p e n t od ia ld o-1,4-fu r a n osyl)-
a d en in e (23b). TsOH‚H2O (85 mg, 0.45 mmol) was added to
a solution of 22b (88 mg, 0.2 mmol) in CH2Cl2/Me2CO (1:1, 10
mL) at ∼0 °C, and stirring was continued for 1 h. TLC (S2)
showed conversion of 22b to more polar products. NH3/MeOH
was added dropwise (to pH ∼7), and volatiles were evaporated.
Preparative RP-HPLC (10% CH3CN/H2O for 30 min, then a
gradient of 10% f 25% CH3CN/H2O for 25 min at 2.8 mL/
min) gave 23b (tR 38-43 min) contaminated with NH4OTs.
RP-HPLC (20% MeOH/H2O for 40 min, then a gradient of 20%
f 40% MeOH/H2O; tR 42-46 min) gave the unstable 23b
hydrate (12 mg, 21%; white solid, precipitated from CH3CN
and dried in vacuo at ambient temperature): mp 165-180 °C
dec; UV max 260 (ꢀ 10 100), min 228 nm (ꢀ 3000); MS (CI)
m/ z 267 (3, MH+), 135 (100, BH).
9-(r-L-Lyxofu r a n osyl)a d en in e (32). Treatment of 27 [169
mg, 0.5 mmol; prepared by hydrolysis (AcOH/H2O, 7:3) of 26
as described27 and chromatography (CHCl3 f 10% MeOH/
CHCl3)] with NaIO4/H2O (0.5 M, 1.3 mL) and chromatography
(Amberlite IR-45 resin)27,29 gave 29. NaBH4 (303 mg, 8 mmol)
was immediately added to the combined aqueous eluent, and
the mixture was allowed to stand for 1 h at ambient temper-
ature and worked up as described27,29 to give 31 (80 mg, 52%
from 27; white foam): 1H NMR δ 1.33, 1.48 (2 × s, 2 × 3, Me’s),
3.57 (ddd, J 5′′-5′ ) 11.8 Hz, J 5′′-4′ ) 7.0 Hz, J 5′,5′′-OH5′ ) 5.5 Hz,
1, H5′′), 3.71 (ddd, J 5′-4′ ) 4.5 Hz, 1, H5′), 4.31-4.39 (m, 1,
H4′), 4.76 (t, 1, OH5′), 5.15 (dd, J 3′-4′ ) 3.6 Hz, J 3′-2′ ) 5.8 Hz,
1, H3′), 5.42 (d, 1, H2′), 6.18 (s, 1, H1′), 7.35 (br s, 2, NH2),
8.18 (s, 1, H2), 8.28 (s, 1, H8); MS m/ z 307 (8, M+), 292 (28, M
- 15), 218 (100), 135 (82, BH).
Treatment of 31 (61 mg, 0.2 mmol) with TFA/H2O (9:1, 5
mL) by procedure B, RP-HPLC (as described for 20b), and
crystallization (MeOH, two crops) gave 32 (39 mg, 73%): mp
226-228 °C dec (lit.27 mp 246-249 °C); UV max 259 (ꢀ 13 500),
9-(â-D-r ibo-P en t od ia ld o-1,4-fu r a n osyl)a d en in e (Ad e-