4518 J . Org. Chem., Vol. 67, No. 13, 2002
Garc´ıa et al.
was taken up in NaHCO3 (aq) and extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4 and evapo-
rated to give monoacylated nucleosides 3 or 4. In case of 3b,
the residue was purified by flash chromatography (gradient
eluent 10-30% MeOH/EtOAc) instead of extraction.
N-Ben zoyl-3′,5′-d i-O-levu lin yl-2′-O-(2-m eth oxyeth yl)-5-
m eth ylcytid in e (6c): 88% yield; 1H NMR (CDCl3, 200 MHz)
δ 1.99 (s, 3H), 2.06 (s, 3H), 2.54 (m, 4H), 2.66 (m, 4H), 3.17 (s,
3H), 3.36 (m, 2H), 3.62 (m, 2H), 4.28 (m, 4H), 4.98 (m, 1H),
3
5.86 (d, 1H, J HH 4.4 Hz), 7.36 (m, 4H), and 8.17 (apparent d,
3
3′-O-Levu lin ylth ym id in e (3a ): this compound was previ-
2H, J HH 6.9 Hz); MS (ESI+, m/z) 616 [(M + H)+, 80], 638 [(M
ously reported;10b 1H NMR (MeOH-d4, 200 MHz) δ 2.09 (d, 3H,
+ Na)+, 80], and 654 [(M + K)+, 100].
3
J HH 1.3 Hz), 2.39 (s, 3H), 2.57 (m, 2H), 2.80 (t, 2H, J HH 6.0
3′,5′-d i-O-Levu lin yl-2′-O-(2-m et h oxyet h yl)a d en osin e
(6d ): 94% yield; 1H NMR (MeOH-d4, 300 MHz) δ 2.33 (s, 3H),
2.38 (s, 3H), 2.82 (m, 4H), 3.00 (m, 4H), 3.32 (s, 3H), 3.56 (m,
2H), 3.83 (m, 2H), 4.57 (m, 3H), 5.16 (apparent t, 1H, 3J HH 5.9
Hz), 3.05 (t, 2H, 3J HH 6.2 Hz), 4.01 (m, 2H), 4.29 (m, 1H), 5.02
3
3
(m, 1H), 6.50 (dd, 1H, J HH 8.1, J HH 6.5 Hz), and 8.04 (d, 1H,
3J HH 1.3 Hz); MS (ESI+, m/z) 363 [(M + Na)+, 100] and 379
[(M + K)+, 30].
3
3
3
Hz), 5.68 (dd, 1H, J HH 2.9, J HH 5.2 Hz), 6.27 (d, 1H, J HH 6.5
Hz), 8.41 (s, 1H), and 8.42 (s, 1H); MS (ESI+, m/z) 522 [(M +
H)+, 20] and 534 [(M + Na)+, 100].
1
3′-O-Levu lin yl-2′-d eoxycytid in e (3b): H NMR (MeOH-
d4, 200 MHz) δ 2.39 (s, 3H), 2.47 (m, 1H), 2.67 (m, 1H), 2.75
(m, 2H), 3.02 (m, 2H), 4.00 (m, 2H), 4.30 (m, 1H), 5.49 (m,
N-Ben zoyl-3′,5′-d i-O-levu lin yl-2′-O-(2-m et h oxyet h yl)-
a d en osin e (6e): 89% yield; 1H NMR (CDCl3, 300 MHz) δ 2.14
(s, 3H), 2.17 (s, 3H), 2.58-2.76 (m, 8H), 3.15 (s, 3H), 3.38 (m,
2H), 3.66 (m, 2H), 4.40 (m, 3H), 4.93 (apparent t, 1H, 3J HH 5.5
3
3
1H), 6.15 (d, 1H, J HH 6.8 Hz), 6.48 (apparent t, 1H, J HH 6.8
Hz), and 8.32 (d, 1H, J HH 7.3 Hz); MS (ESI+, m/z) 326 [(M +
3
H)+, 10], 348 [(M + Na)+, 50], and 364 [(M + K)+, 12].
3′-O-Levu lin yl-2′-d eoxya d en osin e (3d ): 1H NMR (MeOH-
d4, 200 MHz) δ 2.40 (s, 3H), 2.76 (m, 1H), 2.80 (t, 2H, 3J HH 6.2
Hz), 3.05 (t, 2H, 3J HH 6.2 Hz), 3.14 (m, 1H), 4.04 (m, 2H), 4.40
(m, 1H), 5.66 (d, 1H, 3J HH 6.0 Hz), 6.61(dd, 1H′, 3J HH 5.7, 3J HH
9.1 Hz), 8.39 (s, 1H), and 8.50 (s, 1H); MS (ESI+, m/z) 350 [(M
+ H)+, 100], 372 [(M + Na)+, 100], and 388 [(M + K)+, 60].
N-Isobu tyr yl-3′-O-levu lin yl-2′-deoxygu an osin e (3g): this
compound was previously reported;8a 1H NMR (MeOH-d4, 200
3
3
Hz), 5.40 (apparent t, 1H, J HH 4.9 Hz), 6.13 (d, 1H, J HH 5.4
Hz), 7.47 (m, 3H), 8.01 (m, 2H), 8.28 (s, 1H), 8.75 (s, 1H), and
9.54 (s, 1H); MS (ESI+, m/z) 626 [(M + H)+, 45], 648 [(M +
Na)+, 100], and 664 [(M + K)+, 80].
3′,5′-Di-O-Levu lin yl-2′-O-m eth yladen osin e (6f): 92% yield;
1H NMR (CDCl3, 300 MHz) δ 2.17 (s, 3H), 2.18 (s, 3H), 2.64
(m, 4H), 2.76 (m, 4H), 3.38 (s, 3H), 4.40 (m, 3H), 4.69 (apparent
t, 1H, 3J HH 5.4 Hz), 5.40 (t, 1H, 3J HH 4.3 Hz), 6.05 (d, 1H, 3J HH
5.6 Hz), 6.25 (br s, 2H), 8.05 (s, 1H), and 8.31 (s, 1H); MS (ESI+,
m/z) 478 [(M + H)+, 20] and 500 [(M + Na)+, 100].
3
MHz) δ 1.41 (d, 6H, J HH 6.8 Hz), 2.38 (s, 3H), 2.70-3.09 (m,
3
7H), 3.98 (d, 2H′, J HH 3.6 Hz), 4.32 (m, 1H), 5.57 (m, 1H),
6.51 (dd, 1H, 3J HH 6.1, 3J HH 8.0 Hz), and 8.43 (s, 1H); MS (ESI+,
m/z) 436 [(M + H)+, 15] and 458 [(M + Na)+, 50].
N-Isobu tyr yl-3′,5′-di-O-levu lin yl-2′-O-(2-m eth oxyeth yl)-
1
1
gu a n osin e (6g): 92% yield; H NMR (MeOH-d4, 300 MHz) δ
5′-O-Levu lin ylth ym id in e (4a ): H NMR (DMSO-d6, 200
3
1.41 (d, 6H, J HH 6.8 Hz), 2.32 (s, 3H), 2.38 (s, 3H), 2.75-3.05
MHz) δ 1.91 (s, 3H), 2.27 (s, 3H), 2.30 (m, 2H), 2.66 (m, 2H),
3
(several m, 9H), 3.37 (s, 3H), 3.58 (m, 2H), 3.81 (m, 2H), 4.57
(m, 3H), 4.98 (apparent t, 1H′, 3J HH 5.7 Hz) 5.59 (m, 1H), 6.20
(d, 1H′, 3J HH 6.3 Hz), and 8.36 (s, 1H); MS (ESI+, m/z) 608 [(M
+ H)+, 80], 630 [(M + Na)+, 65], and 646 [(M + K)+, 100].
2.89 (t, 2H, J HH 6.2 Hz), 4.07 (m, 1H), 4.35 (m, 3H), 5.55 (d,
3
1H), 6.32 (t, 1H′, J HH 7.0 Hz), 7.6 (s, 1H), and 11.45 (s, 1H);
MS (ESI+, m/z) 341 [(M + H)+, 40], 379 [(M + Na)+, 100], and
379 [(M + K)+, 80].
N-Ben zoyl-5′-O-levu lin yl-2′-deoxycytidin e (4c): 1H NMR
(CDCl3, 300 MHz) δ 2.20 (s, 3H), 2.25 (m, 1H), 2.58 (m, 2H),
2.75 (m, 1H), 2.82 (m, 2H), 3.35 (s, 1H), 4.25 (m, 1H), 4.40 (m,
Gen er a l P r oced u r e for th e En zym a tic Hyd r olysis of
3′,5′-Di-O-levu lin yl-2′-p r ot ect ed R ibon u cleosid es 6. A
similar procedure as that described for 2 was followed.
Reaction time and temperature are indicated in Table 2. In
the case of 8e, the residue was purified by flash chromatog-
raphy (gradient eluent 5-10% iPrOH/CH2Cl2) after extraction.
3
3H), 6.30 (apparent t, 1H′, J HH 6.2 Hz), 7.55 (m, 4H), 7.90
3
3
(apparent d, 2H, J HH 7.1 Hz), 8.20 (d, 1H, J HH 7.4 Hz), and
8.78 (s, 1H); MS (ESI+, m/z) 430 [(M + H)+, 20], 452 [(M +
Na)+, 65], and 468 [(M + K)+, 40].
3′-O-Levu lin yl-2′-O-m eth oxyeth yl-5-m eth ylu r idin e (7a):
1H NMR (CDCl3, 200 MHz) δ 1.85 (s, 3H), 2.16 (s, 3H), 2.61
(m, 2H), 2.74 (m, 2H), 3.24 (s, 3H), 3.42 (m, 2H), 3.64 (m, 2H),
3.79 (m, 2H), 4.16 (m, 1H), 4.41 (apparent t, 1H, 3J HH 5.4 Hz),
N-Ben zoyl-5′-O-levu lin yl-2′-d eoxya d en osin e (4e): 1H
NMR (DMSO-d6, 300 MHz) δ 2.06 (s, 3H), 2.45 (m, 3H), 2.66
(m, 2H), 2.90 (m, 1H), 4.03 (m, 1H), 4.20 (m, 2H), 4.51 (m,
3
3
3
1H), 5.55 (s, 1H), 6.50 (apparent t, 1H′, J HH 6.5 Hz), 7.58 (m,
5.28 (apparent t, 1H, J HH 4.6 Hz), 5.70 (d, 1H, J HH 5.6 Hz),
and 7.48 (s, 1H); MS (ESI+, m/z) 415 [(M + H)+, 20] and 437
[(M + Na)+, 100].
3H), 8.03 (m, 2H), 8.69 (s, 1H), 8.74 (s, 1H), and 11.20 (s, 1H);
MS (ESI+, m/z) 476 [(M + Na)+, 100] and 492 [(M + K)+, 53].
N-Isobu tyr yl-3′-O-levu lin yl-2′-d eoxygu a n osin e (4g): 1H
3′-O-Le vu lin yl-2′-O-(2-m e t h oxye t h yl)-5-m e t h ylcyt i-
3
NMR (MeOH-d4, 300 MHz) δ 1.42 (d, 6H, J HH 6.8 Hz), 2.32
1
d in e (7b): H NMR (CDCl3, 200 MHz) δ 1.92 (s, 3H), 2.20 (s,
(s, 3H), 2.59-3.07 (m, 7H), 4.32 (m, 1H), 4.50 (m, 2H), 4.75
3H), 2.66 (m, 2H), 2.77 (m, 2H), 3.28 (s, 3H), 3.44 (m, 2H),
3.70 (m, 3H), 3.92 (m, 1H), 4.23 (m, 1H), 4.72 (apparent t, 1H,
3
(m, 1H), 6.30 (apparent t, 1H′, J HH 6.5 Hz), and 8.33 (s, 1H);
MS (ESI+, m/z) 436 [(M + H)+, 20], 458 [(M + Na)+, 100], and
3
3J HH 5.4 Hz), 5.38 (apparent t, 1H, J HH 4.6 Hz), 5.48 (d, 1H,
474 [(M + K)+, 50].
3J HH 5.7 Hz), and 7.41 (s, 1H); MS (ESI+, m/z) 414 [(M + H)+,
3′,5′-Di-O-levu lin yl-2′-p r ot ect ed R ib on u cleosid es (6).
The same procedure as that described in Method A was
followed for 2. The crude products were purified by flash
chromatography (gradient eluent EtOAc-20%MeOH/EtOAc
for 6a , 6d , 6f, 6g; gradient eluent 5-20% MeOH/CH2Cl2 for
6b; gradient eluent 80-90% EtOAc/Hex for 6c) to give 3′,5′-
di-O-levulinylnucleosides 6a -g.
55] and 436 [(M + Na)+, 100].
3′-O-Levu lin yl-2′-O-(2-m et h oxyet h yl)a d en osin e (7d ):
1H NMR (CDCl3, 300 MHz) δ 2.18 (s, 3H), 2.71 (m, 2H), 2.78
(m, 2H), 3.06 (s, 3H), 3.24 (m, 2H), 3.44 (m, 1H), 3.56 (m, 1H),
3.76 (m, 1H), 3.90 (m, 1H), 4.32 (s, 1H), 4.89 (dd, 1H, 3J HH 5.1,
3
3
3J HH 7.9 Hz), 5.62 (d, 1H, J HH 4.8 Hz), 5.85 (d, 1H, J HH 7.9
Hz), 6.51 (br s, 2H), 6.90 (br s, 1H), 7.86 (s, 1H), and 8.27 (s,
1H); MS (ESI+, m/z) 424 [(M + H)+, 80] and 446 [(M + Na)+,
100].
3′,5′-Di-O-le vu lin yl-2′-O-m e t h oxye t h yl-5-m e t h ylu r i-
d in e (6a ): 95% yield; 1H NMR (CDCl3, 200 MHz) δ 1.82 (s,
3H), 2.09 (s, 6H), 2.55 (m, 4H), 2.68 (m, 4H), 3.18 (s, 3H), 3.38
(m, 2H), 3.60 (m, 2H), 4.25 (m, 4H), 4.99 (m, 1H), 5.85 (d, 1H,
3J HH 4.8 Hz), 7.24 (s, 1H), and 10.04 (s, 1H); MS (ESI+, m/z)
513 [(M + H)+, 5] and 535 [(M + Na)+, 100].
3′-O-Levu lin yl-2′-O-m et h yla d en osin e (7f): 1H NMR
(CDCl3, 300 MHz) δ 2.20 (s, 3H), 2.69 (m, 2H), 2.80 (m, 2H),
3
3.25 (s, 3H), 3.86 (m, 2H), 4.32 (s, 1H), 4.75 (dd, 1H, J HH
3
3
7.9,3J HH 4.8 Hz), 5.64 (d, 1H, J HH 5.1 Hz), 5.83 (d, 1H, J HH
7.9 Hz), 6.36 (s, 2H), 6.90 (br s, 1H), 7.86 (s, 1H), and 8.31 (s,
1H); MS (ESI+, m/z) 380 [(M + H)+, 100] and 402 [(M + Na)+,
90].
3′,5′-Di-O-levu lin yl-2′-O-(2-m eth oxyeth yl)-5-m eth ylcy-
tid in e (6b): 57% yield; 1H NMR (MeOH-d4, 200 MHz) δ 2.18
(s, 3H), 2.35 (s, 3H), 2.36 (s, 3H), 2.81 (m, 4H), 3.02 (m, 4H),
3.46 (s, 3H), 3.66 (m, 2H), 3.88 (m, 2H), 4.52 (m, 4H), 5.33
3
3
(apparent t, 1H, J HH 5.0 Hz), 6.17 (d, 1H, J HH 4.9 Hz), and
7.75 (s, 1H); MS (ESI+, m/z) 512 [(M + H)+, 95], 534 [(M +
Na)+, 100], and 550 [(M + K)+, 40].
N-Isobu tyr yl-3′-O-levu lin yl-2′-O-(2-m eth oxyeth yl)gu a -
n osin e (7g): 1H NMR (MeOH-d4, 75.5 MHz) δ 1.41 (d, 6H,
3J HH 6.8 Hz), 2.38 (s, 3H), 2.84 (m, 2H), 2.92 (m, 1H), 3.03 (m,