Adenine Nucleotide Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 10 2097
(3 mL) was added NH3 (2 M solution in i-PrOH, 5 mL, 10
mmol), and the reaction mixture was heated at 90 °C in a
closed tube for 15 h for complete reaction. The resulting
mixture was concentrated under reduced pressure, and the
residue obtained was purified by flash chromatography using
9/1 CHCl3/MeOH to furnish 0.182 g of 23 (95%). 1H NMR
(CDCl3) δ 8.35 (s, 1H), 8.30 (s, 1H), 7.37 (s, 5H), 5.87 (bs, 2H),
5.31 (d, 1H, J ) 6.8 Hz), 5.13 (s, 1H), 4.64 (qAB, 2H, J ) 11.7,
20.5 Hz), 4.51 (d, 1H, J ) 6.8 Hz), 3.97 (d, 1H, J ) 10.7 Hz),
3.35 (d, 1H, J ) 10.7 Hz), 1.72-1.62 (m, 1H), 1.55 (s, 3H),
1.32-1.26 (m, 1H), 1.23 (s, 3H), 1.00-0.93 (m, 1H).
tives were synthesized by procedures similar to those used to
prepare the unsubstituted adenine analogue.39
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-ch lor o-9H -p u r in -9-
yl)-1-[(d i-ter t-bu tyl p h osp h a te)m eth yl]bicyclo[3.1.0]h ex-
a n e-2,3-(O-isop r op ylid en e) (31): 1H NMR (CDCl3) δ 8.23 (s,
1H), 6.91 (bs, 2H), 5.41 (d, 1H, J ) 7.1 Hz), 5.16 (s, 1H), 4.64
(d, 1H, J ) 7.1 Hz), 4.59 (dd, 1H, J ) 5.5, 11.0 Hz), 3.98 (dd,
1H, J ) 6.3, 11.0 Hz), 1.84-1.76 (m, 1H), 1.63 (s, 3H), 1.61 (s,
9H), 1.59 (s, 9H), 1.42-1.37 (m, 1H), 1.33 (s, 3H), 1.18-1.13
(m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-m eth ylth io-9H-p u r in -
9-yl)-1-[(d i-ter t-b u t yl p h osp h a t e)m et h yl]b icyclo[3.1.0]-
h exan e-2,3-(O-isopr opyliden e)(32)an d (1′S,2′R,3′S,4′R,5′S)-
4-(6-Am in o-2-m et h ylsu lfoxy-9H -p u r in -9-yl)-1-[(d i-ter t-
bu tyl p h osp h a te)m eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-iso-
p r op ylid en e) (33). To a mixture of 28 (20 mg, 0.055 mmol)
and tetrazole (0.012 g, 0.165 mmol) in anhydrous THF (2 mL)
was added di-tert-butyl-N,N-diethylphosphoramidite (0.023
mL, 0.083 mmol), and the mixture was stirred at room
temperature overnight. The reaction mixture was cooled to
-78 °C, and a solution of 70% mCPBA (0.012 g, 0.066 mmol)
in 1 mL of CH2Cl2 was warmed to room temperature. A total
of 1 mL MeOH was added, and the mixture was concentrated
and purified by preparative TLC using 10% MeOH in CHCl3
to furnish 32 (12 mg) and 33 (12 mg).
Compounds 24 and 25 were synthesized from 21, and 26
was synthesized from 22. All were produced in 90-95% yields.
(1′S,2′R,3′S,4′R,5′S)-4-(6-Met h yla m in o-9H-p u r in -9-yl)-
1-[(p h en ylm eth oxy)m eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-
1
isop r op ylid en e) (24): H NMR (CDCl3) δ 8.41 (s, 1H), 8.22
(s, 1H), 7.40-7.30 (m, 5H), 6.01 (bs, 1H), 5.30 (d, 1H, J ) 7.2
Hz), 5.12 (s, 1H), 4.62 (qAB 2H, J ) 12.1, 20.9 Hz), 4.51 (d,
1H, J ) 7.2 Hz), 3.94 (d, 1H, J ) 9.9 Hz), 3.35 (d, 1H, J ) 9.9
Hz), 3.21 (s, 3H), 1.70-1.62 (m, 1H), 1.55 (s, 3H), 1.29-1.25
(m, 1H), 1.22 (s, 3H), 0.98-0.92 (m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-ch lor o-9H -p u r in -9-
yl)-1-[(p h en ylm eth oxy)m eth yl]bicyclo[3.1.0]h exa n e-2,3-
(O-isop r op ylid en e) (25): 1H NMR (CDCl3) δ 8.22 (s, 1H),
7.40-7.33 (m, 5H), 6.48 (bs, 2H), 5.32 (d, 1H, J ) 7.15 Hz),
5.07 (s, 1H), 4.61 (qAB, 2H, J ) 12.1, 19.2 Hz), 4.51 (d, 1H, J
) 7.2 Hz), 3.94 (d, 1H, J ) 9.9 Hz), 3.42 (d, 1H, J ) 9.9 Hz),
1.64-1.56 (m, 1H), 1.55 (s, 3H), 1.30-1.26 (m, 1H), 1.24 (s,
3H), 0.98-0.933 (m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Meth yla m in o-2-ch lor o-9H-p u -
r in -9-yl)-1-[(ph en ylm eth oxy)m eth yl]bicyclo[3.1.0]h exan e-
2,3-(O-isop r op ylid en e) (26): 1H NMR (CDCl3) δ 8.15 (s, 1H),
7.40-7.28 (m, 5H), 6.29 (bs, 1H), 5.32 (d, 1H, J ) 7.1 Hz),
5.05 (s, 1H), 4.61 (qAB, 2H, J ) 12.4, 17.6 Hz), 3.90 (d, 1H, J
) 10.2 Hz), 3.42 (d, 1H, J ) 10.2 Hz), 3.17 (bs, 3H), 1.60-1.56
(m, 1H), 1.54 (s, 3H), 1.30-1.26 (m, 1H), 1.24 (s, 3H), 0.96-
0.92 (m, 1H).
1
32: H NMR (CDCl3) δ 7.98 (s, 1H), 5.87 (bs, 2H), 5.31 (d,
1H, J ) 7.2 Hz), 5.07 (s, 1H), 4.59 (d, 1H, J ) 7.2 Hz), 4.49
(dd, 1H, J ) 5.8, 11.0 Hz), 3.83 (dd, 1H, J ) 6.3, 11.0 Hz),
2.59 (s, 3H), 1.75-1.70 (m, 1H), 1.55 (s, 3H), 1.49 (s, 18H),
1.30-1.27 (m, 1H), 1.23 (s, 3H), 1.05-1.00 (m, 1H).
33: 1H NMR (CDCl3) δ 8.26 (s, 1H), 6.66 (bs, 2H), 5.33 (d,
J ) 7.14 Hz, 1H), 5.22 (s, 1H), 4.60-4.50 (m, 2H), 3.81-3.71
(m, 2H), 2.93 (s, 3H), 1.76-1.70 (m, 1H), 1.54 (s, 3H), 1.50 (s,
9H), 1.34-1.30 (m, 1H), 1.25 (s, 3H), 1.23 (s, 9H), 1.07-1.02
(m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Met h yla m in o-9H-p u r in -9-yl)-
1-[(d i-ter t-bu tyl p h osp h a te)m eth yl]bicyclo[3.1.0]h exa n e-
2,3-(O-isop r op ylid en e) (34): 1H NMR (CDCl3) δ 8.45 (s, 1H),
8.05 (s, 1H), 6.04 (bs, 1H), 5.30 (d, 1H, J ) 7.2 Hz), 5.08 (s,
1H), 4.57 (d, 1H, J ) 7.2 Hz), 4.47 (dd, 1H, J ) 5.8, 11.0 Hz),
3.90 (dd, 1H, J ) 6.3, 11.0 Hz), 3.20 (bs, 3H), 1.79-1.71 (m,
1H), 1.54 (s, 3H), 1.51 (s, 9H), 1.50 (s, 9H), 1.29-1.26 (m, 1H),
1.22 (s, 3H), 1.08-1.03 (m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Meth yla m in o-2-ch lor o-9H-p u -
r in -9-yl)-1-[(di-ter t-bu tyl ph osph ate)m eth yl]bicyclo[3.1.0]-
h exa n e-2,3-(O-isop r op ylid en e) (35): 1H NMR (CDCl3) δ 8.04
(s, 1H), 5.38 (d, 1H, J ) 7.1 Hz, 1H), 5.04 (s, 1H), 4.58 (d, 1H,
J ) 7.1 Hz), 4.42-4.52 (m, 1H), 3.90-4.08 (m, 1H), 3.20 (bs
3H), 1.79-1.71 (m, 1H), 1.54 (s, 3H), 1.51 (s, 9H), 1.50 (s, 9H),
1.29-1.26 (m, 1H), 1.22 (s, 3H), 1.08-1.03 (m, 1H).
Gen er a l P r oced u r e for Dep r otection of (N)-Meth a n o-
ca r ba a d en osin e 5′-Mon op h osp h a te Der iva tives (Syn th e-
sis of 13a , 10a , 11a , 36, a n d 37). Deprotection was carried
out by procedures similar to those used to prepare the
unsubstituted adenine analogue.39
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-m eth ylth io-9H-p u r in -
9-yl)-1-[p h osp h or yloxym eth yl]bicyclo[3.1.0]h exa n e-2,3-
d iol (10a ): 1H NMR (D2O) δ 8.53 (s, 1H), 4.91 (s, 1H), 4.48
(dd, 1H, J ) 4.7, 11.0 Hz), 4.05 (d, 1H, J ) 6.6 Hz), 3.69 (dd,
1H, J ) 4.7, 11.0 Hz), 2.63 (s, 3H), 1.92-1.84 (m, 1H), 1.58-
1.40 (m, 1H), 1.18-0.98 (m, 1H). 31P NMR (D2O) δ 0.613.
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-m et h ylt h iooxy-9H -
pu r in -9-yl)-1-[ph osph or yloxym eth yl]bicyclo[3.1.0]h exan e-
2,3-d iol (11a ): 1H NMR (D2O) δ 8.83 (s, 1H), 5.46 (d, J ) 6.04
Hz, 1H), 4.52 (dd, J ) 4.94, 10.71 Hz, 1H), 4.06 (d, J ) 6.04
Hz, 1H), 3.72 (dd, J ) 4.94, 10.71 Hz, 1H), 2.99 (s, 3H), 2.04-
1.92 (m, 1H), 1.26-1.22 (m, 1H), 1.04-0.98 (m, 1H). 31P NMR
(D2O) δ 0.623.
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-ch lor o-9H -p u r in -9-
yl)-1-[p h osp h or yloxym eth yl]bicyclo[3.1.0]h exa n e-2,3-d i-
ol (13a ): 1H NMR (D2O) δ 8.60 (s, 1H), 4.72 (s, 1H), 4.48-
4.40 (m, 1H), 3.99 (d, 1H, J ) 6.6 Hz), 3.62-3.76 (m, 1H),
1.94-1.82 (m, 1H), 1.60-1.52 (m, 1H), 1.08-0.95 (m, 1H).
P r oced u r e for Deben zyla tion of 24-26. See ref 39.
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-ch lor o-9H -p u r in -9-
yl)-1-[h yd r oxym eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-isop r o-
1
p ylid en e) (27): H NMR (CDCl3) δ 7.90 (s, 1H), 5.56 (d, 1H,
J ) 7.4 Hz), 4.79 (s, 1H), 4.66 (d, 1H, J ) 7.4 Hz), 4.26 (d, 1H,
J ) 11.5 Hz), 3.37 (d, 1H, J ) 11.5 Hz), 1.78-1.70 (m, 1H),
1.55 (s, 3H), 1.26 (s, 3H), 1.20-1.14 (m, 1H), 1.20-0.96 (m,
1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Met h yla m in o-9H-p u r in -9-yl)-
1-[h yd r oxym eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-isop r op yl-
id en e) (29): 1H NMR (CDCl3) δ 8.36 (s, 1H), 7.77 (s, 1H), 5.61
(d, 1H, J ) 7.4 Hz), 4.78 (s, 1H), 4.65 (d, 1H, J ) 7.4 Hz), 4.33
(d, 1H, J ) 11.5 Hz), 3.25 (d, 1H, J ) 11.5 Hz), 3.20 (bs, 3H),
1.79-1.74 (m, 1H), 1.55 (s, 3H), 1.25 (s, 3H), 1.17-1.13 (m,
1H), 1.01-0.96 (m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Meth yla m in o-2-ch lor o-9H-p u -
r in -9-yl)-1-[h yd r oxym eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-
isop r op ylid en e) (30): 1H NMR (CD3OD) δ 8.14 (s, 1H), 5.30
(d, 1H, J ) 7.1 Hz), 4.87 (s, 1H), 4.61 (d, 1H, J ) 7.1 Hz), 3.91
(d, 1H, J ) 11.5 Hz), 3.52 (d, 1H, J ) 11.5 Hz), 3.00 (bs, 3H),
1.64-1.60 (m, 1H), 1.44 (s, 3H), 1.18 (s, 3H), 1.08-1.04 (m,
1H), 0.92-0.87 (m, 1H).
(1′S,2′R,3′S,4′R,5′S)-4-(6-Am in o-2-m eth ylth io-9H-p u r in -
9-yl)-1-[h yd r oxym eth yl]bicyclo[3.1.0]h exa n e-2,3-(O-iso-
p r op ylid en e) (28). Compound 27 (30 mg, 0.086 mmol) was
dissolved in DMF (1.5 mL) and treated with sodium thio-
methoxide (90 mg, 1.3 mmol). The reaction mixture was heated
in a sealed tube at 90 °C for 1.5 h. The solvent was removed
under vacuum, and the product was purified by preparative
thin-layer chromatography (9/1 CHCl3/MeOH) to furnish 25
1
mg of 28 (80%). H NMR (CDCl3) δ 7.76 (s, 1H), 5.82 (bs, 2H),
5.56 (d, 1H, J ) 7.1 Hz), 4.78 (s, 1H), 4.71 (d, 1H, J ) 7.1 Hz),
4.25 (d, 1H, J ) 11.5 Hz), 3.35 (d, 1H, J ) 11.5 Hz), 2.59 (s,
3H), 1.71-1.66 (m, 1H), 1.55 (s, 3H), 1.26 (s, 3H), 1.18-1.14
(m, 1H), 0.99-0.93 (m, 1H).
P r otected (N)-Meth a n oca r ba a d en osin e 5′-Mon op h os-
p h a te Der iva tives (31-35). These monophosphate deriva-