O6-(Alkyl/ Aralkyl)guanosine and 2′-Deoxyguanosine Derivatives J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2907
8.36 (s, 1H, 8-H), 10.43 (s, 1H, NH, exchanges with D2O); IR
(KBr) ν 1740 (CdO ester), 1590 (CdO amide), 1230 cm-1
(dCO).
(OH), 1670 (CdO amide), 1230 cm-1 (dCO); MS m/ z 541 (M),
452 (B + 44), 409 (B + H), 367 (B + 2H - COCH3), 241 (B +
3H - COCH3 - I), 217 (CH2C6H4I), B ) N2-acetyl-O6-(4-
iodobenzyl)guanine - H. Anal. (C19H20N5O6I‚0.5H2O) C, H,
N.
N2,3′,5′-Tr ia cet yl-O6-m et h yl-2′-d eoxygu a n osin e (9a ):
1
yield 31%; Rf 0.23 (A); mp 46-48 °C; H-NMR (DMSO-d6) δ
N2-Acet yl-O6-(4-iod ob en zyl)-2′-d eoxygu a n osin e (4b ):
2.01, 2.10 (2s, 6H, OCOCH3), 2.26 (s, 3H, NCOCH3), 2.47-
2.58, 3.21-3.35 (2m, 2H, 2′-H), 4.09 (s, 3H, OCH3), 4.24-4.38
(m, 3H, 4′-H, 5′-H), 5.45-5.47 (m, 1H, 3′-H), 6.38 (t, J ) 7.3,
6.5 Hz, 1H, H1′), 8.38 (s, 1H, 8-H), 10.39 (s, 1H, NH, exchanges
with D2O); IR (KBr) ν 1740 (CdO ester), 1590 (CdO amide),
1230 cm-1 (dCO).
yield 53%; Rf 0.35 (B); mp 145-147 °C; [R]25 -9.4 (c ) 4.5,
D
1
DMSO); H-NMR (DMSO-d6) δ 2.23-2.34 (m, 4H, NCOCH3,
2′-H), 2.65-2.69 (m, 1H, 2′-H), 3.52-3.61 (m, 2H, 5′-H), 3.85-
3.87 (m, 1H, 4′-H), 4.43-4.45 (m, 1H, 3′-H), 4.89 (t, J ) 5.4
Hz, 1H, 5′-OH, exchanges with D2O), 5.29 (d, J ) 3.9 Hz 1H,
3′-OH, exchanges with D2O), 5.56 (s, 2H, CH2C6H5), 6.33 (t, J
) 6.5, 6.8 Hz, 1H, 1′-H), 7.34-7.76 (m, 5H, C6H5), 8.42 (s, 1H,8-
H), 10.42 (s, 1H, NH, exchanges with D2O); IR (KBr) ν 3500-
3200 (OH), 1660 (CdO amide), 1230 cm-1 (dCO); MS m/ z 525
(M), 452 (B + 44), 409 (B + H), 367 (B + 2H - COCH3), 241
(B + 3H - COCH3 - I), 217 (CH2C6H4I), B ) N2-acetyl-O6-
(4-iodobenzyl)guanine - H. Anal. (C19H20N5O5I‚H2O) C, H,
N.
N2,2′,3′,5′-Tet r a cet yl-O6-(m et h yl-4-p yr id yl)gu a n osin e
(10a ): yield 25%; Rf 0.36 (B); mp 68-70 °C; 1H-NMR (DMSO-
d6) δ 2.00, 2.05, 2.12 (3s, 9H, OCOCH3), 2.19 (s, 3H, NCOCH3),
4.30-4.46 (m, 3H, 4′-H, 5′-H), 5.68 (s, 2H, CH2C5H4N), 5.74-
5.79 (m, 1H, 3′-H), 5.88-5.94 (m, 1H, 2′-H), 6.21 (d, J ) 4.9
Hz, 1H, 1′-H), 7.51, 8.60 (2d, 4H, C5H4N), 8.44 (s, 1H, 8-H),
10.53 (s, 1H, NH, exchanges with D2O); IR (KBr) ν 1735 (CdO
ester), 1670 (CdO amide), 1230 cm-1 (dCO).
N2,2′,3′,5′-Tet r a cet yl-O6-(d ip h en ylm et h yl)gu a n osin e
(11a ): yield 15%; Rf 0.35 (D); mp 74-76 °C; 1H-NMR (DMSO-
d6) δ 1.98, 2.02, 2.17 (3s, 9H, OCOCH3), 2.24 (s, 3H, NCOCH3),
4.27-4.44 (m, 3H, 4′-H, 5′-H), 5.74-5.76 (m, 1H, 3′-H), 5.88-
5.94 (m, 1H, 2′-H), 6.20 (d, J ) 4.9 Hz, 1H, 1′-H), 7.30-7.53
(m, 11H, CH(C6H5)2), 8.45 (s, 1H, 8-H), 10.47 (s, 1H, NH,
exchanges with D2O); IR (KBr) ν 1730 (CdO ester), 1670 (CdO
amide), 1230 cm-1 (dCO).
N2-Acetyl-O6-(4-br om oben zyl)gu an osin e (5b): yield 72%;
Rf 0.43 (B); mp 134-136 °C; [R]25 -15.8 (c ) 1.5, DMSO);
D
1H-NMR (DMSO-d6) δ 2.22 (s, 3H, NCOCH3), 3.54-3.69 (m,
2H, 5′-H), 3.90-3.93 (m, 1H, 4′-H), 4.17-4.19 (m, 1H, 3′-H),
4.52-4.60 (m, 1H, 2′-H), 4.98 (t, J ) 5.4 Hz, 1H, 5′-OH,
exchanges with D2O), 5.20 (d, J ) 4.7 Hz, 1H, 3′-OH,
exchanges with D2O), 5.49 (d, J ) 5.8 Hz, 1H, 2′-OH,
exchanges with D2O), 5.59 (s, 2H, CH2C6H4Br), 5.89 (d, J )
5.8 Hz, 1H, 1′-H), 7.50-7.62 (m, 4H, C6H4I), 8.46 (s, 1H, 8-H),
10.50 (s, 1H, NH, exchanges with D2O); IR (KBr) ν 3500-3200
(OH), 1670 (CdO amide), 1230 cm-1 (dCO); MS m/ z 495, 493
(M), 363, 361 (B + H), 321, 319 (B + 2H - COCH3), 241 (B +
3H - COCH3 - Br), 171, 169 (CH2C6H4Br), B ) N2-acetyl-O6-
(4-bromobenzyl)guanine - H. Anal. (C19H20N5O6Br‚H2O) C,
H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of N2-Acetyl-
O6-(Alk yl/Ar a lk yl)gu a n osin e a n d 2′-Deoxygu a n osin e 1b-
11b. A solution of the relevant compound 1a -11a (2 mmol)
in pyridine (9 mL) was treated with 2.5 M NaOH (3 mL, 7.5
mmol for guanosine derivatives and 2 mL, 5 mmol for
2′-deoxyguanosine derivatives) and stirred for 6 min. The
mixture was neutralized by adding acidic cation exchanger
(Dowex 50 × 8 resin, 8 mL) with vigorous stirring, filtered,
and washed with a minimum amount of pyridine. The solution
was evaporated under reduced pressure. The residue was
chromatographed on silica gel, eluting with dichloromethane
and dichloromethane/ethanol (98/2, 95/5, 90/10) to afford a
white foam.
N 2-Ac e t y l-O 6-(4-b r o m o b e n zy l)-2′-d e o x y g u a n o s in e
(6b): yield 45%; Rf 0.43 (B); mp 132-134 °C; [R]25 -8.3 (c )
D
1.3, DMSO); 1H-NMR (DMSO-d6) δ 2.24 (s, 3H, NCOCH3),
2.26-2.28 (m, 1H, 2′-H), 2.67-2.73 (m, 1H, 2′-H), 3.52-3.61
(m, 2H, 5′-H), 3.86-3.88 (m, 1H, 4′-H), 4.43-4.45 (m, 1H, 3′-
H), 4.92 (t, J ) 5.4 Hz, 1H, 5′-OH, exchanges with D2O), 5.31
(d, J ) 3.9 Hz 1H, 3′-OH, exchanges with D2O), 5.59 (s, 2H,
CH2C6H5), 6.35 (t, J ) 6.4, 6.9 Hz, 1H, 1′-H), 7.50-7.61 (m,
5H, C6H5), 8.44 (s, 1H, 8-H), 10.45 (s, 1H, NH, exchanges with
D2O); IR (KBr) ν 3500-3200 (OH), 1660 (CdO amide), 1230
cm-1 (dCO); MS m/ z 479, 477 (M), 363, 361 (B + H), 321, 319
(B + 2H - COCH3), 241 (B + 3H - COCH3 - Br), 171, 169
(CH2C6H4Br), B ) N2-acetyl-O6-(4-bromobenzyl)guanine - H.
Anal. (C19H20N5O5Br‚0.5H2O) C, H, N.
N2-Acetyl-O6-ben zylgu a n osin e (1b): yield 68%; Rf 0.28
(B); mp 146-148 °C; [R]25 -16.7 (c ) 2.3, DMSO); water
D
solubility 2 mM; 1H-NMR (DMSO-d6) δ 2.22 (s, 3H, NCOCH3),
3.56-3.62 (m, 2H, 5′-H), 3.89-3.94 (m, 1H, 4′-H), 4.12-4.20
(m, 1H, 3′-H), 4.52-4.61 (m, 1H, 2′-H), 4.99 (t, J ) 5.4 Hz,
1H, 5′-OH, exchanges with D2O), 5.19 (d, J ) 4.8 Hz, 1H, 3′-
OH, exchanges with D2O), 5.48 (d, 1H, 2′-OH, exchanges with
D2O), 5.61 (s, 2H, CH2C6H5), 5.89 (d, J ) 5.8 Hz, 1H, 1′-H),
7.30-7.60 (m, 5H, C6H5), 8.45 (s, 1H, 8-H), 10.49 (s, 1H, NH,
exchanges with D2O); IR (KBr) ν 3500-3200 (OH), 1670 (CdO
amide), 1230 cm-1 (dCO); MS m/ z 415 (M), 326 (B + 44), 283
(B + H), 241 (B + 2H - COCH3), 91 (CH2C6H5), B ) N2-acetyl-
O6-benzylguanine - H. Anal. (C19H21N5O6‚H2O) C, H, N.
N2-Acetyl-O6-ben zyl-2′-d eoxygu a n osin e (2b): yield 54%;
Rf 0.31 (B); mp 184-186 °C; [R]25D -8.4 (c ) 1.1, DMSO); water
solubility: 2 mM; 1H-NMR (DMSO-d6) δ 2.23 (s, 3H, NCOCH3),
2.28-2.32, 2.64-2.77 (2m, 2H, 2′-H), 3.51-3.63 (m, 2H, 5′-
H), 3.83-3.87 (m, 1H, 4′-H), 4.41-4.44 (m, 1H, 3′-H), 4.85 (t,
J ) 5.4 Hz, 1H, 5′-OH, exchanges with D2O), 5.26 (d, J ) 3.8
Hz, 1H, 3′-OH, exchanges with D2O), 5.60 (s, 2H, CH2C6H5),
6.33 (t, J ) 7.0, 6.5 Hz, 1H, 1′-H), 7.35-7.57 (m, 5H, C6H5),
8.43 (s, 1H, 8-H), 10.47 (s, 1H, NH, exchanges with D2O); IR
(KBr) ν 3500-3200 (OH), 1670 (CdO amide), 1230 cm-1
(dCO); MS m/ z 399 (M), 283 (B + H), 241 (B + 2H - COCH3),
91 (CH2C6H5), B ) N2-acetyl-O6-benzylguanine - H. Anal.
(C19H21N5O5‚0.5H2O) C, H, N.
N2-Acetyl-O6-(2-iod oben zyl)gu a n osin e (7b): yield 95%;
Rf 0.33 (B); mp 158-160 °C; [R]25 -14.1 (c ) 1.4, DMSO);
D
1H-NMR (DMSO-d6) δ 2.22 (s, 3H, NCOCH3), 3.50-3.70 (m,
2H, 5′-H), 3.89-3.95 (m, 1H, 4′-H), 4.13-4.19 (m, 1H, 3′-H),
4.56-4.62 (m, 1H, 2′-H), 4.96 (t, J ) 5.4 Hz, 1H, 5′-OH,
exchanges with D2O), 5.17 (d, J ) 4.6 Hz, 1H, 3′-OH,
exchanges with D2O), 5.48 (d, J ) 5.8 Hz, 1H, 2′-OH,
exchanges with D2O), 5.57 (s, 2H, CH2C6H4I), 5.88 (d, J ) 5.8
Hz, 1H, 1′-H), 7.14 (t, 1H, HmetaC6H4I), 7.44 (t, 1H, HparaC6H4I),
7.63 (d, 1H, HmetaC6H4I), 7.92 (d, 1H, HorthoC6H4I), 8.46 (s, 1H,
8-H), 10.51 (s, 1H, NH, exchanges with D2O); IR (KBr) ν 3500-
3200 (OH), 1670 (CdO amide), 1230 cm-1 (dCO); MS m/ z 541
(M), 409 (B + H), 367 (B + 2H - COCH3), 241 (B + 3H -
COCH3 - I), 217 (CH2C6H4I), B ) N2-acetyl-O6-(2-iodobenzyl)-
guanine - H. Anal. (C19H20N5O6I‚1.5H2O) C, H; N: calcd,
12.32; found, 11.66.
N2-Acetyl-O6-m eth ylgu a n osin e (8b): yield 87%; Rf 0.21
N2-Acetyl-O6-(4-iod oben zyl)gu a n osin e (3b): yield 90%;
(B); mp 122-124 °C; [R]25 -0.6 (c ) 1.4, DMSO); water
D
Rf 0.28 (B); mp 146-148 °C; [R]25 -16.6 (c ) 1.4, DMSO);
solubility 5 mM; 1H-NMR (DMSO-d6) δ 2.24 (s, 3H, NCOCH3),
3.51-3.65 (m, 2H, 5′-H), 3.91-3.96 (m, 1H, 4′-H), 4.08 (s, 3H,
OCH3), 4.15-4.21 (m, 1H, 3′-H), 4.55-4.61 (m, 1H, 2′-H), 4.95
(t, J ) 5.4 Hz, 1H, 5′-OH exchanges with D2O), 5.15 (d, J )
4.5 Hz, 1H, 3′-OH exchanges with D2O), 5.46 (d, J ) 5.9 Hz,
1H, 2′-OH exchanges with D2O), 5.90 (d, J ) 5.8 Hz, 1H, 1′-
H), 8.45 (s, 1H, 8-H), 10.45 (s, 1H, NH exchanges with D2O);
IR (KBr) ν 3500-3200 (OH), 1670 (CdO amide), 1230 cm-1
(dCO); MS m/ z 339 (M), 297 (M + H - COCH3), 250 (B +
D
1H-NMR (DMSO-d6) δ 2.24 (s, 3H, NCOCH3), 3.53-3.64 (m,
2H, 5′-H), 3.90-3.94 (m, 1H, 4′-H), 4.13-4.19 (m, 1H, 3′-H),
4.50-4.59 (m, 1H, 2′-H), 4.96 (t, J ) 5.4 Hz, 1H, 5′-OH,
exchanges with D2O), 5.17 (d, J ) 4.6 Hz, 1H, 3′-OH,
exchanges with D2O), 5.46 (d, J ) 5.8 Hz, 1H, 2′-OH,
exchanges with D2O), 5.56 (s, 2H, CH2C6H4I), 5.88 (d, J ) 5.8
Hz, 1H, 1′-H), 7.33-7.76 (dd, 4H, C6H4I), 8.44 (s, 1H, 8-H),
10.47 (s, 1H, NH, exchanges with D2O); IR (KBr) ν 3500-3200