LETTER
Mannich-Type C-Nucleosidations
(100) [M – H]–.
8-[N-(tert-Butyloxycarbonyl)-(2¢S,3¢S)-2¢,3¢-dihydroxy-
(1¢R)-pyrrolidinyl]-7-carba-guanine (16b).
749
(e = 1.55·104), lmin = 233 nm (e = 3200), 216 (e = 2.05·104).
MALDI-MS: m/z (%) = 572.3(100) [M + Na]+, 472.2(48),
432.2(60), 372.2(10), 227.1 (88), 151.1 (46). HR-MALDI:
m/z calcd for C25H39N7O7Na: 572.2803; found: 572.2804.
Anal. Calcd for C25H39N7O7: C, 54.63; H, 7.15; N, 17.84.
Found: C, 54.58; H, 7.01; N, 17.87.
TLC: Rf = 0.14 (CH2Cl2–MeOH, 8.5:1.5). 1H NMR (600
MHz, DMSO-d6, 343 °K): d = 1.26 (s, 9 H, Me), 3.22 [dd,
J = 3.7, 11.0 Hz, 1 H, H-C(4¢)], 3.67 [dd, J = 5.4, 11.0 Hz, 1
H, H-C(4¢)], 3.93 [t, J = 5.1 Hz, 1 H, H-C(2¢)], 4.00 [dd,
J = 4.5 Hz, 1 H, 9.2, H-C(3¢)], 4.75 [d, J = 5.9 Hz, 1 H, H-
C(1¢)], 5.77 (br s, 2 H, NH2), 5.93 [s, 1 H, H-C(7)]. 13C NMR
(150.9 MHz, DMSO-d6, measured at 343 K): d = 28.92 (q,
Me), 52.39 [t, C(4¢)], 58.93 [d, C(1¢)], 73.91 [d, C(3¢)], 77.82
[d, C(2¢)], 79.06 (s, CMe3), 100.22 [d, C(7)], 100.86, 129.44,
151.78, 152.94, 155.03, 159.76. ESI-MS (pos., MeOH): m/z
(%) = 374 (100) [M + Na]+), 352 (30) [M + H])+. ESI-MS
(neg., MeOH): 386 (20) [M + Cl]–, 350(100) [M – H]–).
8-[N-(tert-Butyloxycarbonyl)-(2¢S,3¢S)-2¢,3¢-dihydroxy-
(1¢S)-pyrrolidinyl]-7-carba-xanthine (18a).
Preparation of Free C-Azanucleosides (Scheme 3).
Representative Procedure for Step a: 2,4-Diamino-5-[N-
(tert-butyloxycarbonyl)-(2¢S,3¢S)-2¢,3¢-dihydroxy-(1¢S)-
pyrrolidinyl]-6-oxopyrimidine (12a).
The amount of 333 mg (0.62 mmol) of 4a was dissolved in
50 mL of sat. NH3 in MeOH and stirred at r.t. for 24 h. TLC
(CH2Cl2–MeOH, 8:1) showed the consumption of starting
material 4a (Rf = 0.50) and the formation of a new UV active
spot (Rf = 0.05). Evaporation of the solvent afforded a yellow
oil residue that was purified by CC (silica gel, CH2Cl2–
MeOH, 8:1). Fractions 29–41 (5 mL each) were combined
and evaporated under reduced pressure at 30 °C to give 198
mg (98%) of 12a as white solid. TLC: Rf = 0.21 (CH2Cl2–
MeOH, 4:1). 1H NMR (300 MHz, DMSO-d6, 100 °C): d =
1.30 (s, 9 H, 3 Me), 3.29 [dd, J = 11.2, 3.8 Hz, 1 H, H-C(4¢)],
3.59 [dd, J = 10.8, 6.9 Hz, 1 H, H-C(4¢)], 3.76, 3.93 [br s, 2
H, H-C(2¢), H-C(3¢)], 4.32 (d, J = 2.8 Hz, 1 H, H-1¢), 4.81
(br s, 1 H, OH, exchanges with D2O), 5.67 (br s, 2 H, NH2,
exchanges with D2O), 5.91 (br s, 2 H, NH2, exchanges with
D2O), 6.19 (br d, J = 7.5 Hz, 1 H, OH, exchanges with D2O),
9.75 (br s, 1 H, OH). 13C NMR (75 MHz, DMSO-d6,
100 °C): d = 28.08 (q), 52.96 (br t), 61.07 (d), 73.62 (d),
77.45 (s), 82.06 (br d), 87.41 (s), 153.08 (s), 153.37 (s),
162.61 (s), 162.53 (s). ESI-MS: m/z (%) = 676.9 (32) [2 M +
Na]+, 366.0(20) [M + K]+), 350.0(100) [M + Na]+. UV
(c = 5·10–5 M in MeOH): lmax = 274 nm (e = 1.16·104), 213
(e = 2.24·104), lmin = 251 nm (e = 3500).
TLC: Rf = 0.47 (CH2Cl2–MeOH, 4:1). 1H NMR (600 MHz,
DMSO-d6, 70 °C): d = 1.33 (s, 9 H, Me), 3.35 [d, J = 11.5
Hz, 1 H, H-C(4¢)], 3.62 [dd, J = 4.8, 11.5 Hz, 1 H, H-C(4¢)],
3.99 (s, 1 H), 4.03 (m, 1 H), 4.50 (s, 1 H), 5.29 (br s, 1 H,
OH), 6.10 [s, 1 H, H-C(7)], 10.07 (br s, 1 H, NH). 13C NMR
(150.9 MHz, DMSO-d6, 70 °C): d = 28.94 (q, Me), 53.83 [t,
C(4¢)], 63.50 [d, C(1¢)], 79.64 [d, (C3¢)], 98.81 [s, C(5)],
102.34 [d, C(7)], 130.42 [s, C(8)], 139.76 [s, C(4)], 151.47
[s, C(2)], 160.56 [s, H(C6)]. ESI-MS (positive, MeOH): m/z
(%) = 727 (10) [2 M + Na]+), 705(2) [2 M + H]+), 398 (100)
[M + 2 Na]+, 375 (40) [M + Na]+, 353 (40) [M + H]+). ESI-
MS (neg., MeOH): m/z (%) = 387 (5) [M + Cl]–, 351 (100)
[M – H]–.
8-[N-(tert-Butyloxycarbonyl)-(2¢S,3¢)-2¢,3¢-dihydroxy-
(1¢R)-pyrrolidinyl]-7-carba-xanthine (18b).
TLC: Rf = 0.39 (CH2Cl2–MeOH, 4:1). 1H NMR (600 MHz,
DMSO-d6, 70 °C): 1.27 (s, 9 H, Me), 3.26 [dd, J = 11.2 Hz,
1 H, 2.98, H-C(4¢)], 3.61 [dd, J = 5.1, 11.2 Hz, 1 H, H-
C(4¢)], 3.94 (m, 1 H), 3.97 (s, 1 H), 4.75 (d, J = 5.4 Hz, 1 H),
5.02 (br s, 1 H, OH), 6.00 [s, 1 H, H-C(7)], 10.06 (br s, 1 H,
NH), 10.35 (br s, OH, 0.5 H). ESI-MS (positive, MeOH):
m/z (%) = 375 (10) [M + Na]+), 353 (5) [M + H]+). ESI-MS
(neg., MeOH): m/z (%) = 387(50) [M + Cl]–, 351 (100) [M –
H]–.
4-Amino-5-[N-(tert-butyloxycarbonyl)-(2¢S,3¢S)-2¢,3¢-
dihydroxy-(1¢S)-pyrrolidinyl]-2,6-dioxopyrimidine
(14a).
TLC: Rf = 0.42 (CH2Cl2–MeOH, 4:1]. 1H NMR (300 MHz,
DMSO-d6, 100 °C): d = 1.32 (s, 9 H, 3 Me), 3.29 [dd,
J = 10.8, 5.1 Hz, 1 H, H-C(4¢)], 3.57 [dd, J = 10.8, 6.3 Hz, 1
H, H-C(4¢)], 3.80 (br s, 1 H, H-C(3¢)], 4.01 [br s, 1 H, H-
C(2¢)], 4.32 [d, J = 3.9 Hz, 1 H,), 4.83 [br s, 1 H, HO-C(2¢)],
5.46 [br s, 2 H, HO-C(3¢)], 5.89 (br s, 2 H, NH2, exchanges
with D2O), 9.85 (br s, 2 H, 2 NH). 13C NMR (75 MHz,
DMSO-d6): d = 28.11 (q), 51.66 [br t, C-(4¢)], 58.91 [d, C-
(1¢)], 73.55 [d, C-(3¢)], 77.74 (s, Me3C), 80.11 [br d, C-(2¢)],
84.97 [s, C-(5)], 150.05 (s), 152.48 (s), 153.53 (s), 163.42
(s). ESI-MS: m/z (%) = 679.0(8) [2 M + Na]+), 366.9(12) [M
+ K]+, 351.0(100) [M + Na]+). HR-MALDI: m/z calcd for
C13H20N4O6Na [M + Na+]: 351.1275; found: 351.1272. UV
(c = 5·10–5 M in MeOH): lmax = 269 nm (e = 1.62·104), 222
(e = 5300), lmin = 242 (e = 3200), 215 (e = 5220).
Representative Procedure for Step b: 2,4-Diamino-5-
[(2¢S,3¢S)-2¢,3¢-dihydroxy-(1¢S)-pyrrolidinyl]-6-oxo-
pyrimidine Hydrochloride (13a).
The amount of 151 mg (0.46 mmol) of 12a was suspended
in 50 mL of sat. HCl in Et2O and stirred at r.t. for 2 h. The
off white solid in the reaction mixture was filtered, washed
with 20 mL Et2O and dried to give 113 mg (83%, calcd
according to 2HCl salt) of 13a as white solid. 1H NMR (300
MHz, CD3OD): d = 3.35 [dd, J = 4.5, 12.2 Hz, 1 H, H-C(4¢)],
3.53 [dd, J = 5.6, 12.2 Hz, 1 H, H-C(4¢)], 4.25 [ddd,
Jcis-H-4¢-H-3¢ = 5.6 Hz, Jtrans-H-4¢-H-3¢ = JH-2¢-H-3¢ = 4.2 Hz, 1 H, H-
C(3¢)], 4.44 [dd, J = 3.5, 7.5 Hz, 1 H, H-C(2¢)], 4.55 [d,
J = 7.5 Hz, 1 H, H-C(1¢)]. 13C NMR (75 MHz, DMSO-d6):
d = 48.30 (t), 57.95 (d), 74.01(d), 76.49 (d), 80.38 (s), 151.88
(s), 155.47 (s), 160.75 (s). ESI-MS: m/z (%) = 228.0(100)
[M + H]+). HR-MALDI: m/z calcd for C8H14N5O3 [M + H]+:
228.1091; found: 228.1089.
8-[N-(tert-Butyloxycarbonyl)-(2¢S,3¢S)-2¢,3¢-dihydroxy-
(1¢S)-pyrrolidinyl]-7-carba-guanine (16a).
1H NMR (600 MHz, DMSO-d6, 70 °C): d = 1.31 (s, 9 H, 3
Me), 3.35 [dd, J = 3.2, 11.4 Hz, 1 H, H-C(4¢)], 3.66 [dd,
J = 5.5, 11.4 Hz, 1 H, H-C(4¢)], 3.99 [br s, 1 H, H-C(2¢),
exchanges with D2O), 4.00 (br s, 1 H, H-C(3¢), exchanges
with D2O), 4.47 [br s, 1 H, H-C(1¢)], 5.22 [d, J = 3.3 Hz, 1
H, HO-C(2¢)], 5.39 [br s, 1 H, OH-C(3¢)], 5.85 (br s, 2 H,
NH2), 6.05 [d, J = 1.8 Hz, 1 H, H-C(7)], 10.02 (br s, 1 H,
NH), 10.22 (br s, 1 H, NH). 13C NMR (150.9 MHz, DMSO-
d6, 70 °C): d = 28.96 (q, Me), 53.47 [d, C(4¢)], 63.50 [d,
C(1¢)], 75.13 [d, C(3¢)], 79.37 (s, CMe3), 81.58 [d, C(2¢)],
100.71 [s, C(7)], 118.14, 13.05, 151.77 [s, C(4)], 153.07 [s,
C(2)], 154.94 (s, C=O), 159.49 [s, C(6)]. ESI-MS (pos.,
MeOH): m/z (%) = 374 (10) [M + Na]+, 352 (40) [M + H]+.
ESI-MS (neg., MeOH): m/z (%) = 386 (30) [M + Cl]–), 350
4-Amino-5-[(2¢S,3¢S)-2¢,3¢-dihydroxy-(1¢S)-pyrrolidinyl]-
2,6-dioxopyrimidine Hydrochloride (15a).
1H NMR (300 MHz, DMSO-d6): d = 3.08 [d, J = 5.1 Hz, 1
H, H-C(4¢)], 3.24 [dd, J = 6.3, 11.7 Hz, 1 H, H-C(4¢)], 3.98
[d, J = 4.8 Hz, 1 H, H-C(1¢)], 4.28 (m, 2 H, H-2¢ and H-3¢),
5.69 (br s, 2 H, NH2), 7.01 (br s, 2 H, NH2), 8.45 (br s, 1 H,
OH), 9.56 (br s, 1 H, OH), 10.71, 10.72 (s, 2 H, NH). 13
C
NMR (75 MHz, DMSO-d6): d = 48.16 (t), 58.16 (d), 73.99
(d), 76.48 (d), 77.44 (s), 149.34 (s), 154.42 (s), 164.00 (s).
Synlett 2005, No. 5, 744–750 © Thieme Stuttgart · New York