Journal of Medicinal Chemistry
Article
mmol), furan-2-boronic acid (124 mg, 1.11 mmol), Na2CO3 (235 mg,
2.22 mmol), Pd(OAc)2 (8 mg, 36 μmol), and TPPTS (53 mg, 0.093
mmol) in water/MeCN (2:1, 4 mL) was stirred at 100 °C for 1 h.
After cooling, the mixture was neutralized using aq HCl (1 M) and
concentrated to dryness. The residue was coevaporated with silica and
purified by column chromatography (SiO2, 1→3% MeOH in CHCl3)
to afford product 4a (220 mg, 86%) as a white solid, which was
2′); 6.26 (d, 1H, J1′,2′ = 6.1 Hz, H-1′); 6.62 (dd, 1H, J4,3 = 3.3 Hz, J4,5 =
1.9 Hz, H-4-furyl); 6.66 (dd, 1H, J3,4 = 3.3 Hz, J3,5 = 0.9 Hz, H-3-
furyl); 7.80 (dd, 1H, J5,4 = 1.9 Hz, J5,3 = 0.9 Hz, H-5-furyl); 8.07 (s,
1H, H-6); 8.71 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6):
23.03 (CH3); 61.63 (CH2-5′); 70.71 (CH-3′); 74.31 (CH-2′); 85.50
(CH-4′); 86.79 (CH-1′); 106.79 (C-5); 108.50 (CH-3-furyl); 111.75
(CH-4-furyl); 115.36 (C-4a); 125.82 (CH-6); 142.93 (CH-5-furyl);
147.62 (C-2-furyl); 150.82 (C-7a); 151.38 (CH-2); 159.71 (C-4). IR
(ATR): ν 1571, 1438, 1348, 1201, 1120, 1080, 1031, 968, 892, 792,
736, 637 cm−1. MS (ESI) m/z 332 (M + H), 354 (M + Na). HRMS
(ESI) for C16H18N3O5 [M + H] calcd: 332.12410; found: 332.12406.
Anal. (C16H17N3O5·3/4H2O): C, H, N.
crystallized from water/MeOH. Mp 114−117 °C. [α]20 −70.6 (c
D
0.299, DMSO). 1H NMR (500 MHz, DMSO-d6): 3.04 (d, 3H, JCH3,NH
= 4.8 Hz, CH3); 3.54 (dm, 1H, Jgem = 12.0 Hz, H-5′a); 3.64 (dm, 1H,
Jgem = 11.9 Hz, H-5′b); 3.91 (q, 1H, J4′,5′a = J4′,5′b = J4′,3′ = 3.6 Hz, H-
4′); 4.10 (td, 1H, J3′,2′ = J3′,OH = 4.9 Hz, J3′,4′ = 3.3 Hz, H-3′); 4.41 (td,
1H, J2′1′ = J2′,OH = 6.3 Hz, J2′,3′ = 5.2 Hz, H-2′); 5.18 (d, 1H, JOH,3′
=
5-Ethynyl-4-methoxy-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-
pyrimidine (2g). An argon-purged mixture of 13 (407 mg, 1 mmol),
PdCl2(PPh3)2 (35 mg, 0.05 mmol), CuI (19 mg, 0.1 mmol),
trimethylsilylacetylene (1.4 mL, 10 mmol), and triethylamine (0.5
mL) was stirred in DMF (2 mL) at rt for 16 h. The volatiles were
removed in vacuo, and the residue was coevaporated several times with
EtOH/toluene and loaded on silica by coevaporation. Column
chromatography (SiO2, 0→1.5% MeOH in CHCl3) afforded
trimethylsilylethynyl derivative contaminated by triethylammonium
iodide. This material was directly deprotected by treatment with
K2CO3 (207 mg, 1.5 mmol) in MeOH (5 mL) at rt for 5 h, followed
by coevaporation with silica and final column chromatography (SiO2,
2.5% MeOH in CHCl3) afforded 2g (268 mg, 88% in two steps),
which was crystallized from MeOH. Mp 205−207 °C. [α]D −78.4 (c
0.333, DMSO). 1H NMR (500 MHz, DMSO-d6): 3.56 (ddd, 1H, Jgem
= 11.9 Hz, J5′a,OH = 5.7 Hz, J5′a,4′ = 3.7 Hz, H-5′a); 3.65 (ddd, 1H, Jgem
= 11.9 Hz, J5′b,OH = 5.3 Hz, J5′b,4′ = 3.9 Hz, H-5′b); 3.92 (td, 1H, J4′,5′a
= J4′,5′b = 3.8 Hz, J4′,3′ = 3.5 Hz, H-4′); 4.06 (s, 3H, CH3O); 4.10 (td,
1H, J3′,2′ = J3′,OH = 5.0 Hz, J3′,4′ = 3.4 Hz, H-3′); 4.11 (d, 1H, JCH,6 = 0.4
Hz, C≡CH); 4.38 (td, 1H, J2′,1′ = J2′,OH = 6.2 Hz, J2′,3′ = 5.0 Hz, H-2′);
5.12 (t, 1H, JOH,5′a = JOH,5′b = 5.5 Hz, OH-5′); 5.18 (d, 1H, JOH,3′ = 4.9
4.8 Hz, OH-3′); 5.25 (m, 1H, OH-5′); 5.37 (d, 1H, JOH,2′ = 6.4 Hz,
OH-2′); 6.09 (d, 1H, J1′,2′ = 6.2 Hz, H-1′); 6.61 (dd, 1H, J4,3 = 3.3 Hz,
J4,5 = 1.9 Hz, H-4-furyl); 6.66 (dd, 1H, J3,4 = 3.3 Hz, J3,5 = 0.8 Hz, H-3-
furyl); 6.85 (q, 1H, JNH,CH3 = 4.8 Hz, NH); 7.76 (dd, 1H, J5,4 = 1.9 Hz,
J5,3 = 0.8 Hz, H-5-furyl); 7.82 (s, 1H, H-6); 8.22 (s, 1H, H-2). 13C
NMR (125.7 MHz, DMSO-d6): 28.24 (CH3NH); 61.92 (CH2-5′);
70.81 (CH-3′); 74.12 (CH-2′); 85.45 (CH-4′); 87.31 (CH-1′); 100.03
(C-4a); 105.59 (CH-3-furyl); 106.35 (C-5); 112.20 (CH-4-furyl);
120.52 (CH-6); 142.39 (CH-5-furyl); 148.79 (C-2-furyl); 150.34 (C-
7a); 152.27 (CH-2); 156.84 (C-4). IR (ATR): ν 3649, 2934, 1624,
1319, 1021, 585, 564 cm−1. MS (ESI) m/z 347 (M + H), 369 (M +
Na). HRMS (ESI) for C16H19N4O5 [M + H] calcd: 347.13554; found:
347.13496.
4-Dimethylamino-5-(furan-2-yl)-7-(β-D-ribofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (5a). An argon-purged mixture of iodide 16
(420 mg, 1 mmol), furan-2-boronic acid (168 mg, 1.5 mmol), Na2CO3
(318 mg, 3 mmol), Pd(OAc)2 (11 mg, 49 μmol), and TPPTS (71 mg,
0.125 mmol) in water/MeCN (2:1, 5 mL) was stirred at 100 °C for 3
h. After cooling, the mixture was neutralized using aq HCl (1 M),
concentrated to dryness in vacuo and the residue was purified by
reverse phase HPFC (C-18, 0→100% MeOH in water). Repurification
by column chromatography (SiO2, 2.5% MeOH in chloroform)
furnished 5a (176 mg, 49%) as a beige foam. Reverse phase HPFC
also provided product of reduction 5h (73 mg, 25%). Mp 97−103 °C.
[α]D −42.8 (c 0.358, DMSO). 1H NMR (500 MHz, DMSO-d6): 2.84
(s, 6H, (CH3)2N); 3.54 (ddd, 1H, Jgem = 11.9 Hz, J5′a,OH = 6.0 Hz, J5′a,4′
= 3.8 Hz, H-5′a); 3.62 (ddd, 1H, Jgem = 11.9 Hz, J5′b,OH = 5.1 Hz, J5′b,4′
= 3.8 Hz, H-5′b); 3.90 (btd, 1H, J4′,5′a = J4′,5′b = 3.8 Hz, J4′,3′ = 3.2 Hz,
Hz, OH-3′); 5.41 (d, 1H, JOH,2′ = 6.3 Hz, OH-2′); 6.14 (d, 1H, J1′,2′
=
6.0 Hz, H-1′); 8.05 (s, 1H, H-6); 8.47 (s, 1H, H-2). 13C NMR (125.7
MHz, DMSO-d6): 54.04 (CH3O); 61.55 (CH2-5′); 70.63 (CH-3′);
74.45 (CH-2′); 77.17 (CCH); 81.80 (CCH); 85.56 (CH-4′);
87.31 (CH-1′); 94.82 (C-5); 105.16 (C-4a); 130.01 (CH-6); 151.43
(C-7a); 151.93 (CH-2); 162.95 (C-4). IR (ATR): ν 1596, 1574, 1061,
1005, 653, 604, 535 cm−1. MS (ESI) m/z 306 (M + H), 328 (M +
Na). HRMS (ESI) for C14H15N3O5Na [M + Na] calcd: 328.0904;
found: 328.0892. Anal. (C14H15N3O5·1/4H2O): C, H, N.
H-4′); 4.10 (m, 1H, H-3′); 4.42 (td, 1H, J2′,1′ = J2′,OH = 6.4 Hz, J2′,3′
=
5.1 Hz, H-2′); 5.14 (d, 1H, JOH,3′ = 4.8 Hz, OH-3′); 5.15 (dd, 1H,
JOH,5′a = 5.9 Hz, JOH,5′b = 5.1 Hz, OH-5′); 5.35 (d, 1H, JOH,2′ = 6.5 Hz,
OH-2′); 6.17 (d, 1H, J1′,2′ = 6.4 Hz, H-1′); 6.51 (dd, 1H, J3,4 = 3.2 Hz,
J3,5 = 0.9 Hz, H-3-furyl); 6.58 (dd, 1H, J4,3 = 3.2 Hz, J4,5 = 1.9 Hz, H-4-
furyl); 7.75 (dd, 1H, J5,4 = 1.9 Hz, J5,3 = 0.9 Hz, H-5-furyl); 7.75 (s,
1H, H-6); 8.25 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6):
39.44 ((CH3)2N); 61.73 (CH2-5′); 70.74 (CH-3′); 74.10 (CH-2′);
85.35 (CH-4′); 86.98 (CH-1′); 102.05 (C-4a); 106.87 (C-5); 107.61
(CH-3-furyl); 111.74 (CH-4-furyl); 122.92 (CH-6); 142.56 (CH-5-
furyl); 149.33 (C-2-furyl); 150.71 (CH-2); 152.01 (C-7a); 159.64 (C-
4). IR (ATR): ν 1574, 1515, 1450, 1420, 1410, 1203, 1120, 1077, 1058
cm−1. MS (ESI) m/z 361 (M + H), 383 (M + Na). HRMS (ESI) for
C17H21N4O5 [M + H] calcd: 361.15065; found: 361.15057.
5-(Furan-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-
4(3H)-one (7a). To a stirred slurry of 2a (139 mg, 0.40 mmol) and
NaI (300 mg, 2 mmol) in dry MeCN (5 mL) was slowly added
TMSCl (253 μL, 2 mmol), and the mixture was stirred at rt for 4 h.
The precipitate was filtered off, washed carefully with MeCN, and
dissolved in water, and pH of the solution was quickly adjusted to 7
using solid K2CO3. The mixture was evaporated to dryness, and
crystallization from water gave 7a (50 mg, 38%) as a beige solid.
Reverse phase HPFC (C-18, 0→100% MeOH in water) of the mother
liquors provided additional 7a (31 mg, 23%). Total yield of 7a was
1
61%. Mp 184−186 °C. [α]D −83.8 (c 0.216, DMSO). H NMR (500
MHz, DMSO-d6): 3.56 (ddd, 1H, Jgem = 11.8 Hz, J5′a,OH = 5.4 Hz, J5′a,4′
= 3.7 Hz, H-5′a); 3.63 (ddd, 1H, Jgem = 11.9 Hz, J5′b,OH = 5.3 Hz, J5′b,4′
= 3.7 Hz, H-5′b); 3.90 (q, 1H, J4′,5′a = J4′,5′b = J4′,3′ = 3.5 Hz, H-4′);
4.09 (td, 1H, J3′,2′ = J3′,OH = 4.9 Hz, J3′,4′ = 3.3 Hz, H-3′); 4.35 (td, 1H,
5-(Furan-2-yl)-4-methyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-
pyrimidine (6a). An argon-purged mixture of 19 (258 mg, 0.75
mmol), furan-2-boronic acid (126 mg, 1.125 mmol), Na2CO3 (239
mg, 2.25 mmol), Pd(OAc)2 (8 mg, 35.6 μmol), and TPPTS (53 mg,
93 μmol) in water/MeCN (2:1, 5 mL) was stirred at 100 °C for 1 h.
After cooling, the mixture was neutralized using aq HCl (1 M),
concentrated to dryness in vacuo and the residue was purified by
reverse phase HPFC (C-18, 0→100% MeOH in water) to furnish 6a
J
2′,1′ = J2′,OH = 6.3 Hz, J2′,3′ = 5.1 Hz, H-2′); 5.08 (t, 1H, JOH,5′a = JOH,5′b
= 5.3 Hz, OH-5′); 5.15 (d, 1H, JOH,3′ = 4.8 Hz, OH-3′); 5.36 (d, 1H,
JOH,2′ = 6.4 Hz, OH-2′); 6.08 (d, 1H, J1′,2′ = 6.2 Hz, H-1′); 6.51 (dd,
1H, J4,3 = 3.3 Hz, J4,5 = 1.8 Hz, H-4-furyl); 7.37 (dd, 1H, J3,4 = 3.3 Hz,
J3,5 = 0.9 Hz, H-3-furyl); 7.60 (dd, 1H, J5,4 = 1.9 Hz, J5,3 = 0.9 Hz, H-5-
furyl); 7.68 (s, 1H, H-6); 7.96 (d, 1H, J2,NH = 3.8 Hz, H-2); 12.10 (d,
1H, JNH,2 = 3.7 Hz, NH). 13C NMR (125.7 MHz, DMSO-d6): 61.61
(CH2-5′); 70.75 (CH-3′); 74.60 (CH-2′); 85.41 (CH-4′); 86.93 (CH-
1′); 104.08 (C-4a); 108.41 (CH-3-furyl); 111.14 (C-5); 111.75 (CH-
4-furyl); 116.71 (CH-6); 141.42 (CH-5-furyl); 144.94 (CH-2); 148.68
(C-2-furyl); 148.82 (C-7a); 158.39 (C-4). IR (ATR): ν 1696, 1599,
1045, 788, 723 cm−1. MS (ESI) m/z 334 (M + H), 356 (M + Na).
1
(207 mg, 83%) as an orange foam. [α]D −75.3 (c 0.219, DMSO). H
NMR (500 MHz, DMSO-d6): 2.65 (s, 3H, CH3); 3.57 (bdt, 1H, Jgem
=
11.9 Hz, J5′a,OH = J5′a,4′ = 4.5 Hz, H-5′a); 3.66 (bdt, 1H, Jgem = 11.9 Hz,
J5′b,OH = J5′b,4′ = 4.4 Hz, H-5′b); 3.94 (bq, 1H, J4′,5′a = J4′,5′b = J4′,3′ = 3.6
Hz, H-4′); 4.13 (m, 1H, H-3′); 4.45 (btd, 1H, J2′,1′ = J2′,OH = 6.2 Hz,
J2′,3′ = 5.3 Hz, H-2′); 5.10 (bt, 1H, JOH,5′a = JOH,5′b = 5.4 Hz, OH-5′);
5.20 (d, 1H, JOH,3′ = 4.8 Hz, OH-3′); 5.41 (d, 1H, JOH,2′ = 6.4 Hz, OH-
J
dx.doi.org/10.1021/jm4018948 | J. Med. Chem. XXXX, XXX, XXX−XXX