Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
= 10.4 and 5.6 Hz, 1 H, 1Ј-H), 7.33 (d, 3J = 8.0 Hz, 1 H, 3-H), 7.99
13C NMR (150.9 MHz, D2O): δ = 42.44 (CH2-2Ј), 64.87 (CH2-5Ј),
75.53 (CH-3Ј), 78.33 (CH-1Ј), 89.43 (CH-4Ј), 111.22 (CH-5), 131.48
3
(dt, J = 8.0 Hz, J4,1Ј = J4,P = 0.8 Hz, 1 H, 4-H) ppm. 13C NMR
[125.7 MHz, D2O, ref. (dioxane) = 69.3 ppm]: δ = 38.60, 38.62
[(CH3)2-NP], 43.80 (CH2-2Ј), 64.78 (CH2-5Ј), 75.38 (CH-3Ј), 76.89
(CH-1Ј), 89.64 (CH-4Ј), 123.93 (CH-5), 127.58 (C-3), 142.07 (CH-
4), 149.60 (C-6), 156.15 (C-2) ppm. 31P NMR [202.3 MHz, D2O,
(C-3), 137.81 (C-6), 141.86 (CH-4), 165.89 (C-2) ppm.
1β-[2-Oxo(1H)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose (20): To a
solution of nucleoside 18 (112 mg, 0.46 mmol) in THF/EtOH/H2O
(10:10:1, 10 mL) at room temperature were added 10 % Pd/C
(66 mg, 0.0893 mmol) and NEt3 (0.26 mL). The flask was filled
with H2 (1 atm) and stirred at room temperature. After the reaction
was complete (1.5 h, checked by TLC), Pd was filtered off. After
evaporation of the filtrate, 20 (95 mg, 99%) was obtained as a yel-
ref. (H PO ) = 0 ppm]: δ = 19.60 ppm. IR (CHCl ): ν = 3611, 3371,
˜
3
4
3
2817, 1588, 1573, 1483, 1436, 1309, 1255, 1230, 1205, 1180, 1078,
1053, 1003, 948, 684, 538 cm–1.
1β-(6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]-D-ribofuranose (19):
lowish oil. Rf (dichloromethane/methanol = 90:10) = 0.33. [α]2D0
=
To a dried flask containing a solution of 17 (230 mg, 0.605 mmol)
in dry DMF (28 mL) under an atmosphere of argon was added
imidazole (497 mg, 7.31 mmol) and then TBDMSCl (692 mg,
4.58 mmol). The resulting solution was stirred for 36 h at room
temperature under an atmosphere of argon. The DMF was then
evaporated under vacuum and co-evaporated with toluene. The re-
sulting dark raw oil was then directly chromatographed on silica
gel (hexane/EtOAc = 4:1 to EtOAc). This allowed us to obtain pure
nucleoside 19 (294 mg, 80%) as a yellowish oil. Rf (hexane/ethyl
acetate = 70:30) = 0.37. [α]2D0 = +23.5 (c = 0.034, CHCl3). HRMS
(ESI+): calcd. for C26H52ClN3O5PSi2 [M + H] 608.2866; found
608.2866. HRMS (ESI+): calcd for C26H51ClN3O5NaPSi2 [M +
+19.5 (c = 0.041, H2O). HRMS (ESI+): calcd. for C10H13NO4Na
[M + Na] 234.0737; found 234.0737. H NMR (600.1 MHz, D2O):
δ = 2.05 (ddd, Jgem = 13.7 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 6.0 Hz, 1
1
H, 2Ј-Hb), 2.34 (ddd, Jgem = 13.7 Hz, J2Јa,1Ј = 5.9 Hz, J2Јa,3Ј
=
2.1 Hz, 1 H, 2Ј-Ha), 3.69 (dd, Jgem = 12.1 Hz, J5Јb,4Ј = 5.3 Hz, 1 H,
5Ј-Hb), 3.75 (dd, Jgem = 12.1 Hz, J5Јa,4Ј = 4.1 Hz, 1 H, 5Ј-Ha), 4.05
(ddd, J4Ј,5Ј = 5.3, 4.1 Hz, J4Ј,3Ј = 2.1 Hz, 1 H, 4Ј-H), 4.40 (dt, J3Ј,2Ј
= 6.0, 2.1 Hz, J3Ј,4Ј = 2.1 Hz, 1 H, 3Ј-H), 5.23 (dd, J1Ј,2Ј = 10.2,
5.9 Hz, 1 H, 1Ј-H), 6.59 (dd, J5,4 = 7.1 Hz, J5,6 = 6.5 Hz, 1 H, 5-
H), 7.50 (dd, J6,5 = 6.5 Hz, J6,4 = 2.0 Hz, 1 H, 6-H), 7.84 (dd, J4,5
= 7.1 Hz, J4,6 = 2.0 Hz, 1 H, 4-H) ppm. 13C NMR (150.9 MHz,
D2O): δ = 42.49 (CH2-2Ј), 64.92 (CH2-5Ј), 75.63 (CH-3Ј), 78.64
(CH-1Ј), 89.43 (CH-4Ј), 111.55 (CH-5), 133.28 (C-3), 136.73 (CH-
1
Na] 630.2686; found 630.2683. H NMR [499.8 MHz, CDCl3, ref.
(dioxane) = 3.75 ppm]: δ = 0.06, 0.07 (2 s, 2ϫ6 H, CH3-Si), 0.88,
6), 141.87 (CH-4), 165.43 (C-2) ppm. IR (KBr): ν = 3431, 1645,
˜
1631, 1610, 1567, 1084, 1049, 775 cm–1.
0.89 [2 s, 2ϫ9 H, (CH3)3C], 1.72 (ddd, Jgem = 12.7 Hz, J2Јb,1Ј
=
10.1 Hz, J2Јb,3Ј = 5.3 Hz, 1 H, 2Ј-Hb), 2.31 (ddd, Jgem = 12.7 Hz,
J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.9 Hz, 1 H, 2Ј-Ha), 2.76, 2.77 [2 d, JH,P
1β-(6-Methyl-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]-D-ribofuranose (21):
A solution of Me3Al (3 mmol) in THF was added dropwise to a
vigorously stirred solution of 19 (428 mg, 0.70 mmol) and Pd(PPh3)
= 10.6 Hz, 2ϫ6 H, (CH3)2N-P], 3.63 (dd, Jgem = 10.7 Hz, J5Јb,4Ј
=
5.4 Hz, 1 H, 5Ј-Hb), 3.75 (dd, Jgem = 10.7 Hz, J5Јa,4Ј = 3.5 Hz, 1
H, 5Ј-Ha), 3.95 (ddd, J4Ј,5Ј = 5.4, 3.5 Hz, J4Ј,3Ј = 1.9 Hz, 1 H, 4Ј-
H), 4.38 (dtd, J3Ј,2Ј = 5.3, 1.9 Hz, J3Ј,4Ј = 1.9 Hz, JH,P = 0.6 Hz, 1
(144 mg, 0.125 mmol) in freshly distilled THF (22 mL). The mix-
4
ture was stirred at room temperature for 5 d and then worked up
with dichloromethane and water. The organic phases were col-
lected, dried with MgSO4, filtered, and concentrated in vacuo. The
crude material was chromatographed on silica gel (ethyl acetate/
hexane = 50:50 to ethyl acetate/hexane = 70:30) to give 21 (290 mg,
70%) as a colorless oil. Rf (ethyl acetate) = 0.37. [α]2D0 = +30.6 (c
= 0.157, CHCl3). HRMS (ESI+): calcd. for C27H55N3O5PSi2 [M +
H, 3Ј-H), 5.34 (ddq, J1Ј,2Ј = 10.1, 5.4 Hz, J1Ј,3Ј = J1Ј,4Ј = JH,P
=
0.6 Hz, 1 H, 1Ј-H), 7.06 (d, J5,4 = 7.9 Hz, 1 H, 5-H), 7.89 (ddd, J4,5
= 7.9 Hz, JH,P = 1.4 Hz, J4,1Ј = 0.6 Hz, 1 H, 4-H) ppm. 13C NMR
[125.7 MHz, CDCl3, ref. (dioxane) = 69.3 ppm]: δ = –5.50, –5.43,
–4.74, –4.72 (CH3-Si), 17.93, 18.31 [(CH3)3C], 25.72, 25.88 [(CH3)3-
C], 36.70, 36.77 [d, JC,P = 3.8 Hz, (CH3)2N-P], 42.92 (CH2-2Ј),
63.59 (CH2-5Ј), 74.11 (CH-1Ј), 74.21 (CH-3Ј), 87.87 (CH-4Ј),
120.08 (CH-5), 126.28 (d, JC,P = 5.9 Hz, C-3), 138.37 (CH-4),
146.85 (C-6), 153.83 (d, JC,P = 6.2 Hz, C-2) ppm. 31P NMR
[202.3 MHz, CDCl3, ref. (H3PO4): δ = 0 ppm]: 17.10 ppm. IR
1
H] 588.3412; found 588.3413. H NMR (600.1 MHz, CDCl3): δ =
0.06, 0.07 (2 s, 12 H, CH3Si), 0.88, 0.89 [2 s, 2ϫ9 H, (CH3)3C],
1.71 (ddd, Jgem = 12.8 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 5.3 Hz, 1 H,
2Ј-Hb), 2.29 (ddd, Jgem = 12.8 Hz, J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.9 Hz,
1 H, 2Ј-Ha), 2.44 (s, 3 H, CH3-6), 2.74, 2.76 (2 d, JH,P = 10.5 Hz,
2ϫ6 H, CH3N), 3.60 (dd, Jgem = 10.6 Hz, J5Јb,4Ј = 5.7 Hz, 1 H, 5Ј-
Hb), 3.75 (dd, Jgem = 10.6 Hz, J5Јa,4Ј = 3.7 Hz, 1 H, 5Ј-Ha), 3.94
(ddd, J4Ј,5Ј = 5.7, 3.7 Hz, J4Ј,3Ј = 2.0 Hz, 1 H, 4Ј-H), 4.38 (m, J3Ј,2Ј
(CHCl ): ν = 2956, 2819, 1588, 1574, 1471, 1463, 1438, 1388, 1362,
˜
3
1309, 1257, 1233, 1179, 1085, 1004, 947, 838, 682, 537 cm–1.
1β-[6-Chloro-2-oxo(1H)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose
(18): A solution of nucleoside 17 (440 mg, 1.16 mmol) in 1 m
NaOH (25 mL) was heated to reflux for 5.5 d (monitoring of the
conversion by TLC). Then the reaction was quenched with formic
acid (1 mL). The water was evaporated with the help of ethanol
and toluene co-evaporation. Column chromatography using a RP-
Biotage purification system (water/MeOH) afforded pure 18
(114 mg, 40%) as a colorless oil. Rf (dichloromethane/methanol =
95:5) = 0.33. [α]2D0 = +37.0 (c = 0.054, H2O). MS (ESI–): m/z =
244.2 [M – H]. MS (ESI+): m/z = 246.1 [M + H], 268.1 [M + Na].
HRMS (ESI+): calcd. for C10H13ClNO4 [M + H] 246.05276; found
4
= 5.3, 1.9 Hz, J3Ј,4Ј = 2.0, J = 0.5 Hz, 1 H, 3Ј-H), 5.36 (dd, J1Ј,2Ј
= 10.2, 5.4 Hz, 1 H, 1Ј-H), 6.88 (d, J5,4 = 7.7 Hz, 1 H, 5-H), 7.77
(dt, J4,5 = 7.7 Hz, J4,1Ј = JH,P = 1.0 Hz, 1 H, 4-H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = –5.49, –5.42, –4.74, –4.72 (CH3Si), 17.94,
18.31 [C(CH3)3], 23.80 (CH3-6), 25.74, 25.89 [(CH3)3C], 36.77,
36.85 (d, JC,P = 3.8 Hz, CH3N), 42.91 (CH2-2Ј), 63.69 (CH2-5Ј),
74.28 (CH-3Ј), 74.40 (CH-1Ј), 87.67 (CH-4Ј), 119.27 (CH-5), 123.73
(d, JC,P = 6.3 Hz, C-3), 136.01 (CH-4), 154.15 (d, JC,P = 6.2 Hz,
C-2), 155.32 (C-6) ppm. 31P NMR (202.3 MHz, CDCl3): δ =
246.05295. 1H NMR (600.1 MHz, D2O): δ = 2.03 (ddd, Jgem
13.6 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 6.0 Hz, 1 H, 2Ј-Hb), 2.33 (ddd,
Jgem = 13.6 Hz, J2Јa,1Ј = 6.0 Hz, J2Јa,3Ј = 2.2 Hz, 1 H, 2Ј-Ha), 3.68
=
16.71 ppm. IR (CHCl ): ν = 3053, 2956, 2814, 1608, 1576, 1485,
˜
3
1471, 1464, 1455, 1438, 1410, 1390, 1361, 1307, 1265, 1252, 1232,
1187, 1091, 1071, 1000, 992, 966, 940, 839, 705 cm–1.
(dd, Jgem = 12.1 Hz, J5Јb,4Ј = 5.3 Hz, 1 H, 5Ј-Hb), 3.73 (dd, Jgem
=
12.1 Hz, J5Јa,4Ј = 4.3 Hz, 1 H, 5Ј-Ha), 4.04 (ddd, J4Ј,5Ј = 5.3, 4.3 Hz, 1β-(6-Amino-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
J4Ј,3Ј = 2.2 Hz, 1 H, 4Ј-H), 4.38 (dt, J3Ј,2Ј = 6.0, 2.2 Hz, J3Ј,4Ј 1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]- -ribofuranose (22):
2.2 Hz, 1 H, 3Ј-H), 5.18 (dd, J1Ј,2Ј = 10.2, 6.0 Hz, 1 H, 1Ј-H), 6.61 LiN(SiMe3)2 (1 m in THF, 0.31 mL, 0.31 mmol) was added to a
(d, J5,4 = 7.7 Hz, 1 H, 5-H), 7.73 (d, J4,5 = 7.7 Hz, 1 H, 4-H) ppm. flame-dried argon-purged flask containing 19 (88 mg, 0.145 mmol),
=
D
Eur. J. Org. Chem. 2012, 1759–1767
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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