Cyclic ADP-Ribose Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 18 5509
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as for the synthesis of 3a to give 3c in 84% yield. H NMR (500
MHz, CDCl3) δ 0.00 (s, 6H, (CH3)2Si), 0.86 (s, 9H, (CH3)3C-),
1.39 (s, 3H, isopropyl CH3), 1.46-1.52 (m, 2H, H-3′′), 1.62 (s,
3H, isopropyl CH3), 1.63-1.67 (m, 2H, H-4′′), 1.83-1.89 (m, 2H,
H-2′′), 3.65-3.67 (m, 2H, H-5′′), 3.76-3.86 (m, 2H, H-5′), 4.00-
4.10 (m, 2H, H-1′′), 4.38-4.40 (m, 1H, H-4′), 4.89 (dd, 1H, JH3′,H4′
) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.11 (dd, 1H, JH1′,H2′ ) 2.5 Hz,
JH2′,H3′ ) 6.0 Hz, H-2′), 6.03 (d, 1H, JH2′,H1′ ) 2.5 Hz, H-1′), 7.68,
7.82 (each s, each 1H, H-2, H-8). 13C NMR (125 MHz, CDCl3) δ
152.7, 145.5, 139.4, 134.4, 122.1, 112.3, 89.4, 85.3, 83.5, 79.5,
61.7, 60.3, 46.1, 30.3, 27.9, 26.5, 25.4, 24.1, 23.6, 21.1, 16.5, -7.2,
-7.3. ESI-TOF+-MS: calcd for C24H41N5O5Si [(M + 1)+], 508.3;
found, 508.3. Anal. (C24H41N5O5Si) C, H, N.
(s, 3H, isopropyl CH3), 1.48-1.70(m, 9H, H-2′′, H-3′′, H-4′′,
isopropyl CH3 ), 3.05 (m, 2H, H-5′′), 3.85-3.97 (m, 2H, H-5′),
4.05-4.09 (m, 2H, H-1′′), 4.52-4.53 (m, 1H, H-4′), 4.90 (dd, 1H,
JH3′,H4′ ) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.05 (dd, 1H, JH1′,H2′
)
2.5 Hz, JH2′,H3′ ) 6.0 Hz, H-2′), 5.95 (d, 1H, JH2′,H1′ ) 2.5 Hz,
H-1′), 6.85-7.42 (m, 10H, Ar-H), 7.65, 7.70 (each s, each 1H,
H-2, H-8). 13C NMR (125 MHz, CDCl3) δ 152.7, 145.5, 139.4,
134.4, 132.7, 129.5, 129.2, 125.7, 122.1, 112.3, 89.4, 85.3, 83.5,
79.5, 61.7, 60.3, 46.1, 30.3, 27.9, 26.5, 25.4, 24.1, 23.6. 31P NMR
(CDCl3, 81 MHz, decoupled with 1H) δ 49.50 ppm (s). ESI-TOF+-
MS: calcd for C30H36N5O6PS2 [(M + 1)+], 658.2; found, 658.2.
Anal. (C30H36N5O6PS2) C, H, N.
N1-(5′′-Phosphonoxypentyl)-5′-O-[(phenylthio)phosphoryl]-
2′,3′-O-isopropylideneadenosine 8c. POCl3 (283 µL, 3.04 mmol)
was added to a solution of 7c (200 mg, 0.304 mmol) in PO(OMe)3
(3 mL) at 0 °C, and the mixture was stirred at the same temperature
for 35 min. The following procedure was the same as for the
synthesis of 8a to give 8c in 51% yield. 1H NMR (300 MHz, D2O)
δ 1.41 (s, 3H, isopropyl CH3), 1.52-1.75 (m, 9H, H-2′′, H-3′′,
H-4′′, isopropyl CH3), 3.20 (m, 2H, H-5′′), 3.85-4.00 (m, 2H, H-5′
), 4.10-4.21 (m, 2H, H-1′′), 4.52-4.53 (m, 1H, H-4′), 5.02 (dd,
1H, JH3′,H4′ ) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.38 (dd, 1H, JH1′,H2′
) 2.5 Hz, JH2′,H3′ ) 6.0 Hz, H-2′), 6.05 (d, 1H, JH2′,H1′ ) 2.5 Hz,
H-1′), 6.90-7.35 (m, 5H, Ar-H), 8.15, 8.32 (each s, each 1H, H-2,
N1-(5′′-Monomethoxytrityloxypentyl)-5′-O-TBDMS-2′,3′-O-
isopropylideneadenosine 4c. A mixture of 3c (469 mg, 0.924
mmol) and MMTrCl (572 mg, 1.848 mmol) in pyridine (10 mL)
was stirred at room temperature for 8 h. The procedure was the
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same as for the synthesis of 4a to give 4c in 91% yield. H NMR
(300 MHz, CDCl3) δ 0.00 (s, 6H, (CH3)2Si), 0.86 (s, 9H, (CH3)3C-
), 1.39 (s, 3H, isopropyl CH3 ), 1.45-1.78 (m, 9H, H-2′′, H-3′′,
H-4′′, isopropyl CH3), 3.06 (m, 2H, H-5′′), 3.78-3.83 (m, 5H, H-5′,
OCH3 ), 3.99-4.04 (m, 2H, H-1′′), 4.39-4.40 (m, 1H, H-4′), 4.89
(dd, 1H, JH3′,H4′ ) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.09 (dd, 1H,
JH1′,H2′ ) 2.5 Hz, JH2′,H3′ ) 6.0 Hz, H-2′), 6.03 (d, 1H, JH2′,H1′
)
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2.5 Hz, H-1′), 6.81-7.44 (m, 14H, Ar-H), 7.64, 7.82 (each s, each
1H, H-2, H-8). 13C NMR (75 MHz, CDCl3) δ 158.3, 153.7, 147.4,
144.6, 141.3, 139.5, 136.3, 130.0, 128.1, 127.7, 124.3, 114.1, 112.8,
93.2, 86.4, 84.2, 81.9, 63.1, 55.5, 49.1, 29.4, 28.3, 27.5, 26.3, 25.2,
23.5, 17.2, -7.1, -7.2. ESI-TOF+-MS: calcd for C44H57N5O6Si
[(M + 1)+], 780.4; found, 780.3. Anal. (C44H57N5O6Si) C, H, N.
N1-(5′′-Monomethoxytrityloxypentyl)-2′,3′-O-isopropylidene-
adenosine 5c. A mixture of 4c (656 mg, 0.84 mmol), TBAF (1 M
in THF, 8.4 mL, 8.4 mmol), and AcOH (273 µL, 4.3 mmol) in
THF (20 mL) was stirred at room temperature for 2 h. The
procedure was the same as for the synthesis of 5a to give 5c in
H-8). 31P NMR (D2O, 81 MHz, decoupled with H) δ 3.01 ppm
(s), 17.65 ppm (s). HRMS (ESI-TOF-) calcd for C24H33N5O10P2S
[(M - 1)-], 644.1345; found, 644.1338.
N1-[(5′′-O-Phosphoryl)pentyl]-2′,3′-O-isopropylidene-5′-O-
phosphoryladenosine 5′,5′′-Cyclicpyrophosphate 9c. A solution
of 8c (15 mg, 23.2 µmol) in pyridine (5 mL) was added slowly
over 20 h, using a syringe pump, to a mixture of AgNO3 (84 mg,
494 µmol) and 3 Å molecular sieves (2.02 g) in pyridine (50 mL)
at room temperature in the dark. The procedure was the same as
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for the synthesis of 9a to give 9c in 59% yield. H NMR (300
MHz, D2O) δ 1.38 (s, 3H, isopropyl CH3), 1.49-1.72(m, 9H, H-2′′,
H-3′′, H-4′′, isopropyl CH3), 3.25 (m, 2H, H-5′′), 3.95-4.15 (m,
2H, H-5′), 4.20-4.32 (m, 2H, H-1′′), 4.55 (m, 1H, H-4′), 5.05 (dd,
1H, JH3′,H4′ ) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.55 (dd, 1H, JH1′,H2′
) 2.5 Hz, JH2′,H3′ ) 6.0 Hz, H-2′), 6.10 (d, 1H, JH2′,H1′ ) 2.5 Hz,
H-1′), 8.25, 8.35 (each s, each 1H, H-2, H-8). 31P NMR (D2O, 81
MHz, decoupled with1H) δ -9.99 ppm (d, JP,P ) 10.0 Hz), -10.72
ppm (d, JP,P ) 10.0 Hz). HRMS (ESI-TOF-) calcd for C18H27N5O10P2
[(M - 1)-], 534.1155; found, 534.1139.
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90% yield. H NMR (300 MHz, CDCl3) δ 1.37 (s, 3H, isopropyl
CH3), 1.45-1.78 (m, 9H, H-2′′, H-3′′, H-4′′, isopropyl CH3), 3.06
(m, 2H, H-5′′), 3.73-3.91 (m, 5H, H-5′, OCH3 ), 3.95-4.03(m,
2H, H-1′′), 4.49-4.50 (m, 1H, H-4′), 4.95 (dd, 1H, JH3′,H4′ ) 3.0
Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.05 (dd, 1H, JH1′,H2′ ) 2.5 Hz, JH2′,H3′
) 6.0 Hz, H-2′), 5.78 (d, 1H, JH2′,H1′ ) 2.5 Hz, H-1′), 6.81-7.44
(m, 14H, Ar-H), 7.64, 7.66 (each s, each 1H, H-2, H-8). 13C NMR
(75 MHz, CDCl3) δ 158.3, 153.3, 147.2, 144.7, 141.0, 139.0, 136.0,
130.2, 128.3, 127.7, 124.1, 114.1, 112.9, 93.4, 86.0, 83.9, 81.4,
62.9, 55.1, 48.7, 29.6, 28.4, 27.5, 25.2, 23.3. ESI-TOF+-MS: calcd
for C38H43N5O6 [(M + 1)+], 666.3; found, 666.2. Anal. (C38H43N5O6)
C, H, N.
N1-[(5′′-O-Phosphoryl)pentyl]-5′-O-phosphoryladenosine 5′,5′′-
Cyclicpyrophosphate 10c. A solution of 9c (7.3 mg, 13.7 µmol)
in 60% HCOOH (5 mL) was stirred for 8 h. The procedure was
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the same as for the synthesis of 10a to give 10c in 89% yield. H
N1-(5′′-Monomethoxytrityloxypentyl)-5′-O-[bis(phenylthio)-
phosphoryl]-2′,3′-O-isopropylideneadenosine 6c. To a solution
of 5c (503 mg, 0.756 mmol) in pyridine (10 mL) were added TPSCl
(460 mg, 1.51 mmol), PSS (861 mg, 2.27 mmol), and tetrazole
(159 mg, 2.27 mmol). The mixture was stirred at room temperature
for 12 h. The procedure was the same as for the synthesis of 6a to
NMR (300 MHz, D2O) δ 1.55-1.69 (m, 6H, H-2′′, H-3′′, H-4′′),
3.32 (m, 2H, H-5′′), 3.86-4.05 (m, 2H, H-5′ ), 4.15-4.28 (m, 2H,
H-1′′), 4.38 (m, 1H, H-4′), 4.98 (dd, 1H, JH3′,H4′ ) 3.0 Hz, JH2′,H3′
) 6.0 Hz, H-3′), 5.45 (dd, 1H, JH1′,H2′ ) 2.5 Hz, JH2′,H3′ ) 6.0 Hz,
H-2′), 6.15 (d, 1H, JH2′,H1′ ) 2.5 Hz, H-1′), 8.15, 8.55 (each s, each
1
1H, H-2, H-8). 31P NMR (D2O, 81 MHz, decoupled with H) δ
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give 6c in 65% yield. H NMR (300 MHz, CDCl3) δ 1.39 (s, 3H,
-9.72 ppm (d, JP,P ) 10.1 Hz), -10.10 ppm (d, JP,P ) 10.1 Hz).
HRMS (ESI-TOF-) calcd for C15H23N5O10P2 [(M - 1)-], 494.0842;
found, 494.0836.
isopropyl CH3), 1.41-1.72 (m, 9H, H2′′, H-3′′, H-4′′, isopropyl
CH3), 3.11 (m, 2H, H-5′′), 3.75-3.95 (m, 5H, H-5′, OCH3 ), 4.00-
4.10(m, 2H, H-1′′), 4.51-4.52 (m, 1H, H-4′), 4.89 (dd, 1H, JH3′,H4′
) 3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.10 (dd, 1H, JH1′,H2′ ) 2.5 Hz,
JH2′,H3′ ) 6.0 Hz, H-2′), 5.78 (d, 1H, JH2′,H1′ ) 2.5 Hz, H-1′), 6.80-
N1-[(6′′-Hydroxyl)hexyl]-5′-O-TBDMS-2′,3′-O-isopropylide-
neadenosine 3d. A mixture of 1 (486 mg, 1.1 mmol), 2d (157 mg,
1.3 mmol), and K2CO3 (8 mg, 0.06 mmol) in MeOH (15 mL) was
stirred at room temperature for 4 h. The procedure was the same
7.56 (m, 24H, Ar-H), 7.56, 7.68 (each s, each 1H, H-2, H-8). 13
C
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NMR (75 MHz, CDCl3) δ 158.3, 153.5, 147.2, 144.8, 140.9, 138.9,
136.1, 132.5, 130.2, 129.4, 129.1, 128.3, 127.7, 126.3, 124.1, 114.0,
112.9, 93.5, 86.1, 84.0, 81.6, 63.1, 55.1, 48.6, 29.5, 28.5, 27.6, 25.3,
23.4. 31P NMR (CDCl3, 81 MHz, decoupled with 1H) δ 49.45 ppm
(s). ESI-TOF+-MS: calcd for C50H52N5O7PS2 [(M + 1)+], 930.3;
found, 930.3. Anal. (C50H52N5O7PS2) C, H, N.
as for the synthesis of 3a to give 3d in 83% yield. H NMR (500
MHz, DMSO-d6) δ 0.00 (s, 6H, (CH3)2Si), 0.80 (s, 9H, (CH3)3C-
), 1.31 (s, 3H, isopropyl CH3 ), 1.32-1.69 (m, 11H, H-2′′, H-3′′,
H-4′′, H-5′′, isopropyl CH3), 3.34-3.38 (m, 2H, H-6′′ ), 3.64-
3.73 (m, 2H, H-5′), 3.92-4.08 (m, 2H, H-1′′), 4.19-4.20 (m, 1H,
H-4′ ), 4.32 (t, 1H, JH6′′,OH ) 4.5 Hz, OH), 4.88 (dd, 1H, JH3′,H4′
)
N1-[(5′′-Hydroxyl)pentyl]-5′-O-[bis(phenylthio)phosphoryl]-
2′,3′-O-isopropylideneadenosine 7c. A solution of 6c (457 mg,
0.491 mmol) in 80% aqueous AcOH (10 mL) was stirred at room
temperature for 8 h. The procedure was the same as for the synthesis
of 7a to give 7c in 82% yield. 1H NMR (300 MHz, CDCl3) δ 1.36
3.0 Hz, JH2′,H3′ ) 6.0 Hz, H-3′), 5.28 (dd, 1H, JH1′,H2′ ) 2.5 Hz,
JH2′,H3′ ) 6.0 Hz, H-2′), 6.04 (d, 1H, JH2′,H1′ ) 2.5 Hz, H-1′), 7.07
(s, br, NH), 8.05,8.06 (each s, each 1H, H-2, H-8). 13C NMR (125
MHz, CDCl3) δ 154.5, 147.3, 141.2, 136.7, 123.9, 114.1, 91.2, 87.0,
85.3, 81.3, 63.5, 62.5, 47.7, 32.5, 29.7, 28.6, 27.2, 26.3, 25.9, 25.2,