Journal of Medicinal Chemistry
Article
3-Butylamino-4-ethoxycyclobut-3-ene-1,2-dione 56. Butylamine
(135 μL, 1.367 mmol), DIPEA (141 μL, 0.811 mmol), and
diethylsquarate 53 (222 μL, 1.503 mmol) were reacted under general
protocol C to leave the desired product as a white foam (230 mg,
91%). 1H (400 MHz, CDCl3) δ 4.77 (q, 2H, J = 7.2, OCH2-Me), 3.66
(t, 1H, J = 7.0, CHH), 3.48 (t, 1H, J = 7.0, CHH), 1.69−1.62 (m, 2H,
CH2), 1.53−1.40 (br m, 5H, CH2 and CH3) and 1.01 (t, 3H, J = 7.2,
CH3). 13C (100 MHz, CDCl3) δ 189.9 (C-2), 184.5 (C-1), 177.6 (C-
3), 174.7 (C-4), 70.7, 45.3, 33.7, 20.6 (4 × CH2), 16.2 (Et:CH3) and
14.0 (Bu:CH3). HRMS (ES+) calcd for C10H16NO3, 198.1125 (MH)+;
found, 198.1124. Rf = 0.5 (petrol−EtOAc, 6:4 v/v).
3-(2′,3′-O-Isopropylidene-5′-amino-5′-deoxyadenosine)-4-buty-
lamino-cyclobut-3-ene-1,2-dione 62. To a solution of 3-butylamino-
4-ethoxycyclobut-3-ene-1,2-dione 56 (200 mg, 1.081 mmol) and
DIPEA (92 μL, 0.531 mmol) in EtOH (5 mL) was added 2′,3′-O-
isopropylidene-5′-amino-5′-deoxyadenosine 59 (300 mg, 0.983
mmol). The reaction mixture was stirred at rt for 24 h. The solvent
was removed under reduced pressure, and the residue was purified on
an Isco chromatographic system (DCM−MeOH, 8:2 v/v) to yield the
desired product as a white foam (364 mg, 81%). 1H (400 MHz,
DMSO-d6) δ 8.38 (s, 1H, H-8), 8.23 (s, 1H, H-2), 7.39 (br s, 2H,
NH2), 6.25 (d, 1H, J1′,2′ = 2.4, H-1′), 5.50 (dd, 1H, J2′,3′ = 6.3 and J2′,1′
= 2.4, H-2′), 5.04 (dd, 1H, J3′,2′ = 6.3 and J3′,4′ = 3.5, H-3′), 4.33−4..29
(m, 1H, H-4′), 3.95 (br, 1H, H-5′a), 3.81−3.75 (br, 1H, H-5′b), 3.51
(br, 2H, CH2), 3.38−3.34 (m, 1H, CHH), 1.60 (s, 3H, CH3), 1.51 (br,
1H, CHH), 1.32 (s, 3H, CH3), 1.32 (q, 2H, J = 7.3, CH2-Me) and 0.91
(t, 3H, J = 7.3, CH3). 13C (100 MHz, DMSO-d6) δ 182.7 (CO),
182.2 (CO), 167.7 (CC), 167.1 (CC), 156.1 (C-6), 152.8 (C-
2), 148.8 (C-4), 139.9 (C-8), 119.1 (C-5), 113.7 (C), 88.7 (C-1′),
85.1 (C-4′), 83.6 (C-2′), 81.2 (C-3′), 45.0 (CH2), 42.9 (C-5′), 32.7
(CH2), 27.0, 25.2 (2 × CH3), 18.9 (CH2) and 13.4 (CH3). HRMS
(ES+) calcd for C21H28N7O5, 458.2146 (MH)+; found, 458.2142.
3-(5′-Amino-5′-deoxyadenosine)-4-butylamino-cyclobut-3-ene-
1,2-dione 66. 3-(2′,3′-O-Isopropylidene-5′-amino-5′-deoxyadeno-
sine)-4-butylamino-cyclobut-3-ene-1,2-dione 62 (50 mg, 0.109
mmol) was deprotected under general protocol D to give the desired
compound as a white solid (41 mg, 91%). 1H (400 MHz, DMSO-d6) δ
8.40 (s, 1H, H-8), 8.26 (s, 1H, H-2), 7.56−7.45 (br m, 4H, NH2 and 2
and J2′,1′ = 2.4, H-2′), 5.07 (dd, 1H, J3′,2′ = 6.2 and J3′,4′ = 3.5, H-3′),
4.33−4.29 (m, 1H, H-4′), 3.96 (br, 1H, H-5′a), 3.81−3.74 (br, 1H, H-
5′b), 3.50 (br, 2H, CH2), 1.60 (s, 3H, CH3), 1.51 (br, 1H, CHH), 1.38
(s, 3H, CH3), 1.30 (br, 7H, 3 × CH2 and CHH) and 0.91−0.88 (m,
3H, CH3). 13C (100 MHz, DMSO-d6) δ 182.7 (C-2), 182.2 (C-1),
167.9 (C-3), 168.5 (C-4), 156.1 (C-6), 152.8 (C-2), 148.8 (C-4),
139.9 (C-8), 119.2 (C-5), 113.7 (C), 88.7 (C-1′), 85.2 (C-4′), 83.1
(C-2′), 81.2 (C-3′), 45.1 (CH2), 43.2 (C-5′), 30.7, 30.6 (2 × CH2),
27.0 (CH3), 25.4 (CH2), 25.3 (CH3) 21.9 (CH2) and 13.8 (CH3).
HRMS (ES+) calcd for C23H32N7O5, 486.2459 (MH)+; found,
486.2475.
3-(5′-Amino-5′-deoxyadenosine)-4-(hexylamino)cyclobut-3-ene-
1,2-dione 67. 3-(2′,3′-O-Isopropylidene-5′-amino-5′-deoxyadeno-
sine)-4-(hexylamino)cyclobut-3-ene-1,2-dione 63 (50 mg, 0.102
mmol) was deprotected under general protocol D to yield the desired
compound as a white solid (41 mg, 91%). 1H (400 MHz, DMSO-d6) δ
8.42 (s, 1H, H-8), 8.27 (s, 1H, H-2), 7.65 (br s, 2H, NH2), 7.44 (br s,
2H, 2 × NH), 5.98 (d, 1H, J1′,2′ = 5.7, H-1′), 4.72 (app t, 1H, J = 5.0,
H-2′), 4.22 (app t, 1H, J = 4.3, H-3′), 4.10−4.06 (m, 2H, H-4′ and H-
5′a), 3.85−3.79 (m, 1H, H-5′b), 3.51 (br s, 2H, CH2-NH), 1.51−1.29
(m, 8H, 4 × CH2) and 0.91−0.88 (m, 3H, CH3). 13C (100 MHz,
DMSO-d6) δ 182.6 (C-2), 182.3 (C-1), 167.9 (2 × CC), 155.2 (C-
6), 151.5 (C-2), 149.2 (C-4), 140.2 (C-8), 119.2 (C-5), 87.6 (C-1′),
83.7 (C-4′), 72.9 (C-2′), 70.8 (C-3′), 45.5 (CH2), 43.2 (C-5′), 30.7,
30.6, 25.4, 21.9 (4 × CH2) and 13.8 (CH3). HRMS (ES+) calcd for
C20H28N7O5, 446.2146 (MH)+; found, 446.2157. Rf = 0.55 (DCM−
MeOH, 8:2 v/v).
Synthesis of Click Analogue: 8-Phenyladenosine-1,4-Tria-
zole Ribose (8-Ph-ATrR). 1-O-Methyl-2,3-O-isopropylidene-5-O-
propargyl-β-D-ribofuranose 70. A solution of 1-O-methyl-2,3-O-
isopropylidene-β-D-ribofuranose 49 (600 mg, 2.94 mmol) in DMF (40
mL) was cooled to 0 °C, and NaH (156 mg, 3.91 mmol, 60% in
mineral oil) was added. The mixture was stirred at 0 °C for 30 min,
after which TBAI (65 mg, 0.176 mmol) and propargyl chloride (0.25
mL, 3.528 mmol) were added. The reaction mixture was stirred at rt
for 16 h, the solvent was removed under reduced pressure, and the
residue was purified by column chromatography using an Isco
chromatographic system (petrol−EtOAc, 1:0 → 0:1 v/v). The product
1
was obtained as a colorless liquid (512 mg, 72%). H (400 MHz,
× NH), 5.98 (d, 1H, J1′,2′ = 5.8, H-1′), 4.73 (app t, 1H, J2′,3′ = J2′,1′
=
CDCl3) δ 4.95 (s, 1H, H-1′), 4.65 (d, 1H, J2′,3′ = 6.0, H-2′), 4.55 (d,
1H, J3′,2′ = 6.0, H-3′), 4.33−4.30 (m, 1H, H-4′), 4.17 (d, 2H, J = 2.4,
CH2), 3.58 (dd, 1H, J5′a,5′b = 9.5 and J5′a,4′ = 6.5, H-5′a), 3.52−3.47 (m,
1H, H-5′b), 3.32 (s, 3H, OMe), 2.42 (t, 1H, J = 6.3 Hz, CH), 1.46 (s,
3H, CH3) and 1.30 (s, 3H, CH3). 13C (100 MHz, CDCl3) δ 112.3
(C), 109.2 (C-1′), 85.0 (C-4′), 84.8 (C-2′), 81.9 (C-3′), 79.3 (C),
74.6 (HC≡), 70.5 (C-5′), 58.3 (CH2), 54.8 (OCH3), 26.4 and 24.9 (2
× CH3). HRMS (ES+) calcd for C12H18NaO5, 265.1046 (MH)+;
found, 265.1042. Rf = 0.9 (petrol−EtOAc, 1:1 v/v).
5.8, H-2′), 4.23 (app t, 1H, J3′,2′ = J3′,4′ = 5.8, H-3′), 4.10−4.06 (m, 1H,
H-4′), 3.86−3.79 (m, 2H, 2 × H-5′), 3.53−5.52 (m, 2H, CH2), 1.51−
1.49 (m, 2H, CH2), 1.34 (q, 2H, J = 7.3) and 0.92 (t, 3H, J = 7.3). 13
C
(100 MHz, DMSO-d6) δ 182.2 (2 × CO), 167.6 (C-3), 167.2 (C-
4), 154.9 (C-6), 151.2 (C-2), 149.2 (C-4), 140.4 (C-8), 119.2 (C-5),
87.8 (C-1′), 83.7 (C-4′), 72.9 (C-2′), 70.8 (C-3′), 45.2 (C-5′), 33.4,
24.8, 23.8 (3 × CH2) and 15.8 (CH3). HRMS (ES+) calcd for
C18H24N7O5, 418.1833 (MH)+; found, 418.1834.
3-Hexylamino-4-ethoxycyclobut-3-ene-1,2-dione 57. Hexylamine
(130 μL, 0.988 mmol), DIPEA (92 μL, 0.533 mmol), and
diethylsquarate 53 (161 μL, 1.087 mmol) were reacted under general
protocol C to yield the desired product as a white foam (200 mg,
95%). 1H (400 MHz, CDCl3) δ 4.80−4.75 (m, 2H, CH2-Me), 3.65 (t,
1H, J = 7.0, CHH-NH), 3.48 (t, 1H, J = 7.0, CHH-NH), 1.69−1.64
(m, 2H, CH2), 1.53−1.44 (m, 9H, 3 × CH2 and CH3) and 0.99−0.96
(m, 3H, CH3). 13C (100 MHz, CDCl3) δ 189.9 (C-2), 184.5 (C-1),
177.5 (C-3), 174.8 (C-4), 70.7 (Et:CH2), 45.6, 32.5, 31.6, 27.1, 23.6 (5
× CH2), 16.2 (Et:CH3) and 14.5 (hex:CH3). HRMS (ES+) calcd for
C12H20NO3, 226.1438 (MH)+; found, 226.1443. Rf = 0.62 (petrol−
EtOAc, 6:4 v/v).
3-(2′,3′-O-Isopropylidene-5′-amino-5′-deoxyadenosine)-4-
(hexylamino)cyclobut-3-ene-1,2-dione 63. To a solution of 3-
hexylamino-4-ethoxycyclobut-3-ene-1,2-dione 57 (190 mg, 0.892
mmol) and DIPEA (76 μL, 0.438 mmol) in EtOH (5 mL) was
added 2′,3′-O-isopropylidene-5′-amino-5′-deoxyadenosine 59 (248
mg, 0.811 mmol). The reaction was stirred at rt for 20 h. The solvent
was removed under reduced pressure, and the residue was purified on
an Isco chromatographic system (DCM−MeOH, 8:2 v/v) to yield the
desired product as a white foam (291 mg, 74%). 1H (400 MHz,
DMSO-d6) δ 8.37 (s, 1H, H-8), 8.23 (s, 1H, H-2), 7.38 (br s, 4H, NH2
and 2 × NH), 6.26 (d, 1H, J1′,2′ = 2.4, H-1′), 5.49 (dd, 1H, J2′,3′ = 6.2
2′,3′-O-Isopropylidene-5′-azido-5′-deoxy-8-bromoadenosine 69.
2′,3′-O-Isopropylidene-5′-azido-5′-deoxyadenosine 68 (100 mg, 0.30
mmol) was taken up in NaOAc buffer (pH 4, 1 M, 15 mL) and Br2 (12
μL, 0.45 mmol) added. The resulting solution was stirred in the dark
for 24 h and then a solution of NaHSO3 (4 M, aq) added until the
solution was colorless. All solvents were evaporated and the residue
purified by column chromatography using an Isco chromatographic
system (DCM−acetone, 6:4 v/v). The title compound was obtained as
1
an off-white solid (123 mg, 99%). H (400 MHz, CDCl3) δ 8.27 (s,
1H, H-2), 6.20 (d, 1H, J1′,2′ = 1.8 Hz, H-1′), 5.99 (br s, 2H, NH2), 5.68
(dd, 1H, J2′,3′ = 6.3 and J2′,1′ = 1.8, H-2′), 5.15 (dd, 1H, J3′,2′ = 6.3 and
J3′,4′ = 3.6, H-4′), 4.36−4.31 (m, 1H, H-4′), 3.54−3.43 (m, 2H, 2 × H-
5′), 1.61 (s, 3H, CH3) and 1.39 (s, 3H, CH3). 13C (100 MHz, CDCl3)
δ 154.4 (C-6), 152.8 (C-2), 150.3 (C-4), 127.5 (C-8), 120.1 (C-5),
114.5 (C), 91.2 (C-1′), 86.4 (C-4′), 83.4 (C-2′), 82.4 (C-3′), 52.1 (C-
5′), 27.0 and 25.3 (2 × CH3). HRMS (ES+) calcd for C13H16N8O379Br,
411.0523 (MH)+; found, 411.0532; and calcd for C13H16N8O381Br,
413.0503 (MH)+; found, 413.0522. Rf = 0.58 (DCM−acetone, 3:2 v/
v).
1-(2′,3′-O-Isopropylidene-5′-deoxy-8-bromoadenosine)-4-(2″,3″-
O-isopropylidene-5″-O-methylribosyl)-1,2,3-triazole 71. To a sol-
ution of 2′,3′-O-isopropylidene-5′-deoxy-5′-azido-8-bromoadenosine
10097
dx.doi.org/10.1021/jm401497a | J. Med. Chem. 2013, 56, 10079−10102