Organic & Biomolecular Chemistry
Paper
silica gel (gradient: DCM–MeOH 9 : 1, v/v; 8 : 2, v/v; 7 : 3, v/v) to sodium salt (150 mg, 0.36 mmol), compound 19 (212 mg,
afford compound 20 (4.17 g, 58%) as a white solid. 1H NMR 1.00 mmol), triethylamine (0.30 mL, 2.15 mmol) and DMF
(300 MHz, D2O) δ = 4.15 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 3.45 (4 mL). 1H NMR (300 MHz, D2O) δ = 7.99 (s, 1H, H-8), 6.26
(t, J = 6.6 Hz, 2H, CH2αCH2SO3H), 3.35 (t, J = 6.5 Hz, 2H, (app t, J = 7.0 Hz, 1H, H-1′), 4.65–4.63 (m, 1H, H-3′), 4.17–4.15
CH2αCH2CO2Et), 3.23 (t, J = 6.6 Hz, 2H, CH2CH2βSO3H), 2.80 (m, 1H, H-4′), 4.04 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.96–3.93
(t, J = 6.5 Hz, 2H, CH2CH2βCO2Et), 1.20 (t, J = 7.1 Hz, 3H, (m, 2H, H-5′ and H-5″), 3.74 (d, J = 10.5 Hz, 2H, CH2CO2Et),
CO2CH2CH3); 13C NMR (75 MHz, D2O) δ = 172.1, 62.1, 46.1, 3.40–3.33 (m, 2H, CH2αCH2SO3H), 3.01–2.96 (m, 2H,
43.1, 42.9, 29.9, 12.9; HRMS for C7H15NO5S [M − H]− calcd: CH2CH2βSO3H), 2.83–2.71 (m, 1H, H-2′), 2.50–2.43 (m, 1H,
224.0598, found: 224.0598.
H-2″), 1.13 (t, J = 7.4 Hz, 3H, OCH2CH3); 13C NMR (75 MHz,
3
Thymidine-5′-O-[N-(ethylacetate)-2-aminoethanesulfonic acid] D2O) δ = 173.4 (d, JC,P = 2.9 Hz, CO2Et), 159.4 (C-6), 153.4
phosphoramidate triethylammonium salt (21). The triethylam- (C-2), 151.0 (C-4), 135.4 (C-8), 117.0 (C-5), 85.3 (d, JC,P
monium salt of compound 21 was obtained as a white solid 9.3 Hz, C-4′), 82.6 (C-1′), 71.2 (C-3′), 64.0 (d, JC,P = 5.4 Hz, C-5′),
(123 mg, 52%) following the general procedure (B), starting 61.6 (OCH2CH3), 49.8 (CH2CβH2SO3H), 48.5 (d, JC,P
from thymidine-5′-phosphorimidazolide sodium salt (130 mg, 5.4 Hz, CH2CO2Et), 43.4 (d, JC,P = 4.6 Hz, CαH2CH2SO3H), 38.4
0.33 mmol), compound 19 (195 mg, 0.92 mmol), triethylamine (C-2′), 12.9 (OCH2CH3); 31P NMR (121 MHz, D2O) δ = 7.2; HRMS
(0.28 mL, 1.98 mmol) and DMF (4 mL). 1H NMR (300 MHz, for C16H25N6O11PS [M − H]− calcd: 539.0967, found: 539.0969.
3
=
2
2
=
2
D2O) δ = 7.69 (s, 1H, H-6), 6.37 (t, J = 7.1 Hz, 1H, H-1′),
2′-Deoxycytidine-5′-O-[N-(ethyl acetate)-2-aminoethanesulfo-
4.58–4.54 (m, 1H, H-3′), 4.17–4.19 (m, 3H, H-4′ and OCH2CH3), nic acid] phosphoramidate triethylammonium salt (24). The
4.05–3.98 (m, 2H, H-5′ and H-5″), 3.85 (d, J = 10.6 Hz, 2H, triethylammonium salt of compound 24 was obtained as a
CH2CO2Et), 3.48–3.37 (m, 2H, CH2αCH2SO3H), 3.18–3.10 (m, white solid (130 mg, 47%) following the general procedure (B),
2H, CH2CH2βSO3H) (merged with Et3N), 2.37–2.32 (m, 2H, H-2′ starting from 2′-deoxycytidine-5′-phosphorimidazolide sodium
and H-2″), 1.92 (s, 3H, CH3), 1.27–1.22 (m, 3H, OCH2CH3) salt (150 mg, 0.39 mmol), compound 19 (234 mg, 1.11 mmol),
(merged with Et3N); 13C NMR (75 MHz, D2O) δ = 173.5 (d, triethylamine (0.33 mL, 2.37 mmol) and DMF (4 mL).1H NMR
3JC,P = 2.4 Hz, CO2Et), 171.0 (C-4), 155.1 (C-2), 136.5 (C-6), (300 MHz, D2O) δ = 7.94 (d, J = 7.6 Hz, 1H, H-6), 6.29 (app t,
3
111.5 (C-5), 85.0 (d, JC,P = 9.4 Hz, C-4′), 84.6 (C-1′), 71.0 (C-3′), J = 6.8 Hz, 1H, H-1′), 6.08 (d, J = 7.5 Hz, 1H, H-5), 4.53–4.49
2
63.9 (d, JC,P
= 5.1 Hz, C-5′), 61.6 (OCH2CH3), 49.7 (m, 1H, H-3′), 4.17–4.10 (m, 3H, H-4′ and OCH2CH3), 4.03–3.98
2
(CH2CβH2SO3H), 48.5 (d, JC,P = 5.5 Hz, CH2CO2Et), 43.4 (d, (m, 2H, H-5′ and H-5″), 3.82 (d, J = 10.7 Hz, 2H, CH2CO2Et),
2JC,P = 4.7 Hz, CαH2CH2SO3H), 38.5 (C-2′), 13.0 (OCH2CH3), 3.44–3.35 (m, 2H, CH2αCH2SO3H), 3.19–3.09 (unresolved m,
11.9 (CH3); 31P NMR (121 MHz, D2O) δ = 7.1; HRMS for 2H, CH2CH2βSO3H, merged with Et3N), 2.43–2.21 (m, 2H, H-2′
C16H26N3O12PS [M − H]− calcd: 514.0902, found: 514.0902.
and H-2″), 1.27–1.22 (unresolved m, 3H, OCH2CH3, merged
2′-Deoxyadenosine-5′-O-[N-(ethylacetate)-2-aminoethanesul- with Et3N); 13C NMR (75 MHz, D2O) δ = 173.4 (d, 3JC,P = 2.5 Hz,
fonic acid] phosphoramidate triethylammonium salt (22). The CO2Et), 165.8 (C-4), 157.1 (C-2), 141.2 (C-6), 96.1 (C-5), 85.6
3
2
triethylammonium salt of compound 22 was obtained as a (C-1′), 85.4 (d, JC,P = 9.3 Hz, C-4′), 70.7 (C-3′), 63.7 (d, JC,P
=
white solid (47 mg, 38%) following the general procedure (B), 5.2 Hz, C-5′), 61.6 (OCH2CH3), 49.7 (CH2CβH2SO3H), 48.6
2
2
starting
from
2′-deoxyadenosine-5′-phosphorimidazolide (d, JC,P = 5.5 Hz, CH2CO2Et), 43.4 (d, JC,P = 4.7 Hz, CαH2CH2-
sodium salt (70 mg, 0.17 mmol), compound 19 (103 mg, SO3H), 39.3 (C-2′), 13.0 (OCH2CH3); 31P NMR (121 MHz, D2O)
0.49 mmol), triethylamine (0.145 mL, 1.04 mmol) and DMF δ = 7.2; HRMS for C15H25N4O11PS [M − H]− calcd: 499.0905,
(3 mL). 1H NMR (300 MHz, D2O) δ = 8.40 (s, 1H, H-8), 8.13 found: 499.0898.
(s, 1H, H-2), 6.40 (t, J = 6.7 Hz, 1H, H-1′), 4.72–4.68 (m, 1H,
Thymidine-5′-O-[N-(ethyl propionate)-2-aminoethanesulfonic
H-3′), 4.24–4.23 (m, 1H, H-4′), 4.05–3.95 (m, 4H, H-5′,H-5″ and acid] phosphoramidate triethylammonium salt (25). The
OCH2CH3), 3.70 (d, J = 10.5 Hz, 2H, CH2CO2Et), 3.41–3.28 triethylammonium salt of compound 25 was obtained as a
(m, 2H, CH2αCH2SO3H), 3.11–3.03 (m, 2H, CH2CH2βSO3H), white solid (0.204 g, 51%) following the general procedure (A),
2.91–2.74 (m, 1H, H-2′), 2.64–2.53 (m, 1H, H-2″), 1.13 (t, J = starting from TMP-triethylammonium salt (0.286 g,
7.1 Hz, 3H, OCH2CH3); 13C NMR (75 MHz, D2O) δ = 173.3 (d, 0.55 mmol), compound 20 (0.553 g, 2.46 mmol), DCC (0.563 g,
3JC,P = 2.8 Hz, CO2Et), 155.0 (C-6), 152.2 (C-2), 148.1 (C-4), 2.73 mmol), triethylamine (0.38 mL, 2.73 mmol) in a 4 : 1
139.4 (C-8), 118.1 (C-5), 85.7 (d, 3JC,P = 9.3 Hz, C-4′), 83.3 (C-1′), tBuOH–H2O mixture (11 mL) at 90 °C for 6 h. 1H NMR
2
71.1 (C-3′), 63.8 (d, JC,P = 5.2 Hz, C-5′), 61.5 (OCH2CH3), 49.7 (500 MHz, D2O) δ = 7.75 (s, 1H, H-6), 6.35 (app t, J = 7.1 Hz,
2
(CH2CβH2SO3H), 48.4 (d, JC,P = 5.3 Hz, CH2CO2Et), 43.4 1H, H-1′), 4.58–4.56 (m, 1H, H-3′), 4.13–4.12 (m, 1H, H-4′),
2
(d, JC,P = 4.6 Hz, CαH2CH2SO3H), 38.6 (C-2′), 12.3 (OCH2CH3); 4.09–4.03 (m, 2H, OCH2CH3), 3.96–3.90 (m, 2H, H-5′ and
31P NMR (121 MHz, D2O) δ = 7.2; HRMS for C10H14N5O9PS H-5″), 3.42–3.35 (m, 2H, CH2αCH2SO3H), 3.34–3.10 (m, 2H,
[M − H]− calcd: 523.1017, found: 523.1019.
CH2αCH2CO2Et), 3.12–3.07 (m, 2H, CH2CH2βSO3H), 2.63–2.51
2′-Deoxyguanosine-5′-O-[N-(ethyl acetate)-2-aminoethanesul- (m, 2H, CH2CH2βCO2Et), 2.41–2.30 (m, 2H, H-2′ and H-2″),
fonic acid] phosphoramidate triethylammonium salt (23). The 1.90 (s, 3H, CH3), 1.19 (t, J = 7.1 Hz, 3H, OCH2CH3); 13C NMR
triethylammonium salt of compound 23 was obtained as an (125 MHz, D2O) δ = 174.2 (CO2Et), 165.9 (C-4), 151.2 (C-2),
off-white solid (58 mg, 22%) following the general procedure 136.8 (C-6), 111.2 (C-5), 84.9 (d, 3JC,P = 9.4 Hz, C-4′), 84.2 (C-1′),
2
(B), starting from 2′-deoxyguanosine-5′-phosphorimidazolide 70.5 (C-3′), 63.3 (d, JC,P = 5.0 Hz, C-5′), 61.1 (OCH2CH3), 49.5
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 3950–3962 | 3959