PAPER
Metal-Chelating Phosphoramidites
1841
Anal. Calcd for C52H68N6O13·0.5H2O: C, 62.82; H, 7.00; N, 8.45.
Found: C, 62.96; H, 6.94; N, 8.68.
Hz, H-1¢), 6.58–6.85 and 7.15–7.42 (2 m, 13 H, Ar), 7.80 (br s, 1 H,
H-6).
UV (EtOH): lmax = 275 (13300), 235 nm (28300).
5¢-O-(4,4¢-Dimethoxytrityl)-N4-[2-(2-{[2-bis(ethoxycarbonyl-
methylamino)ethyl]ethoxycarbonylmethylamino}acetylamino)
ethyl]-2¢-deoxycytidine (17)
Anal. Calcd for C58H79N7O15: C, 62.52; H, 7.15; N, 8.80. Found: C,
62.78; H, 7.23; N, 9.14.
Prepared from 15 (300 mg, 0.52 mmol) and EDTA(OEt)3 (197 mg,
0.52 mmol) according to the procedure used for 7 (Method B). After
purification of the crude material on silica gel (CH2Cl2–MeOH–
TEA, 98:1.5:0.5) the product was recovered as a pale yellow foam
(290 mg, 60%); Rf = 0.28 (CH2Cl2–MeOH–TEA, 98:1.5:0.5); [a]D
+37.5 (c = 1, EtOH).
5¢-O-(4,4¢-Dimethoxytrityl)-N4-[trans-4-(2-{[2-bis(ethoxycarbo-
nylmethylamino)ethyl]ethoxycarbonylmethylamino}acetylami-
no)cyclohexyl]-2¢-deoxycytidine-3¢-O-(2-cyanoethyl)-N,N-
diisopropylphosphoramidite (1)
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To a stirred solution of 9 (137 mg, 0.14 mmol) (previously coevap-
orated with anhyd pyridine and dried overnight under high vacuum)
and i-Pr2NEt (72 mg, 0.56 mmol) in anhyd CH2Cl2 (3.0 mL) was
added 2-cyanoethyldiisopropylchlorophosphoramidite (66 mg, 0.28
mmol) by a syringe over 2 min under N2. The mixture was left for
30 min at r. t., diluted with CH2Cl2 (30 mL) and washed with ice-
cold brine (2 × 20 mL). The organic phase was dried (Na2SO4), fil-
tered, concentrated to small volume at low pressure and added drop-
wise to stirred n-hexane cooled to –78 °C. The product, recovered
as oil, was redissolved in benzene and lyophilized (155 mg, 93%,
mixture of diastereomers); Rf = 0.67 and 0.64 (EtOAc–MeOH,
85:15); [a]D20 +15 (c = 1, EtOH).
IR (CHCl3): 3295, 3014, 1736, 1648, 1509, 1234, 1201 cm–1.
1H NMR (CDCl3): d = 1.36 (t, 9 H, J = 7.5 Hz, 3 × OCH2CH3),
1.68–2.30 (m, 6 H, CH2CH2, H-2¢ and H-2¢¢), 2.75 (s, 4 H,
NCH2CH2NEDTA), 3.26 (s, 2 H, NCH2CON), 3.36 (s, 2 H,
CH2CO2Et), 3.48 (s, 4 H, 2 × CH2CO2Et), 3.76 (s, 6 H, 2 ×
PhOCH3), 4.09 [q, 9 H, J = 7.5 Hz, 3 × OCH2CH3, (obscured H-4¢,
H-5¢ and H-5¢¢)], 4.60–4.88 (m, 1 H, H-3¢), 5.46 (d, 1 H, J = 7.5 Hz,
H-5), 6.30 (t, 1 H, J = 6.0 Hz, H-1¢), 6.75–6.92 and 7.10–7.50 (2 m,
13 H, Ar), 7.70 (d, 1 H, J = 7.5 Hz, H-6).
UV (EtOH): lmax = 275 (16500), 234 nm (35600).
IR (CHCl3): 3274, 1736, 1642, 1503, 1380, 1113 cm–1.
Anal. Calcd for C48H62N6O13·0.5H2O: C, 61.33; H, 6.75; N, 8.94.
Found: C, 61.58; H, 6.66; N, 9.05.
1H NMR (CDCl3): d = 1.04 (d, 4 H, J = 6.6 Hz, 2 × CH2cyclohexyl),
1.16–1.30 [m, 21 H, 3 × OCH2CH3 and 2 × (CH3)2CHN], 1.43 (d, 4
H, J = 6.6 Hz, 2 × CH2cyclohexyl),1.85–2.01 (m, 2 H, H-2¢ and H-2¢¢),
2.03–2.18 [m, 2 H, 2 × (CH3)2CHN], 2.20–2.33 (m, 2 H, 2 × CHcy-
clohexyl), 2.61 (t, 2 H, J = 6.6 Hz, CH2CN), 2.70–2.86 (m, 4 H,
NCH2CH2N), 3.27 (s, 2 H, NCH2CON), 3.54 (s, 2 H, CH2CO2Et),
3.48–3.67 (m, 3 H, H-4¢, H-5¢ and H-5¢¢), 3.97 (s, 4 H, 2 ×
CH2CO2Et), 3.79 (s, 6 H, 2 × PhOCH3), 4.50 (br s, 1 H, H-3¢), 4.16
(q, 6 H, J = 7.2 Hz, 3 × OCH2CH3), 4.54–4.68 (m, 2 H, CH2OP),
5.29 (d, 1 H, J = 8.0 Hz, H-5), 6.37 (br s, 1 H, H-1¢), 6.79–6.84 and
7.20–7.33 (2 m, 13 H, Ar), 7.95 (d, 1 H, J = 8.0 Hz, H-6).
5¢-O-(4,4¢-Dimethoxytrityl)-N4-[6-(2-{[2-bis(ethoxycarbonyl-
methylamino)ethyl]ethoxycarbonylmethylamino}acetylamino)
hexyl]-2¢-deoxycytidine (18)
Prepared from 1618 (212 mg, 0.37 mmol) and EDTA(OEt)3 (139
mg, 0.37 mmol) according to the procedure used for 7 (Method B).
After purification of the crude material on silica gel (CH2Cl2–
MeOH–TEA, 99:0.5:0.5) the product was obtained as a pale yellow
20
foam (280 mg, 76%); Rf = 0.33 (CH2Cl2–MeOH, 90:10); [a]D
+27.5 (c = 1, EtOH).
IR (CHCl3): 3324, 3011, 1736, 1646, 1509, 1250, cm–1.
13C NMR (CDCl3): d = 171.41, 171.08, 170.45 (COEDTA), 162.98
(C-4), 160.19 (COMe), 158.66 (C-2), 144.51, 135.55, 130.20,
128.35, 127.93, 127.04, 113.23 (Ar and C-6), 117.55 (CN), 105.23
(C-5), 76.63–77.48 (C-1¢ and C-4¢, obscured by CDCl3), 60.70 (C-
5¢), 60.64 (C-3¢), 58.71, 58.44 and 58.20 (OCH2CH3), 55.95
(PhOCH3), 55.28 (CH2OP), 55.25, 53.39, 53.12 and 52.15
(NCH2CO), 51.71 (NCH2CH2N), 47.38 and 47.05 (CHNcyclohexyl),
43.40 and 43.17 [NCH(CH3)3], 31.82 and 31.29 (CH2cyclohexyl),
24.70 and 24.50 [NCH(CH3)3], 20.41 (CH2CN), 14.29 (OCH2CH3).
1H NMR (CDCl3): d = 1.12–1.66 (m, 17 H, 3 × OCH2CH3 and 2–5
CH2hexyl), 1.85–2.30 (m, 2 H, H-2¢ and H-2¢¢), 2.75 (s, 4 H,
NCH2CH2N), 3.15–3.55 (m, 15 H, NCH2CON, 3 × CH2CO2Et, H-
4¢, H-5¢, H-5¢¢ and 1,6 CH2hexyl), 3.78 (s, 6 H, 2 × PhOCH3), 4.12 (q,
6 H, J = 7.5 Hz, 3 × OCH2CH3), 4.40 (br s, 1 H, H-3¢), 5.45 (d, 1 H,
J = 8.0 Hz, H-5), 6.25 (br s, 1 H, H-1¢), 6.68–6.86 and 7.12–7.40 (2
m, 13 H, Ar), 7.80 (br s, 1 H, H-6).
UV (EtOH): lmax 274 (13600), 234 nm (28000).
UV (EtOH): lmax = 274 (12300), 235 nm (26800).
Anal. Calcd for C52H70N6O13·0.5H2O: C, 62.70; H, 7.18; N, 8.44.
Found: C, 62.63; H, 7.22; N, 8.52.
Anal. Calcd for C61H85N8O14P: C, 61.81; H, 7.23; N, 9.45. Found:
C, 62.93; H, 6.95; N, 9.33.
5¢-O-(4,4¢-Dimethoxytrityl)-N4-[trans-4-(N,N-bis{2-[bis(2-eth-
oxycarbonylmethylamino)ethyl]ethoxycarbonylmethylamino}-
acetylamino)cyclohexyl]-2¢-deoxycytidine (19)
5¢-O-(4,4¢-Dimethoxytrityl)-N4-[2-(2-{[2-bis(ethoxycarbonyl-
methylamino)ethyl]ethoxycarbonylmethylamino}acetylamino)
ethyl]-2¢-deoxycytidine-3¢-O-(2-cyanoethyl)-N,N-diisopropyl-
phosphoramidite (2)
Prepared from 17 (207 mg, 0.22 mmol) according to the procedure
used for 1 (230 mg, 92%, mixture of diastereomers); Rf = 0.58 and
0.50 (CH2Cl2–MeOH, 90:10); [a]D20 +16 (c = 1, MeCN).
Prepared from 14 (125 mg, 0.20 mmol) and 23 (101 mg, 0.20 mmol)
according to the procedure used for 7 (Method B). After purification
of the crude material on silica gel (CH2Cl2–MeOH–TEA,
98:1.5:0.5) the product was recovered as a pale yellow foam (147
20
mg, 66%); Rf = 0.55 (EtOAc–MeOH, 80:20); [a]D +39.2 (c = 1,
EtOH).
IR (CHCl3): 3293, 2988, 1735, 1651, 1509, 1234, 1057 cm–1.
IR (CHCl3): 2936, 1743, 1642, 1499, 1177 cm–1.
1H NMR (CDCl3): d = 1.00–1.40 [m, 21 H, 3 × OCH2CH3 and 2 ×
(CH3)2CHN], 1.70–2.26 [m, 8 H, NHCH2CH2NH , H-2¢, H-2¢¢ and
2 × (CH3)2CHN], 2.53 (br s, 2 H, CH2CN), 2.70–2.88 (m, 4 H,
NCH2CH2N), 3.25 (s, 2 H, NCH2CON), 3.37 (s, 2 H, CH2CO2Et),
3.45–3.68 (m, 3 H, H-4¢, H-5¢ and H-5¢¢), 3.50 (s, 4 H, 2 ×
CH2CO2Et), 3.76 (s, 6 H, 2 × PhOCH3), 4.15 (q, 6 H, J = 7.2 Hz, 3
× OCH2CH3), 4.45 (br s, 1 H, H-3¢), 4.50–4.90 (m, 2 H, CH2OP),
5.40 (d, 1 H, J = 8.0 Hz, H-5), 6.53 (br s, 1 H, H-1¢), 6.65–6.90 and
7.15–7.45 (2 m, 13 H, Ar), 7.90 (d, 1 H, J = 8.0 Hz, H-6).
1H NMR (CDCl3): d = 0.95 (d, 4 H, J = 6.5 Hz, 2 × CH2cyclohexyl),
1.06–1.25 (m, 12 H, 4 × OCH2CH3), 1.40 (d, 4 H, J = 6.5 Hz, 2 ×
CH2cyclohexyl), 1.75–2.28 (2 m, 4 H, H-2¢, H-2¢¢ and 2 × CHcyclohexyl),
2.48 and 2.90 (2 m, 8 H, 2 × NCH2CH2N), 3.09 (s, 2 H, NCH2CON),
3.50 [s, 10 H, 4 × CH2CO2Et (obscured 5¢ and 5¢¢)], 3.75 (s, 6 H, 2
× PhOCH3), 4.15 [q, 9 H, J = 7.5 Hz, 4 × OCH2CH3 (obscured H-
4¢)], 4.53 (m, 1 H, H-3¢), 5.38 (br s, 1 H, H-5), 6.29 (t, 1 H, J = 6.0
Synthesis 2004, No. 11, 1835–1843 © Thieme Stuttgart · New York