a-Tricyclo-DNA
FULL PAPER
action was quenched with silica gel (1 g), the solvent was evaporated, and
the residue was purified by CC (silica gel, EtOAc/EtOH 9:1) to yield
compound 11 as a white foam (100%). Rf = 0.62 (EtOAc/EtOH 9:1);
1H NMR (300 MHz, CD3OD): d = 0.80 (m, 1H; H-C(8’)), 0.95 (m, 1H;
H-C(8’)), 1.48 (m, 1H; H-C(6’)), 1.59 (d, J = 13.9 Hz, 1H; H-C(7’)), 2.10
(dd, J = 6.2, 13.4 Hz, 1H; H-C(7’)), 2.24 (dd, J = 5.1, 13.9 Hz, 1H; H-
C(2’)), 2.71 (dd, J = 6.2, 13.4 Hz, 1H; H-C(2’)), 4.32 (s, 1H; H-C(4’)),
6.09 (t, J = 6.2 Hz, 1H; H-C(1’)), 7.45 (m, 2H; arom. H), 7.55 (m, 2H;
arom. H), 7.99 (m, 2H; arom. H), 8.21 ppm (d, J = 7.5 Hz, 1H; H-C(6));
13C NMR (75 MHz, CD3OD): d = 18.4, 18.7, 41.5, 58.61, 87.3, 89.8, 91.7,
98.8, 129.5, 130.1, 134.4, 135.0, 146.3, 158.0, 165.1, 169.4 ppm; HRMS
(ESI-MS+): m/z: calcd for C19H20N3O5: 370.1400; found: 370.1402
[M+H]+.
(3’S,5’R,6’R)-N2-(N,N-Dimethylformamidino)-9-{2’-deoxy-5’-O-(4,4’-di-
methoxytrityl)-3’,5’-ethano-5’,6’-methano-a-d-ribofuranosyl}guanine (12):
DMT-OTf (1.2 g, 2.36 mmol) was added to a solution of 8 (460 mg,
1.27 mmol) in anhydrous pyridine (4.4 mL) and ethyldiisopropylamine
(2.2 mL, 13.2 mmol). After 1 h at RT the reaction mixture was diluted
133.7, 144.1, 146.2, 150.4, 158.4, 158.5 ppm; HRMS (ESI-MS+): m/z:
calcd for C41H38N5O6: 696.2787; found: 696.2822 [M+H+].
(3’S,5’R,6’R)-N4-Benzoyl-1-{2’-deoxy-5’-O-(4,4’-dimethoxytrityl)-3’,5’-
ethano-5’,6’-methano-a-d-ribofuranosyl}cytosine (15): DMT-OTf (1.01 g,
2.20 mmol, 2.1 equiv) was added to a solution of compound 11 (392 mg,
1.06 mmol) in pyridine (4.2 mL) and the mixture was stirred for 4 h at
RT.The reaction mixture was then diluted with EtOAc (10 mL) and
washed with sat.NaHCO (10 mL), the organic phase was dried over
3
MgSO4, the solvent was evaporated, and purification by CC (silica gel,
EtOAc/EtOH 9:1
+
1% Et3N) yielded compound 15 (706 mg,
1.05 mmol, 99%) as a yellow foam. Rf = 0.70 (EtOAc/EtOH 9:1 + 1%
Et3N); 1H NMR (300 MHz, CD3OD): d = 0.70 (t, J = 5.7 Hz, 1H; 1H-
C(8’)), 1.28 (t, J = 7.0 Hz, 1H; 1H-C(8’)), 1.63 (d, J = 13.7 Hz, 1H; H-
C(7’)), 1.82 (m, 1H; H-C(6’)), 1.98 (dd, J = 5.0, 14.1 Hz, 1H; H-C(7’)),
2.33 (dd, J = 5.1, 13.7 Hz, 1H; H-C(2’)), 2.75 (s, 1H; H-C4’)), 2.88 (m,
1H; H-C(2’)), 3.84, 3.85 (2s, 6H; 2OMe), 6.11 (t, J = 5.8 Hz, 1H; H-
C(1’)), 6.91 (m, 4H; arom. H), 7.15 (m, 1H; arom. H), 7.16 (m, 4H;
arom. H), 7.41 (m, 4H; arom. H), 7.50 (m, 2H; arom. H), 7.62 (m, 4H;
arom.H), 8.02 ppm (d, J = 7.2 Hz, 2H; arom. H); 13C NMR (75.5 MHz,
with EtOAc (5 mL) and washed with sat.NaHCO (5 mL).The organic
3
phase was then dried over MgSO4 and the solvent was evaporated under
reduced pressure.CC (silica gel, 5% CH 3OH in CH2Cl2) yielded 12
(816 mg, 1.23 mmol, 97%) as a yellow foam. Rf = 0.68 (CH2Cl2/CH3OH
9:1); 1H NMR (300 MHz, CDCl3): d = 0.49 (m, 1H; H-C(8’)), 1.23 (m,
1H; H-C(8’)), 1.83 (d, J = 43.7 Hz, 1H; H-C(7’)), 1.87 (m, 1H; H-C(6’)),
2.29 (dd, J = 4.9, 13.7 Hz, 1H; H-C(7’)), 2.50 (s, 1H; H-C(4’)), 2.59 (dd,
J = 2.3, 14.7 Hz, 1H; H-C(2’)), 2.78 (dd, J = 8.2, 14.6 Hz, 1H; H-C(2’)),
3.09, 3.13 (2s, 6H; NMe2), 3.49, 3.71 (2s, 6H; 2MeO), 5.13 (s, 1H;
OH), 6.10 (dd, J = 2.3, 8.0 Hz, 1H; H-C(1’)), 6.63 (m, 4H; arom. H),
7.14 (m, 3H; arom. H), 7.31 (m, 4H; arom. H), 7.42 (m, 2H; arom. H),
7.71 (s, 1H; H-C(8)), 8.11 ppm (s, 1H; N=CHNMe2); HRMS (ESI-MS+):
m/z: calcd for C37H39N6O6: 663.2853; found: 663.2918 [M+H]+.
CD3OD): d = 7.02, 25.76, 56.06, 68.26, 87.70, 90.14, 114.03, 114.09,
128.81, 129.45, 130.14, 130.25, 130.75, 132.63, 132.80, 138.57, 148.29,
152.28, 160.71, 160.81, 217.98, 234.12 ppm; HRMS (ESI-MS+): m/z: calcd
for C40H38N3O7: 672.2720; found: 672.2709 [M+H]+.
(3’S,5’R,6’R)-N2-(N,N-Dimethylformamidino-9-{3’-O-[2-cyanoethoxy)-
A
ethano-5’,6’-methano-a-d-ribofuranosyl}guanine (16): Tritylated nucleo-
side 12 (389 mg, 0.59 mmol) was dissolved in anhydrous CH3CN (5.4 mL)
and ethyldiisopropylamine (0.4 mL, 2.32 mmol). Chloro-(2-cyanoethyl)-
diisopropylaminophosphine (0.27 mL, 1.29 mmol) was then added and
the solution was stirred for 2 h at RT.The reaction was quenched by the
addition of anhydrous glycerol (0.1 mL, 1.33 mmol), and stirring was con-
tinued for 15 min.The mixture was diluted with EtOAc (10 mL) and
(3’S,5’R,6’R)-1-{2’-Deoxy-5’-O-(4,4’-dimethoxytrityl)-3’,5’-ethano-5’,6’-
methano-a-d-ribofuranosyl}thymine
(13):
DMT-OTf[24]
(760 mg,
washed with a H2O/sat.NaHCO (10:1) solution (10 mL).After drying of
3
1.64 mmol, 2 equiv) was added to a solution of compound 9 (230 mg,
0.82 mmol) in pyridine (3.1 mL). The mixture was protected from light,
stirred for 6 h at RT, and then diluted with CH2Cl2 (20 mL) and washed
with sat.NaHCO .The organic phase was dried over MgSO and the sol-
vent was evaporated.The resulting oil was purified by CC (silica,
EtOAc/hexane 9:1 + 1% Et3N) to yield the tritylated compound 13
the organic phase over MgSO4 and evaporation of the solvent, the resi-
due was subjected to CC (silica gel, 3% CH3OH in CH2Cl2) and phos-
phoramidite 16 (290 mg, 0.34 mmol, 58%) was obtained as a white foam.
Rf = 0.59 (6% CH3OH in CH2Cl2); 1H NMR (300 MHz, CDCl3): d =
0.65, 0.80 (2t, J = 5.6 Hz, 1H; H-C(8’)), 1.10 (m, 12H; (Me3-CH)2N),
1.19 (m, 1H; H-C(8’)), 1.26 (m, 1H; H-C(7’)), 1.87 (m, 1H; H-C(6’)),
2.25 (m, 1H; H-C(7’)), 2.51 (m, 3H; H-C(4’), NC-CH2), 2.61 (m, 1H; H-
C(2’)), 2.73 (m, 1H; H-C(2’)), 3.12, 3.13 (2s, 3H; MeN), 3.21 (s, 3H;
MeN), 3.49 (m, 3H; CH2O, CHMe2), 3.77, 3.79 (2s, 6H; 2MeO), 6.35
(m, 1H; H-C(1’)), 6.71 (m, 4H; arom. H), 7.14 (m, 3H; arom. H), 7.28
(m, 4H; arom. H), 7.42 (m, 2H; arom. H), 8.62, 8.65 (2s, 1H; H-C(8)),
3
4
(436 mg, 0.75 mmol, 91%) as a yellowish foam. Rf
= 0.18 (EtOAc/
1
hexane 9:1 + 1% Et3N); H NMR (300 MHz, CD3OD): d = 0.64 (t, J =
5.6 Hz, 1H; H-C(8’)), 1.21 (m, 1H; H-C(8’)), 1.62 (d, J = 14.0 Hz, 1H;
H-C(7’)), 1.80 (m, 1H; H-C(6’)), 1.94 (d, J = 1.1 Hz, 3H; Me-C(5)), 2.28
(m, 2H; H-C(2’), H-C(7’)), 2.61 (m, 2H; H-C(2’), H-C(4’)), 3.82, 3.83 (2
s, 6H; 2MeO), 6.19 (t, J
=
6.6 Hz, 1H; H-C(1’)), 6.86 (m, 4H;
9.06 ppm (br, 1H; N=CHNMe2); 31P NMR (161.9 MHz, CDCl3): d
=
arom. H), 7.23–7.33, 7.35–7.42 ppm (2m, 7H; arom. H); 13C NMR
(75.5 MHz, CD3OD): d = 56.0, 68.5, 87.6, 90.4, 114.0, 128.7, 130.3, 132.6,
132.7, 137.7, 138.7, 150.4, 178.7 ppm; HRMS (ESI-MS+): m/z: calcd for
C34H34N2O7Na: 605.2261; found: 605.2263 [M+Na]+.
142.13, 144.33 ppm; HRMS (ESI-MS+): m/z: calcd for C46H56N8O7P:
863.4009; found: 863.4005 [M+H]+.
(3’S,5’R,6’S)-1-{3’-O-[(2-Cyanoethoxy)(diisopropylamino)phosphino]-2’-
deoxy-5’-O-(4,4’-dimethoxytrityl)-3’,5’-ethano-5’,6’-methano-a-d-ribofura-
nosyl}thymine (17): Compound 13 (400 mg, 0.69 mmol) and ethyldiiso-
propylamine (0.69 mL, 3.97 mmol) were dissolved in dry CH3CN
(3.5 mL), chloro-(2-cyanoethyl)diisopropylaminophosphine (0.30 mL,
1.84 mmol) was added dropwise, and the clear solution was stirred for 2 h
at RT.The reaction was quenched by the addition of glycerol (05. mL)
and stirring was continued for an additional hour.After dilution with
(3’S,5’R,6’R)-N6-Benzoyl-9-{2’-deoxy-5’-O-(4,4’-dimethoxytrityl)-3’,5’-
ethano-5’,6’-methano-a-d-ribofuranosyl}adenine (14): DMT-OTf (1.0 g,
2.28 mmol, 2 equiv) was carefully added to a solution of 10 (450 mg,
1.14 mmol) in pyridine (4.6 mL) and the mixture was stirred at RT for
3 h.After addition of EtOAc (20 mL) the yellow solution was washed
twice with sat.NaHCO
(30 mL), the organic phase was dried over
3
MgSO4 and evaporated, and the residue was then purified by CC (silica
gel, EtOAc + 5% Et3N).Tritylated compound 14 (730 mg, 1.05 mmol,
92%) was readily obtained as a yellow foam. Rf = 0.19 (EtOAc + 5%
Et3N); 1H NMR (300 MHz, CDCl3): d = 0.57 (t, J = 5.6 Hz, 1H; H-
C(8’)), 1.15 (m, 1H; H-C(8’)), 1.89 (m, 1H; H-C(6’)), 1.97 (d, J = 4.9 Hz,
1H; H-C(7’)), 2.06 (s, 1H; H-C(4’)), 2.31 (dd, J = 5.0, 13.8 Hz, 1H; H-
C(7’)), 2.86 (m, 2H; H2C(2’)), 3.66, 3.67 (2s, 6H; 2MeO), 5.79 (s, 1H;
OH), 6.17 (m, 1H; H-C(1’)), 6.52 (m, 4H; arom. H), 7.01 (m, 1H;
arom. H), 7.09 (m, 2H; arom. H), 7.27 (m, 4H; arom. H), 7.39 (d, J =
7.5 Hz, 2H; arom. H), 7.56 (m, 3H; arom. H), 8.03, 8.68 (2s, 2H; H-
C(2), H-C(8)), 8.09 (d, J = 7.0 Hz, 2H; arom. H), 9.22 ppm (brs, 1H;
C(6)-NH); 13C NMR (75.5 MHz, CDCl3): d = 14.8, 16.4, 24.7, 34.4, 41.6,
55.2, 66.3, 86.8, 87.4, 89.6, 112.3, 112.3, 127.2, 127.9, 128.6, 130.7, 132.9,
EtOAc (30 mL) and washing with sat.NaHCO (30 mL), the organic
phase was dried over MgSO4 and the solvent was evaporated.CC (3 g
silica conditioned with EtOAc + 1% Et3N, elution with EtOAc) afford-
3
ed phosphoramidite 17 (432 mg, 0.55 mmol, 80%) as a white foam. Rf
=
0.39, 0.34 (2 diastereomers, hexane/EtOAc/Et3N 10:20:1); 1H NMR
(300 MHz, CDCl3): d = 0.64, (t, J = 5.6 Hz, 1H; H-C(8’)), 1.11 (m,
12H; 2Me3CH), 1.18 (m, 2H; H-(7’), H-(8’)), 1.81 (m, 1H; H-C(6’)),
1.95 (d, J = 1.0 Hz, 3H; MeC(5)), 2.20 (m, 2H; H-C(6’), H-C(7’)), 2.5–
2.7 (2m, 4H; H2C(2’), H-C(4’), NC-CH2), 3.41 (m, 2H; P-O-CH2-C),
3.5–3.7 (2m, 2H; 2CH(Me)2), 3.79, 3.80 (2s, 6H; 2MeO), 6.18 (m,
1H; H-C(1’)), 6.79 (m, 4H; arom. H), 6.91, 6.94 (2s, 1H; H-C(6)), 7.23
(m, 3H; arom. H), 7.38 (m, 4H; arom. H), 7.49 (m, 2H; arom. H), 8.13
(s, 1H; H-N(3)) ppm; 31P NMR (161.9 MHz, CDCl3):
d
=
142.51,
Chem. Eur. J. 2006, 12, 8014 – 8023
ꢀ 2006 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
8021