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Helvetica Chimica Acta Vol. 85(2002)
(7.1 mmol) of DMT chloride in 45ml of dry pyridine was added slowly over 4 h at r.t. The mixture was stirred
overnight, then 250 ml of AcOEt was added, and the mixture was washed 3 Â with sat. aq. NaHCO3 soln., dried
(Na2SO4), and evaporated under reduced pressure. The resulting residue was purified by CC (silica gel; AcOEt,
0.5% 4-methylmorpholine). The fractions were combined, evaporated, and dried under high vacuum to furnish
2.1 g (43%) of 4. White foam. TLC (AcOEt): Rf 0.32. 1H-NMR (300 MHz, CDCl3): 1.67 (t, J 5.1, 2 H); 1.98 (t,
J 5.8, 2 H); 3.34 (t, J 5.3, 2 H), 3.67 (s, 6H); 3.72 (m, 4 H); 3.80 (t, J 5.3, 2 H); 6.74 (m, 4 H) 7.2 8.9 (m,
15H); 8.92 ( s, 1 H); 9.02 (s, 1 H). 13C-NMR (75MHz, CDCl 3): 29.2; 32.0, 37.9; 55.2; 60.4; 62.6; 86.7; 113.3;
121.6; 122.3; 124.6; 125.6; 126.9; 128.0; 128.2; 128.7; 128.9; 129.6; 129.8; 130.1; 132.6; 133.7; 133.8; 136.2; 144.8;
158.6; 168.0; 168.6. ESI-MS (pos.): 683 (20, [M H] ) , 303 (100, DMT).
N-{3-[Bis(4-methoxyphenyl)(phenyl)methoxy]propyl}-N'-(3-{[bis(1-methylethyl)amino](2-cyanoethyl)-
phosphinoxy}propyl)phenanthrene-3,6-carboxamide (5). A suspension of 345mg (2.01 mmol) of diisopropyl-
ammonium tetrazolide and 661 ml (1.84 mmol) (cyanoethoxy)bis(dimethylamino)phosphine in 5ml of dry
CH2Cl2, was placed under N2; then a soln. of 1 g (1.46 mmol) 4 in 10 ml of dry CH2Cl2 was added slowly at r.t.
After 45min, 100 ml CH 2Cl2 was added to the mixture, the mixture was washed with 100 ml of sat. aq. NaHCO3
soln., dried (K2CO3), and evaporated under reduced pressure. The resulting oil was purified by CC (silica gel;
AcOEt/hexane 1:1, 1% 4-methylmorpholine). The fractions were combined, evaporated, and dried under high
1
vacuum to furnish 980 mg (76%) of 5. White foam. TLC (AcOEt/hexane 1:1): Rf 0.21. H-NMR (300 MHz,
CDCl3): 1.08 (m, 12 H); 1.92 (m, 4 H); 2.53 (m, 2 H); 3.26 (m, 2 H); 3.50 (m, 2 H); 3.62 (m, 10 H); 3.72 (m,
2 H); 3.79 (m, 2 H); 6.90 (m, 4 H); 6.89 (m, 2 H); 7.1 7.4 (m, 7 H); 7.6 8.0 (m, 6 H); 9.06 (s, 1 H); 9.11 (s, 1 H).
13C-NMR (75MHz, CDCl 3): 20.7; 24.7; 24.8; 29.4; 30.7; 38.3; 39.2; 43.1; 43.3; 55.2; 55.6; 58.3; 58.6; 62.3; 62.6;
113.3; 122.2; 122.6; 124.9; 125.3; 126.9; 128.0; 128.17; 128.3; 129.0; 130.1; 133.3; 134.0; 136.2; 158.6; 167.7. 31P-
NMR (161.9 MHz, CDCl3): 149.3.
Experiments Referring to Scheme 2. N,N'-Bis(3-hydroxypropyl)propanediamide (6). A soln. of 1.73 ml
(15.1 mmol) of dimethyl malonate in 6.8 ml of 3-aminopropan-1-ol was heated under reflux (1608) for 1 h; then,
1
the solvent was removed by vacuum destillation, the white solid residue was pure 6 (3.3 g, quant.). H-NMR
(300 MHz, CDCl3): 1.73 (m, 4 H); 3.20 (s, 2 H); 3.46 (m, 4 H); 3.67 (t, J 5.6, 4 H) 13C-NMR (75MHz,
(D6)DMSO): 32.3; 35.9; 43.4; 58.4; 166.9. LSI-MS (DTT/DTE): 219 ([M H] ).
N-{3-[Bis(4-methoxyphenyl)(phenyl)methoxy]propyl}-N'-(3-hydroxypropyl)propanediamide (7). A soln.
of 2.0 g (9.7 mmol) of 6 in 70 ml of dry pyridine was placed under N2. A soln. of 3.3 g (7.1 mmol) of DMT
chloride in 45ml of dry pyridine was added slowly over 1 h at r.t. The mixture was stirred overnight, then 250 ml
of AcOEt was added, and the mixture was washed 3 Â with sat. aq. NaHCO3 soln., then dried (Na2SO4), and
evaporated under reduced pressure. The resulting residue was purified by CC (silica gel; AcOEt/MeOH 9 :1,
0.5% 4-methylmorpholine). The fractions were combined, evaporated, and dried under high vacuum to furnish
1.71 g (35%) of 7. Colorless oil. TLC (AcOEt/MeOH 9 :1): Rf 0.24. 1H-NMR (300 MHz, CDCl3): 1.69 (m, 2 H);
1.80 (m, 2 H); 3.05( s, 2 H); 3.21 (t, J 5.6, 2 H); 3.41 (m, 4 H); 3.61 (t, J 5.6, 2 H); 3.80 (s, 6 H); 6.84 (m, 4 H);
7.2 7.4 ( m, 9 H). 13C-NMR (75MHz, CDCl 3): 29.3; 32.1; 36.3; 38.0; 42.8; 46.5; 55.3; 59.4; 61.5; 86.3; 113.3;
.
126.9; 127.9; 128.1; 130.0; 136.2; 145.0; 158.6; 167.5; 168.0. EI-MS: 520 (2, M ), 303 (100, DMT).
N-(3-{[Bis(1-methylethyl)amino](2-cyanoethoxy)phosphino}propyl)-N'-{3-[bis(4-methoxyphenyl)(phen-
yl)methoxy]propyl}phenanthrene-3,6-dicarboxamide (8). A suspension of 461 mg (2.69 mmol) of diisopropyl-
ammonium tetrazolide and 880 ml (2.46 mmol) of (cyanoethoxy)bis(dimethylamino)phosphine in 8 ml of dry
CH2Cl2 was placed under N2; then, a soln. of 1 g (1.97 mmol) of 7 in 13.3 ml of dry CH2Cl2 was added slowly at
r.t. After 3 h, 100 ml of CH2Cl2 was added to the mixture, which was washed with 100 ml of sat. aq. NaHCO3
soln., dried (K2CO3), and evaporated under reduced pressure. The resulting oil was purified by CC (silica gel;
AcOEt/hexane 2 :1, 1% 4-methylmorpholine). The fractions were combined, evaporated, and dried under high
1
vacuum to furnish 959 mg (69%) of 8. Colorless oil. TLC (AcOEt/hexane 2 :1): Rf 0.25. H-NMR (300 MHz,
CDCl3): 1.10 (m, 12 H); 1.72 (m, 4 H); 2.57 (t, J 6.4, 2 H); 2.96 (s, 2 H); 3.10 (t, J 5.7, 2 H), 3.3 3.6 (m, 6 H);
3.71 (s, 6 H); 6.76 (m, 4 H); 7.15 7.22 ( m, 9 H). 13C-NMR (75MHz, CDCl 3): 20.5; 24.7; 24.8; 29.3; 30.6; 30.7;
37.0; 37.9; 42.9; 43.0; 43.2; 55.3; 58.2; 58.5; 61.5; 61.7; 86.2; 113.2; 117.9; 126.9; 127.9; 128.1; 130.0; 136.2; 145.0;
158.5; 167.1; 167.4 31P-NMR (161.9 MHz, CDCl3): 149.0.
REFERENCES
[1] S. T. Crooke, Antisense Nucleic Acid Drug Dev. 1998, 8, 115.
[2] A. De Mesmaeker, R. H‰ner, P. Martin, H. E. Moser, Acc. Chem. Res. 1995, 28, 366.
[3] C. Brotschi, A. Haberli, C. J. Leumann, Angew. Chem., Int. Ed. 2001, 40, 3012.