Chacko et al.
Pd(P(t-Bu)3)2 (1.9 mg, 0.004 mmol) with (5-fluoropentyl)zinc
bromide (268 µL of 0.84 M solution in DMA, 0.23 mmol) afforded
26 mg of 5f, 53% yield: 1H NMR (200 MHz, CD3CN) δ 8.13-7.95
(m, 6H), 7.75-7.50 (m, 9H + 1H,), 6.33 (dd, 1H, J1 ) 3.0 Hz, J2
) 20.8 Hz), 5.70 (dd, 1H, J1 ) 3.0 Hz, J2 ) 18.9 Hz), 5.46 (dd,
1H, J1 ) 2.6 Hz, J2 ) 50.2 Hz), 4.80 (dd, 1H, J1 ) 12.1 Hz, J2 )
31.0 Hz), 4.78 (dd, 1H, J1 ) 12.1 Hz, J2 ) 32.5 Hz), 4.65-4.61
(m, 1H), 4.38 (dt, 2H, J1 ) 6.0 Hz, J2 ) 47.5 Hz), 2.21-2.14 (m,
2H), 1.71-1.28 (m, 6H); 13C NMR (50 MHz, CD3CN) δ 170.4,
166.4, 163.5, 150.1, 138.0, 137.9, 136.5, 134.9, 134.6, 134.2, 132.6,
131.3, 130.8, 130.6, 130.5, 130.1, 129.83, 129.81, 129.6, 115.0,
94.4 (d, J ) 189.8 Hz), 85.6 (d, J ) 16.3 Hz), 85.0 (d, J ) 160.8
Hz), 81.5, 77.8 (d, J ) 30.3 Hz), 64.2, 30.8 (d, J ) 19.3 Hz), 28.9,
27.4, 25.4 (d, J ) 5.6 Hz); HRMS calcd for C35H33F2N2O8 ([M +
H]+) 647.2205, found 647.2202; HPLC A: tR ) 15.2 min.
4.76 (dd, 1H, J1 ) 12.2 Hz, J2 ) 31.4 Hz), 4.58-4.57 (m, 1H),
4.00 (t, 2H, J ) 6.6 Hz), 2.78 (dd, 1H, J1 ) 5.2 Hz, J2 ) 14.1 Hz),
2.48-2.33 (m, 1H), 2.18-2.05 (m, 2H), 2.05 (s, 3H), 1.59-1.21
(m, 6H); 13C NMR (50 MHz, CDCl3) δ 171.3, 169.0, 166.2, 162.4,
149.4, 135.3, 134.4, 134.0, 131.8, 130.6, 130.0, 129.8, 129.6, 129.4,
129.2, 129.1, 128.8, 116.1, 85.6, 83.1, 75.2, 64.5, 38.3, 28.5, 27.2,
25.8, 21.2; HRMS calcd for C37H36N2O10Na ([M + Na]+) 691.2248,
found 691.2268; HPLC A tR ) 11.8 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-(4-ethoxy-4-oxobutyl)-2′-deoxy-
uridine (5k). Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2
(1.9 mg, 0.004 mmol) with (4-ethoxy-4-oxobutyl)zinc bromide (300
µL of 0.75 M solution in DMA, 0.23 mmol) afforded 19 mg of
5k, 39% yield: 1H NMR (200 MHz, CDCl3) δ 8.09-7.91 (m, 6H),
7.65-7.41 (m, 9H + 1H), 6.44 (dd, 1H, J1 ) 5.4 Hz, J2 ) 8.6
Hz), 5.69-5.66 (m, 1H), 4.78 (dd, 1H, J1 ) 12.2 Hz, J2 ) 22.4
Hz), 4.76 (dd, 1H, J1 ) 12.2 Hz, J2 ) 23.2 Hz), 4.57-4.56 (m,
1H), 4.1 (q, 2H, J ) 7.1 Hz), 2.77 (dd, 1H, J1 ) 5.1 Hz, J2 ) 13.8
Hz), 2.42 (ddd, 1H, J1 ) 6.5 Hz, J2 ) 8.3 Hz, J3 ) 14.5 Hz),
2.21-2.14 (m, 2H), 2.17 (t, 2H, J ) 7.2 Hz), 1.77-1.67 (m, 2H),
1.25 (t, 3H, J ) 7.1 Hz); 13C NMR (50 MHz, CDCl3) δ 173.2,
168.9, 166.2, 162.3, 149.4, 135.2, 135.0, 133.9, 131.8, 130.7, 130.0,
129.8, 129.6, 129.4, 129.2, 129.0, 128.8, 128.3, 115.2, 85.7, 83.1,
75.2, 64.5, 38.3, 33.9, 26.8, 23.9, 14.5; HRMS calcd for
C36H34N2O10Na ([M + Na]+) 677.2111, found 677.2093; HRMS
calcd for C36H35N2O10 ([M + H]+) 655.2292, found 655.2272;
HPLC A tR ) 11.4 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-(3-cyanopropyl)-2′-deoxyuri-
dine (5l). Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2 (1.9
mg, 0.004 mmol) with (3-cyanopropyl)zinc bromide (256 µL of
0.88 M solution in DMA, 0.23 mmol) afforded 13 mg of 5l, 29%
yield: 1H NMR (200 MHz, CDCl3) δ 8.11-7.91 (m, 6H),
7.67-7.43 (m, 9H + 1H), 6.43 (dd, 1H, J1 ) 5.4 Hz, J2 ) 8.5
Hz), 5.69-5.66 (m, 1H), 4.80 (dd, 1H, J1 ) 12.2 Hz, J2 ) 27.3
Hz), 4.79 (dd, 1H, J1 ) 12.2 Hz, J2 ) 28.6 Hz), 4.59 (m, 1H),
2.81 (dd, 1H, J1 ) 5.3 Hz, J2 ) 14.2 Hz), 2.47-2.36 (m, 1H),
2.33-2.08 (m, 4H), 1.79-1.69 (m, 2H); 13C NMR (50 MHz,
CDCl3) δ 168.7, 166.2, 162.3, 149.3, 135.8, 135.4, 134.1, 134.0,
131.7, 130.7, 130.0, 129.8, 129.6, 129.5, 129.2, 128.9, 119.4, 113.6,
85.9, 83.4, 75.2, 53.6, 38.5, 26.9, 24.2, 16.9; HRMS calcd for
C34H29N3O8Na ([M + Na]+) 630.1852, found 630.1874; HPLC A
tR ) 8.5 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-butyl-2′-deoxyuridine (5g/5g′).
Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2 (1.9 mg, 0.004
mmol) with butylzinc iodide (281 µL of 0.8 M solution in DMA,
0.23 mmol) afforded 7 mg of 5g, 15% yield. Employing (n-Bu)2Zn
(230 µL of 1 M in heptane, 0.23 mmol) afforded 20 mg of 5i′,
1
44% yield: H NMR of 5g (200 MHz, CDCl3) δ 8.10-7.90 (m,
6H), 7.69-7.43 (m, 9H) 7.34 (s, 1H), 6.47 (dd, 1H, J1 ) 5.5 Hz,
J2 ) 8.7 Hz), 5.70-5.67 (m, 1H), 4.78 (dd, 1H, J1 ) 12.2 Hz, J2
) 28.5 Hz), 4.76 (dd, 1H, J1 ) 12.2 Hz, J2 ) 29.3 Hz), 4.57-4.56
(m, 1H), 2.77 (dd, 1H, J1 ) 5.0 Hz, J2 ) 13.9 Hz), 2.47-2.33 (m,
1H), 2.10-2.05 (m, 2H), 1.29-1.12 (m, 4H), 0.81 (t, 3H, J ) 7.0
Hz); 13C NMR of 5g (50 MHz, CDCl3) δ 169.0, 166.2, 162.4, 149.5,
135.2, 134.1, 134.0, 131.9, 130.6, 130.0, 129.8, 129.5, 129.4, 129.2,
129.0, 128.8, 116.5, 85.5, 83.1, 75.2, 64.6, 38.3, 30.8, 27.0, 22.5,
13.8; HRMS calcd for C34H32N2O8Na ([M + Na]+) 619.2056, found
619.2048; HPLC A tR ) 16.1 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-propyl-2′-deoxyuridine (5h′).
Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2 (1.9 mg, 0.004
mmol) with propylzinc iodide (281 µL of 0.8 M solution in DMA,
0.23 mmol) afforded 8 mg of 5h′, 17% yield: 1H NMR (200 MHz,
CDCl3) δ 8.10-7.90 (m, 6H), 7.69-7.43 (m, 9H) 7.32 (s, 1H),
6.47 (dd, 1H, J1 ) 5.5 Hz, J2 ) 8.7 Hz), 5.71-5.68 (m, 1H), 4.78
(dd, 1H, J1 ) 12.3 Hz, J2 ) 32.6 Hz), 4.76 (dd, 1H, J1 ) 12.3 Hz,
J2 ) 33.4 Hz), 4.57 (m, 1H), 2.77 (dd, 1H, J1 ) 4.7 Hz, J2 ) 14.1
Hz), 2.47-2.32 (m, 1H), 2.11-2.01 (m, 2H), 1.42-1.31 (m, 2H),
0.77 (t, 3H, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 169.0,
166.2, 162.4, 149.5, 135.2, 134.2, 134.0, 131.9, 130.6, 130.0, 129.7,
129.5, 129.4, 129.2, 129.0, 128.8, 116.2, 85.4, 83.0, 75.2, 64.5,
38.3, 29.2, 21.8, 13.8; HRMS calcd for C33H30N2O8Na ([M + Na]+)
605.1900, found 605.1944; HPLC A tR ) 13.5 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-(3-tert-butyldimethylsilyloxy-
propyl)-2′-deoxyuridine (5m). Compound 2a (50 mg, 0.08 mmol)
and Pd(P(t-Bu)3)2 (1.9 mg, 0.004 mmol) with (3-tert-butyldim-
ethylsilyloxypropyl)zinc bromide (321 µL of 0.7 M solution in
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-ethyl-2′-deoxyuridine (5i/5i′).
Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2 (1.9 mg, 0.004
mmol) with ethylzinc iodide (312 µL of 0.72 M solution in DMA,
0.23 mmol) afforded 10 mg of 5i, 23% yield. Employing Et2Zn
(230 µL of 1 M in heptane, 0.23 mmol) afforded 10 mg of 5i′,
1
DMA, 0.23 mmol) afforded 25 mg of 5m, 47% yield: H NMR
(200 MHz, CD3CN) δ 8.09-7.90 (m, 6H), 7.69-7.42 (m, 9H),
7.40 (s, 1H), 6.43 (dd, 1H, J1 ) 5.4 Hz, J2 ) 8.7 Hz), 5.67-5.64
(m, 1H), 4.77 (dd, 1H, J1 ) 12.2 Hz, J2 ) 14.4 Hz), 4.75 (dd,
1H, J1 ) 12.2 Hz, J2 ) 14.6 Hz), 4.59-4.55 (m, 1H), 3.51 (t,
2H, J ) 6.2 Hz), 2.77 (ddd, 1H, J1 ) 1.4 Hz, J2 ) 5.4 Hz, J3
) 14.2 Hz), 2.40 (ddd, 1H, J1 ) 6.6 Hz, J2 ) 8.6 Hz, J3 ) 14.4
Hz), 2.30-2.19 (m, 2H), 1.66-1.52 (m, 2H), 0.88 (s, 9H), 0.03
(s, 6H); 13C NMR (50 MHz, CDCl3) δ 169.0, 166.2, 162.4, 149.4,
135.2, 134.4, 134.0, 133.9, 131.9, 130.7, 130.0, 129.8, 129.6,
129.4, 129.2, 129.0, 128.8, 115.9, 85.8, 83.1, 75.2, 64.5, 62.6,
38.3, 31.5, 26.2, 24.1, 18.5, -5.1; HRMS calcd for
C39H44N2O9SiNa ([M + Na]+) 735.2714, found 735.2688; HRMS
calcd for C39H45N2O9Si ([M + H]+) 713.2894, found 713.2881;
HPLC A tR ) 15.1 min.
Typical Procedure for Deprotection of Tribenzoyl-Protected
Nucleosides. In a vial equipped with a stir bar was added
tribenzoylprotected nucleosides. Dry sodium methoxide solution
(0.5 M in MeOH, 3 mL) was added dropwise. Reaction vial was
sealed and then stirred at 80 °C for 15 min. Reaction judged to be
complete by HPLC (method B, MeOH/H2O (30/70)). After the
mixture was cooled to room temperature, the reaction was quenched
with 1 N HCl (1.5 mL) and the solvent removed in vacuo. The
1
23% yield: H NMR of 5i (200 MHz, CDCl3) δ 8.09-7.91 (m,
6H), 7.69-7.43 (m, 9H), 7.33 (s, 1H), 6.47 (dd, 1H, J1 ) 5.4 Hz,
J2 ) 8.6 Hz), 5.70-5.67 (m, 1H), 4.79 (dd, 1H, J1 ) 12.2 Hz, J2
) 29.2 Hz), 4.77 (dd, 1H, J1 ) 12.2 Hz, J2 ) 29.9 Hz), 4.57-4.56
(m, 1H), 2.77 (dd, 1H, J1 ) 5.1 Hz, J2 ) 13.9 Hz), 2.40 (ddd, 1H,
J1 ) 6.7 Hz, J2 ) 8.3 Hz, J3 ) 14.5 Hz), 2.15 (q, 2H, J ) 7.3 Hz),
0.93 (t, 3H, J ) 7.4 Hz); 13C NMR of 5i (50 MHz, CDCl3) δ 169.0,
166.21, 166.16, 162.4, 149.5, 135.2, 134.0, 133.7, 131.9, 130.7,
130.4, 130.0, 129.8, 129.6, 129.4, 129.2, 129.0, 128.8, 128.7, 117.7,
85.5, 83.1, 75.2, 64.5, 38.3, 20.6, 13.0; HRMS calcd for
C32H28N2O8Na ([M + Na]+) 591.1743, found 591.1739; HPLC A
tR ) 10.7 min.
3-N-Benzoyl-3′,5′-di-O-benzoyl-5-(5-acetoxypentyl)-2′-deoxyuri-
dine (5j). Compound 2a (50 mg, 0.08 mmol) and Pd(P(t-Bu)3)2 (1.9
mg, 0.004 mmol) with (5-acetoxypentyl)zinc bromide (281 µL of
0.8 M solution in DMA, 0.23 mmol) afforded 17 mg of 5j, 33%
yield. 1H NMR (200 MHz, CDCl3) δ 8.41-7.90 (m, 6H), 7.69-7.43
(m, 9H), 7.36 (s, 1H), 6.46 (dd, 1H, J1 ) 5.4 Hz, J2 ) 8.6 Hz),
5.70-5.67 (m, 1H), 4.78 (dd, 1H, J1 ) 12.2 Hz, J2 ) 30.5 Hz),
4880 J. Org. Chem. Vol. 73, No. 13, 2008