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M. D. Chordia et al. / Bioorg. Med. Chem. 9 (2001) 171±178
0.0048 mmol) in dry THF (1 mL) was added HF-pyri-
dine (70%, 150 mL, excess) and the solution was stirred
at room temperature for 4 h. The reaction mixture was
diluted with EtOAc and washed with saturated Na
HCO3 and dilute HCl (1 N), the organic layers were
combined and washed with water and brine, dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was puri®ed by preparative
TLC (silica gel, 500 mM; EtOAc:hexanes, 7:3) to aord
4-deacetyl-4-(O-benzylglutaryl)-paclitaxel 7b (3.5mg,
71%). 1H NMR (CDCl3, 399.951 MHz) d 8.11 (m, 2H),
7.75 (m, 2H), 7.60±7.27 (m, 16H), 7.09 (d, J=8.4 Hz,
1H), 6.24 (s, 1H), 6.19 (t, J=8.8 Hz, 1H), 5.73 (dd,
J=8.8, 3.2 Hz, 1H), 5.66 (d, J=7.2 Hz, 1H), 5.07 (s,
2H), 4.87 (br d, J=8.0 Hz, 1H), 4.77 (dd, J=6.0, 3.2 Hz,
1H), 4.41 (m, 1H), 4.28 (d, J=8.4 Hz, 1H), 4.18 (d,
J=8.4 Hz, 1H), 3.77 (d, J=6.8 Hz, 1H), 3.65 (d,
J=6.0 Hz, 1H), 2.75±2.50 (m, 3H), 2.46 (d, J=4.0 Hz,
1H), 2.44±1.84 (m, 7H), 2.24 (s, 3H), 1.76 (br s, 3H),
1.68 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H).
(m, 3H), 2.53 (m, 2H), 2.35±2.15 (m, 6H), 2.24 (s, 3H),
1.87 (m, 1H), 1.78 (br s, 3H), 1.66 (s, 3H), 1.26 (s, 3H),
1.12 (s, 3H); 13C NMR (CDCl3, 90.562 MHz) d 203.5,
172.8, 172.7, 171.4, 167.0, 166.4, 142.6, 139.0, 134.0,
133.8, 132.9, 131.7, 130.0, 129.1, 128.7, 128.64, 128.58,
128.0, 127.6, 127.0, 84.4, 81.5, 79.7, 77.2, 76.2, 75.4,
75.1, 73.5, 72.0, 71.1, 58.3, 55.6, 45.7, 43.2, 36.8, 36.3,
35.3, 34.8, 26.7, 22.4, 20.9, 14.7, 9.7. HRFABMS cal-
culated for C48H54N2O14 (M+H)+ 883.3653, found
883.3647, error 0.7 ppm.
20-O-tert-Butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-
4-deacetyl-4-(methoxycarbonyl)-paclitaxel (5c). To
a
solution of 20-O-tert-butyldimethylsilyl-7-O-triethylsilyl-
2-debenzoyl-4-deacetyl-4-(methoxycarbonyl)-paclitaxel
1,2-carbonate (4c, 50 mg, 0.49 mmol) in THF (1 mL)
and water (0.1 mL) was added LiOH (20 mg, 0.64 mmol)
and stirred at room temperature for 1.5 h. The mixture
was taken up in EtOAc (10 mL) and washed with water,
brine and dried over sodium sulfate. The residue
obtained after concentration was puri®ed by PTLC
(silica gel, 1000 mM; EtOAc:hexane, 2:3) to furnish 20-O-
tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-4-
deacetyl-4-(methoxycarbonyl)-paclitaxel (5c, 20mg, 59%
yield based on the recovery of 15mg unreacted starting
compound) and 20-O-tert-butyldimethylsilyl-7-O-triethyl-
silyl-2-debenzoyl-4-deacetyl-paclitaxel (6 mg). Compound
5c: 1H NMR: d, 0.27 (s, 3H), 0.06 (s, 3H), 0.54±0.60
(m, 6H), 0.79 (s, 9H), 0.89±0.96 (m,9H), 1.03 (s, 3H),
1.09 (s, 3H), 1.22±1.27 (m, 1H), 1.85 (s, 3H), 1.86±1.95
(m, 1H), 2.04 (s, 3H), 2.08±2.14 (m, 1H), 2.12 (s, 3H),
2.25±2.29 (m, 1H), 2.45±2.53 (m, 1H), 3.24 (d, J=4.3 Hz,
1H), 3.30 (s, 1H), 3.52 (d, J=6.9Hz, 1H), 3.86 (s, 3H),
3.92±3.95 (m, 1H), 4.37±4.41 (m, 1H), 4.52 (d, J=1.4Hz,
1H), 4.65 (d, J=9.5 Hz, 1H), 4.70 (d, J=9.6 Hz, 1H), 4.98
(d,J=7.8 Hz, 1H), 5.70 (d, J=9.3Hz, m 1H), 6.18 (dd,
J=8.7, 8.2 Hz, 1H), 6.35 (s, 1H), 7.09 (d, J=9.5Hz, 1H),
7.29±7.52 (m, 8H), 7.72 (d, J=7.2 Hz, 2H); 13C NMR d
5.78, 5.25, 5.23, 6.71, 10.32, 14.21, 18.14, 20.81, 21.12,
25.42, 25.48, 26.26, 35.41, 37.24, 42.92, 46.73, 55.41,
55.87, 58.09, 71.46, 72.05, 73.75, 74.96, 75.14, 77.78, 78.03,
83.66, 84.26, 126.22, 126.62, 126.91, 126.99, 127.93, 128.49,
128.59, 128.83, 131.86, 134.17, 143.20, 138.41, 139.72,
152.91, 167.56, 169.24, 171.51, 202.27; HRFABMS: m/z
[M+H]+ 994.4822 (C52 H76NO14Si2 requires 994.4802).
4-Deacetyl-4-glutaryl-paclitaxel (8b). A catalytic amount
of palladium on activated carbon (5%) was added to a
solution of 4-deacetyl-4-(O-benzylglutaryl)-paclitaxel (7b,
3.5 mg, 0.0035 mmol) in EtOAc (1 mL). This suspension
was stirred in an atmosphere of hydrogen gas for 1 h.
TLC analysis indicated complete conversion of the
starting material to a very polar compound. The solid
was removed by ®ltration and the ®ltrate was con-
centrated under reduced pressure to aord 4-deacetyl-4-
glutaryl-paclitaxel (8b, 3.0 mg, 94%). 1H NMR (CDCl3,
399.951 MHz) d 8.10 (d, J=8.0 Hz, 2H), 7.79 (d, J=
7.6 Hz, 2H), 7.62±7.28 (m, 12H), 6.24 (s, 1H), 6.15 (t,
J=8.4 Hz, 1H), 5.70 (dd, J=8.8, 4.8 Hz, 1H), 5.66 (d, J=
7.2 Hz, 1H), 4.88 (br d, J=8.0 Hz, 1H), 4.77 (d, J=4.0 Hz,
1H), 4.41 (m, 1H), 4.28 (d, J=8.8 Hz, 1H), 4.19 (d,
J=8.8 Hz, 1H), 3.75 (d, J=6.8 Hz, 1H), 3.42 (m, 1H),
2.75±2.40 (m, 5H), 2.23 (s, 3H), 2.20±1.89 (m, 5H), 1.75
(br s, 3H), 1.67 (s, 3H), 1.23 (s, 3H), 1.12 (s, 3H); 13C
NMR (CDCl3, 100.578 MHz) d 203.8, 175.5, 173.8,
172.8, 172.3, 171.3, 167.2, 142.5, 137.4, 133.7, 132.9,
132.0, 130.1, 129.3, 128.8, 128.65, 128.61, 128.3, 127.3,
127.1, 84.6, 81.2, 77.8, 76.4, 75.5, 75.0, 73.2, 71.8, 71.7,
58.4, 55.9, 45.5, 43.8, 35.4, 34.6, 32.9, 29.9, 26.8, 22.1, 20.8,
20.7, 14.6, 9.6. HRFABMS calculated for C50H55NO16
(M+Li)+ 932.2931, found 932.2955, error 2.6 ppm.
20-O-tert-Butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-
2-(3-azidobenzoyl)-4-deacetyl-4-(methoxycarbonyl)-pacli-
taxel (6f). Toluene (0.8 mL) was added to a mixture of
20-O-tert-butyldimethylsilyl-7-O-triethylsilyl-2-debenzoyl-
4-deacetyl-4-(methoxycarbonyl)-paclitaxel 5c (10 mg,
0.01mmol), m-azidobenzoic acid (16 mg, 0.09 mmol),
DCC (20 mg), and pyrrolidinopyridine (1.0 mg), and the
reaction mixture was stirred at room temperature for
24 h and then puri®ed by PTLC (silica gel, 1000 mM;
EtOAc:hexane, 2:3) to yield 20-O-tert-butyldimethylsilyl-
7-O-triethylsilyl-2-debenzoyl-2-(3-azidobenzoyl)-4-de-
acetyl-4-(methoxycarbonyl)-paclitaxel (6f, 9.0 mg, 79%).
1H NMR: d 0.30 (s, 3H), 0.03 (s, 3H), 0.54±0.61 (m,
6H), 0.78 (s, 9H), 0.91±0.94 (m,9H), 1.15 (s, 3H), 1.22 (s,
3H), 1.66±1.68 (m, 1H), 1.70 (s, 3H), 1.81 (s, 3H), 1.89±
1.96 (m, 1H), 2.06 (s, 3H), 2.12±2.17 (m, 1H), 2.17 (s,
3H), 2.38±2.44 (m, 1H), 2.52±2.55 (m, 1H), 3.94 (d,
4-Deacetyl-4-ꢀ-alanyl-paclitaxel (8a). A catalytic amount
of palladium on activated carbon (5%) was added to a
solution of 4-deacetyl-4-(N-carbobenzyloxy-b-alanyl)-
paclitaxel (7a, 9.0 mg, 0.0089 mmol) in EtOAc (2 mL).
This suspension was stirred in an atmosphere of hydro-
gen gas for 2 h. TLC analysis indicated complete conver-
sion of the starting material to a very polar compound.
The solid was removed by ®ltration and the ®ltrate was
concentrated under reduced pressure to aord 4-deacetyl-
4-b-alanyl-paclitaxel (8a, 7.5 mg, 94%). 1H NMR
(CDCl3, 399.951 MHz) d 8.04 (m, 2H), 7.82 (m, 2H),
7.62±7.28 (m, 12H), 6.22 (s, 1H), 6.21 (t, J=8.8 Hz, 1H),
5.73 (dd, J=8.8, 4.0 Hz, 1H), 5.67 (d, J=7.2 Hz, 1H),
4.93 (d, J=8.0 Hz, 1H), 4.73 (d, J=4.0 Hz, 1H), 4.41
(m, 1H), 4.29 (d, J=8.4 Hz, 1H), 4.16 (d, J=8.8 Hz,
1H), 3.70 (d, J=7.6 Hz, 1H), 3.19 (m, 1H), 2.92±2.77