Synthesis of Antitumor Aglycon (()-Calicheamicinone
J. Am. Chem. Soc., Vol. 120, No. 40, 1998 10357
0.82-0.72 (6H, m); 13C NMR (75 MHz, C6D6) δ 153.3, 144.8, 124.6,
124.2, 122.1, 103.5, 102.7, 102.5, 99.9, 87.7, 84.9, 78.8, 67.9, 54.2,
51.9, 50.9, 7.4, 7.0; HRMS (CI) calcd for C22H30O5Si (M+) 402.1863,
found 402.1862.
trimethylsilyl cyanide (5 mL) was stirred for 30 min. The solvent was
distilled in vacuo and the residue dissolved in dichloromethane (100
mL). To this solution was added successively Et3N (2.9 mL, 21 mmol),
di-tert-butyl dicarbonate (3.9 mL, 17 mmol), and 4-N,N-(dimethylami-
no)pyridine (1.0 g, 8 mmol), and the mixture was stirred for 30 min,
after which time Et2O (200 mL) was added. The solution was washed
with water (150 mL) and citric acid (2 × 150 mL of a 0.5 M solution),
dried (MgSO4), filtered, and evaporated in vacuo. The residue was
dissolved in MeOH (40 mL), and citric acid monohydrate (880 mg,
4.2 mmol) was added. The mixture was stirred for 2 h, diluted with
Et2O (100 mL), washed with saturated aqueous NaHCO3 (2 × 75 mL),
dried (MgSO4), filtered, and evaporated in vacuo to leave a residue
which was chromatographed over silica gel, eluting with 30% Et2O/
petroleum ether to give 37 (2.35 g, 85%) as a colorless foam: mp
135-137 °C dec (Et2O/petroleum ether); IR (thin film) 3509, 2959,
13,13-Dimethoxy-5-(triethylsilyl)oxy-12r-hydroxy-3-oxobicyclo-
[7.3.1]trideca-6,10-diyne-1,8-diene (32). A solution of 29 (5.4 g, 13
mmol) in 1,4-dioxane (100 mL) and water (10 mL) was treated with
pyridinium p-toluenesulfonate (250 mg, 1 mmol), and the mixture was
heated at 60 °C overnight. After the solution was cooled to ambient
temperature, solid NaHCO3 (500 mg) was added, and the solvent was
evaporated in vacuo. The residue was dissolved in EtOAc (300 mL),
washed with saturated aqueous NaHCO3 (100 mL), water (100 mL),
and brine (100 mL), and dried (MgSO4). Filtration and evaporation
afforded a yellow oil which was purified by filtration through a pad
Florisil, eluting with 5-20% EtOAc/hexanes, to give 32 (5.0 g, 95%)
as a pale yellow oil: IR (thin film) 3499, 2960, 2870, 1677 cm-1; H
1800, 1770, 1698 cm-1; H NMR (300 MHz, C6D6) δ 6.24 (1H, s),
1
1
NMR (300 MHz, acetone-d6) δ 6.08 (1H, s), 6.07 (1H, d, J ) 9.5 Hz),
5.97 (1H, dd, J ) 9.5, 1.5 Hz), 5.38 (1H, m), 4.39 (1H, d, J ) 12.0
Hz), 3.72 (3H, s), 3.39 (3H, s), 3.00 (1H, dd, J ) 17.0, 0.5 Hz), 2.83
(1H, br s), 2.71 (1H, dd, J ) 17.0, 1.0 Hz), 1.08-0.97 (9H, m), 0.82-
0.71 (6H, m); 13C NMR (75 MHz, acetone-d6) δ 195.6, 161.1, 127.6,
124.4, 123.9, 104.2, 102.5, 99.6, 88.6, 86.1, 78.5, 68.0, 52.9, 52.2, 50.0,
7.1, 6.6; HRMS (CI) calcd for C21H29O5Si (M + 1) 389.1784, found
389.1774.
3,13-Dioxo-5-(triethylsilyl)oxy-12r-hydroxybicyclo[7.3.1]trideca-
6,10-diyne-1,8-diene (34). To a solution of 32 (5.0 g, 13 mmol) in
dichloromethane (500 mL) at -20 °C was added cooled (-20 °C) boron
trichloride (80 mL of 1.0 M solution in heptane, 80 mmol), and the
resulting yellow solution was stirred at -20 °C for 3 h. To the mixture
was added Et2O (300 mL), and the mixture was poured into saturated
5.73 (1H, dd, J ) 10.0, 2.0 Hz), 5.31 (2H, m), 4.66 (1H, d, J ) 10.0
Hz), 1.43 (9H, s), 1.37 (9H, s), 1.27 (9H, s), 1.07 (9H, t, J ) 8.0 Hz),
0.84 (6H, m); 13C NMR (75 MHz, C6D6) δ 196.6, 150.6, 148.3, 148.2,
142.3, 136.1, 132.7, 127.9, 126.0, 123.5, 101.3, 94.5, 92.6, 87.8, 84.1,
83.9, 83.3, 75.2, 63.5, 27.4, 26.9, 26.8, 6.9, 6.0; HRMS (CI) calcd for
C34H48NO10Si (M + 1) 658.3048, found 658.3043.
Tris-(tert-Butyloxycarbonyl)-Protected Lactone 38. To a solution
of hexamethyldisilazane (2.72 mL, 13 mmol) in THF (250 mL) at -78
°C was added dropwise n-BuLi (5.4 mL of a 2.40 M solution in
hexanes, 13 mmol), and the solution was stirred at -78 °C for 30 min.
A solution of trimethylphosphonoacetate (2.1 mL, 13 mmol) in THF
(50 mL) was added via cannula and the mixture stirred for 1 h. A
solution of 37 (2.12 g, 3.2 mmol) in THF (100 mL) was added via
cannula, and the mixture was stirred at 0 °C for 30 min, and then at 23
°C for 2 h, and quenched by the addition of saturated aqueous NH4Cl
(100 mL). To the mixture was added Et2O (200 mL) and water (100
mL), and the layers were separated. The aqueous layer was washed
with Et2O (100 mL), and the combined extracts were washed with brine
(100 mL), dried (MgSO4), filtered, and evaporated in vacuo to leave a
residue which was dissolved in Et2O (25 mL) and filtered through a
pad of silica gel, washing with Et2O. Evaporation in vacuo gave 38
(2.14 g, 97%) as a pale yellow foam: IR (thin film) 2979, 1800, 1762,
aqueous NaHCO3 (500 mL) and stirred to ambient temperature.
A
further quantity of Et2O (300 mL) was added, and the organic phase
was separated, washed with saturated aqueous NaHCO3 (300 mL), water
(300 mL), brine (300 mL), and dried (Na2SO4). Filtration and
evaporation in vacuo gave a solid, 33: 1H NMR (300 MHz, C6D6) δ
5.57 (1H, d, J ) 1.0 Hz), 5.21 (2H, s), 5.07 (1H, d, J ) 11.0 Hz), 3.66
(1H, d, J ) 11.0 Hz), 3.51 (3H, s), 3.08 (1H, d, J ) 16.0 Hz), 2.91
(1H, dd, J ) 16.0, 1.0 Hz), 0.92 (9H, t, J ) 7.5 Hz) 0.54 (6H, m) The
solid was dissolved in dichloromethane (200 mL) and treated with basic
alumina (25 g, 10% w/w water). The suspension was stirred at ambient
temperature for 1 h and filtered through a pad of Florisil, washing the
filter cake with Et2O. Evaporation in vacuo gave 34 (4.5 g, 94%) as
a pale yellow solid: mp 101-104 °C dec; IR (thin film) 3508, 2953,
1
1736 cm-1; H NMR (300 MHz, C6D6) δ 6.45 (1H, s), 6.15 (1H, s),
6.00 (1H, d, J ) 2.0 Hz), 5.47 (1H, d, J ) 9.5 Hz), 5.35 (1H, dd, J )
9.5, 2.0 Hz), 1.34 (9H, s), 1.33 (9H, s), 1.27 (9H, s), 0.90 (9H, t, J )
8.0 Hz), 0.67 (6H, m); 13C NMR (75 MHz, C6D6) δ 160.8, 154.4, 150.7,
148.7, 148.4, 144.0, 125.6, 125.0, 123.3, 119.9, 114.9, 98.2, 97.1, 95.2,
90.3, 84.1, 83.8, 83.1, 70.3, 67.9, 27.6, 27.5, 27.4, 7.0, 6.2; HRMS
(CI) calcd for C36H48NO10Si (M + 1) 682.3048, found 682.3060.
Enamine Lactone 50. To a solution of 38 (1.33 g, 1.95 mmol) in
dichloromethane (60 mL) was added trifluoroacetic acid (30 mL), and
the mixture was stirred for 45 min. The solution was diluted with Et2O
(250 mL), and the mixture was cautiously washed with saturated
aqueous NaHCO3 (5 × 100 mL). The combined aqueous layers were
extracted with Et2O (100 mL), and the combined Et2O extracts were
washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL),
dried (MgSO4), filtered, and evaporated in vacuo to give 50 (717 mg,
96%) as yellow crystals: mp 146-150 °C dec (Et2O/petroleum ether);
1
1709, 1674 cm-1; H NMR (300 MHz, C6D6) δ 5.64 (1H, d, J ) 1.5
Hz), 5.14 (1H, dd, J ) 10.0, 1.5 Hz), 5.09 (1H, d, J ) 10.0 Hz), 4.92
(1H, dd, J ) 11.0, 1.5 Hz), 4.54 (1H, d, J ) 11.0 Hz), 3.06 (1H, dd,
J ) 17.0, 1.5 Hz), 2.47 (1H, d, J ) 17.0 Hz), 1.04 (9H, t, J ) 7.5 Hz),
0.79 (6H, m); 13C NMR (75 MHz, C6D6) δ 194.7, 192.5, 147.7, 132.2,
124.4, 122.6, 100.2, 96.0, 93.0, 89.1, 75.4, 67.7, 50.4, 7.1, 6.4; HRMS
(CI) calcd for C19H23O4Si (M + 1) 343.1367, found 343.1356.
3,13-Dioxo-2-amino-5-(triethylsilyl)oxy-12r-hydroxybicyclo[7.3.1]-
trideca-6,10-diyne-1,8-diene (35). Diphenylsulfilimine monohydrate
(7.8 g, 36 mmol, freshly prepared, see Supporting Information) was
dried in vacuo for 2 h at 70 °C, cooled to ambient temperature under
argon, dissolved in THF (300 mL), and cooled to 0 °C. To this solution
was added a solution of 34 (3.26 g, 9.5 mmol) in THF (150 mL) via
cannula, and the mixture was stirred for 5 h at 23 °C. Petroleum ether
(500 mL) was added and the mixture filtered through a pad of silica
gel, washing with Et2O (500 mL). The filtrate was evaporated in vacuo
and the residue chromatographed over silica gel, eluting with 20-50%
Et2O/petroleum ether to give 35 (2.75 g, 81%) as colorless crystals:
mp 124-125 °C dec; IR (thin film) 3450, 3354, 2956, 2877, 2818,
1
IR (thin film) 3458, 3340, 2956, 2877, 1696, 1622 cm-1; H NMR
(300 MHz, CDCl3) δ 6.13 (1H, s), 5.99 (1H, d, J ) 1.5 Hz), 5.90 (1H,
d, J ) 9.5 Hz), 5.81 (1H, dd, J ) 9.5, 1.5 Hz), 4.67 (2H, br s), 3.14
(1H, d, J ) 16.5 Hz), 2.97 (1H, d, J ) 16.5 Hz), 1.02 (9H, t, J ) 8.0
Hz), 0.79 (6H, m); 13C NMR (75 MHz, C6D6) δ 189.6, 162.7, 154.5,
133.8, 125.1, 123.5, 113.0, 107.5, 99.1, 95.6, 88.8, 86.9, 70.8, 67.3,
49.1, 6.9, 5.8; HRMS (CI) calcd for C21H24NO4Si (M + 1) 382.1474,
found 382.1464.
Enol Carbonate 52. To a solution of 50 (693 mg, 1.8 mmol), Et3N
(2.54 mL, 18 mmol), and 4-N,N-(dimethylamino)pyridine (890 mg, 7.3
mmol) in dichloromethane (150 mL) was added methyl chloroformate
(850 µL, 11 mmol) as a solution in dichloromethane (75 mL) via
cannula, and the reaction was stirred for 1 h. The mixture was diluted
with Et2O (250 mL), and the solution was washed with water (200
mL), citric acid (2 × 150 mL of a 0.5 M aqueous solution), and brine
(100 mL), dried (MgSO4), filtered, and evaporated in vacuo to give 51
(850 mg, 94%) as brown crystals. The crystals were dissolved in
dichloromethane (100 mL), and Et3N (720 µL, 5.1 mmol), di-tert-butyl
1
1697, 1660, 1633 cm-1; H NMR (300 MHz, C6D6) δ 6.11 (1H, d, J
) 10.0 Hz), 5.19 (1H, dd, J ) 8.0, 1.5 Hz), 5.11 (1H, d, J ) 8.0 Hz),
5.02 (1H, dd, J ) 10.0, 1.5 Hz), 3.87 (2H, br s), 3.10 (1H, d, J ) 18.5
Hz), 2.51 (1H, d, J ) 18.5 Hz), 1.10 (9H, t, J ) 8.0 Hz), 0.89 (6H,
m); 13C NMR (75 MHz, CDCl3) δ 193.6, 190.3, 142.1, 124.3, 123.2,
114.3, 99.9, 96.8, 91.1, 85.0, 74.2, 63.1, 48.9, 6.9, 6.0; HRMS (CI)
calcd for C19H24NO4Si (M + 1) 358.1475, found 358.1472.
13-Oxo-2-[bis(tert-butoxycarbonyl)amino]-3-[(tert-butoxycarbo-
nyl)oxy]-5-(triethylsilyl)oxy-12r-hydroxybicyclo[7.3.1]trideca-6,10-
diyne-1,3,8-triene (37). A solution of 35 (1.50 g, 4.2 mmol) in