Total Syntheses of Staurosporine and ent-Staurosporine
J. Am. Chem. Soc., Vol. 118, No. 12, 1996 2839
1-[(Benzyloxy)methyl]-3,4-dihydro-4-([3-[[(benzyloxy)methyl]-
amino]-3-N,4-O-carbonyl-6-O-(4-methoxybenzyl)-2-deoxy-r-D-
allopyranosyl]-1H-indol-3-yl)-3-(1-[2-(trimethylsilyl)ethoxy]-1H-
indol-3-yl)-1H-pyrrole-2,5-dione (48). To an orange, clear degassed
solution of 3.045 g (2.47 mmol) of 47 in 200 mL of PhH was added
6.7 mL (24.7 mmol) of tri-n-butyltin hydride and 0.0406 g (0.247 mmol)
of AIBN. The resulting mixture was heated to reflux for 2 h.
Additional AIBN (0.0203 g) was added every 20 min until the reaction
was complete. The reaction was then cooled and was concentrated in
Vacuo. The residue was purified by flash chromatography (5:4 EtOAc:
hexane) to yield 1.81 g (74%) of 48 as a red solid: mp 58-60 °C
(sublimes); Rf 0.45 (1:1 hexane:EtOAc); [R]20D +12.8° (c 2.31, CH2Cl2);
157.4, 156.6, 130.7, 130.5, 130.4, 129.1, 128.9, 128.8, 128.9, 128.6,
128.4, 128.3, 128.2, 127.8, 123.2, 122.9, 122.8, 122.7, 122.6, 122.5,
122.4, 121.7, 121.2, 120.6, 117.3, 112.5, 112.4, 111.3, 79.2, 74.1, 73.3,
71.8, 70.9, 70.5, 88.0, 62.6, 62.4, 51.7, 30.8; CI HRMS (NH3) m/e
calcd for (M+) C43H38N4O8 738.2690, found 738.2686.
6-[[(Benzyloxy)methyl]-12-(3-[[(benzyloxy)methyl]amino]-3-N,4-
O-carbonyl-2-deoxy-r-D-allopyranosyl]indolo[2,3-a]pyrrolo[3,4-c]-
carbazole-5,7-dione (51). A red solution of 1.1492 g (1.56 mmol) of
50 in 800 mL of PhH was treated with 0.0395 g (0.156 mmol) of iodine.
Air was continuously bubbled through the reaction which was irradiated
with a medium pressure mercury lamp equipped with a Vycor filter
for 8 h. PhH was added to the reaction each hour to keep the solvent
volume constant. The crude products were diluted with EtOAc,
extracted with saturated Na2S2O4, rinsed with brine, dried over Na2SO4,
filtered, and concentrated in Vacuo. Purification by flash chromatog-
raphy (EtOAc f 20:1 EtOAc:MeOH) yielded 0.8366 g (73%) of 51
as a yellow solid: Rf 0.3 (EtOAc); [R]20D +112° (c 0.89, CH2Cl2); IR
(film) 3350, 2915, 1750, 1700, 1565, 1325, 1065, 750 cm-1; 1H NMR
(400 MHz, acetone-d6) 10.57 (s, 1H), 9.26 (d, J ) 7.8 Hz, 1H), 9.13
(d, J ) 8.1 Hz, 1H), 7.75 (m, 2H), 7.58 (m, 2H), 7.27-7.44 (m, 5H),
7.04 (m, 4H), 6.93 (m, 2H), 5.26 (d, J ) 11.0 Hz, 1H), 5.22 (d, J )
11.0 Hz, 1H), 5.01 (m, 1H), 4.86 (dd, J ) 6.6, 2.1 Hz, 1H), 4.61 (m,
5H), 4.35 (m, 4H), 2.55 (m, 1H), 2.42 (m, 1H); 13C NMR (75.4 MHz,
acetone-d6) 169.9, 169.8, 157.1, 141.1, 140.6, 139.2, 138.5, 128.8,
128.6, 128.2, 128.0, 127.9, 126.2, 125.6, 123.0, 122.1, 121.5, 119.5,
112.9, 112.8, 110.9, 78.6, 76.6, 74.0, 72.1, 71.7, 70.8, 67.5, 63.9, 63.7,
52.9, 33.8; FAB HRMS m/e calcd for (M+) C43H36N4O8 736.2533,
found 736.2540.
IR (film) 2940, 1755, 1700, 1610, 1540, 1300, 1240, 1075, 750 cm-1
;
1H NMR (400 MHz, CDCl3) 7.72 (s, 1H), 7.63 (s, 1H), 7.05-7.45
(m, 17H), 6.88 (m, 3H), 6.73 (m, 2H), 6.09 (dd, J ) 10.5, 4.2 Hz,
1H), 5.46 (s, 2H), 5.20 (s, 2H), 4.96 (d, J ) 11.2 Hz, 1H), 4.71 (d, J
) 11.2 Hz, 1H), 4.69 (s, 2H), 4.61 (d, 12.0 Hz, 1H), 4.55 (d, J ) 12.0
Hz, 1H), 4.51 (t, J ) 8.1 Hz, 1H), 4.45 (s, 2H), 4.15 (m, 1H), 3.87 (m,
1H), 3.76 (s, 3H), 3.67 (dd, J ) 10.1, 2.0 Hz, 1H), 3.56 (dd, J ) 10.1,
4.0 Hz, 1H), 3.51 (t, J ) 8.1 Hz, 2H), 2.56 (m, 1H), 2.10 (m, 1H),
0.91 (t, J ) 8.4, 2H), 0.05 (s, 9H); 13C NMR (300 MHz, CDCl3)
171.3, 159.3, 156.5, 137.7, 137.2, 136.3, 135.5, 132.2, 129.3, 129.2,
128.5, 128.4, 129.3, 128.2, 127.9, 127.7, 127.5, 127.4, 127.0, 126.6,
125.9, 122.7, 122.6, 122.3, 122.1, 120.9, 120.5, 113.8, 110.3, 110.0,
107.2, 106.3, 78.2, 75.9, 73.3, 73.1, 71.4, 71.2, 70.9, 69.8, 69.5, 67.1,
66.0, 55.1, 50.6, 29.9, 17.5, -1.5; FAB HRMS m/e calcd for (M+)
C57H60N4O10Si1 988.4078, found 988.4074.
1-[(Benzyloxy)methyl]-3,4-dihydro-4-([3-[[(benzyloxy)methyl]-
amino]-3-N,4-O-carbonyl-2-deoxy-r-D-allopyranosyl]-1H-indol-3-
yl)-3-(1-[2-(trimethylsilyl)ethoxy]-1H-indol-3-yl)-1H-pyrrole-2,5-
dione (49). A red solution of 2.13 g (2.15 mmol) of indole glycoside
48 in 180 mL of CH2Cl2 and 10 mL of H2O at 0 °C was treated with
0.7316 g (3.22 mmol) of DDQ. The reaction was slowly warmed to
ambient temperature and stirred vigorously overnight. The crude
products were diluted with EtOAc, extracted with saturated NaHSO3,
rinsed with brine, dried over Na2SO4, filtered, and concentrated in
Vacuo. Purification by flash chromatography (3:1 EtOAc:hexane) on
silica gel yielded 1.8110 g (97%) of 49 as a red solid: Rf 0.31 (1:2
hexane:EtOAc); [R]20D +18.25° (c 1.09, CH2Cl2); IR (film) 3450, 2950,
6-[(Benzyloxy)methyl]-12-(3-[[(benzyloxy)methyl]amino]-3-N,4-
O-carbonyl-2,6-dideoxy-6-iodo-r-D-allopyranosyl)indolo[2,3-a]-
pyrrolo[3,4-c]carbazole-5,7-dione (52). To a solution of 0.9785 g
(3.73 mmol) of triphenylphosphine and 0.5079 g (7.461 mmol) of
imidazole in 38 mL of CH2Cl2 at 0 °C was added 0.9784 g (7.46 mmol)
of iodine. The reaction turned from clear and colorless to bright yellow
over 30 min. A green solution of 0.9162 g (1.244 mmol) of
indolocarbazole glycoside 51 in 65 mL of CH2Cl2 was added dropwise
via cannula. The reaction was slowly warmed to ambient temperature
and stirred for 6 h. The crude products were diluted with CH2Cl2,
extracted with H2O, rinsed with brine, dried over Na2SO4, filtered, and
concentrated in Vacuo. Flash chromatography (3:1 EtOAc:hexane) on
silica gel yielded 0.9445 g (84%) of 52 as a yellow solid: Rf 0.7
(EtOAc); [R]20D +43.3° (c 0.85, CH2Cl2); IR (film) 3375, 2915, 1755,
1
1760, 1700, 1610, 1545, 1350, 1075, 745 cm-1; H NMR (400 MHz,
CDCl3) 7.75 (s, 1H), 7.52 (s, 1H), 7.05-7.42 (m, 15H), 6.97 (m,
1H), 6.65 (m, 2H), 5.98 (dd, J ) 10.9, 4.8 Hz, 1H), 5.56 (d, J ) 10.6
Hz, 1H), 5.48 (d, J ) 10.6 Hz, 1H), 5.19 (s, 2H), 4.82 (d, J ) 11.2
Hz, 1H), 4.71 (d, J ) 11.2 Hz, 1H), 4.68 (s, 2H), 4.59 (d, J ) 11.9
Hz, 1H), 4.52 (d, J ) 11.9 Hz, 1H), 4.31 (t, J ) 9.1 Hz, 1H), 4.04 (m,
1H), 3.48-3.55 (m, 4H), 3.22 (m, 1H), 2.63 (m, 1H), 1.97 (m, 1H),
0.89 (t, J ) 8.2 Hz, 2H), -0.05 (s, 9H); 13C NMR (75.4 MHz, CDCl3)
171.4, 156.5, 137.6, 137.1, 136.5, 135.1, 132.3, 128.5, 128.4, 128.3,
128.0, 127.8, 127.6, 127.4, 126.8, 125.5, 125.4, 122.9, 122.8, 122.6,
122.3, 121.1, 120.5, 110.4, 109.9, 107.0, 106.4, 78.6, 75.9, 73.2, 71.8,
71.5, 71.0, 69.4, 67.1, 66.3, 61.8, 50.2, 29.8, 17.7, -1.5; HRMS (FAB)
m/e calcd for (M+) C49H52N4O9Si1 868.3503, found 686.3534.
1
1700, 1570, 1325, 1075, 745 cm-1; H NMR (400 MHz, CDCl3)
9.59 (s, 1H), 9.11 (d, J ) 8.1 Hz, 1H), 9.01 (d, J ) 8.1 Hz, 1H),
7.06-7.59 (m, 16H), 6.20 (dd, J ) 11.7, 3.2 Hz, 1H), 5.08 (d, J )
10.9 Hz, 1H), 5.01 (d, J ) 10.9 Hz, 1H), 4.81 (d, J ) 11.5 Hz, 1H),
4.74 (m, 1H), 4.70 (s, 2H), 4.63 (d, J ) 11.5 Hz, 1H), 4.38 (m, 3H),
4.24 (m, 1H), 3.62 (m, 2H), 2.41 (m, 1H), 2.35 (m, 1H); 13C NMR
(75.4 MHz, CDCl3) 168.8, 168.7, 155.6, 140.6, 139.8, 137.7, 137.1,
129.3, 128.3, 128.1, 128.0, 127.9, 127.7, 127.6, 127.4, 127.2, 126.0,
125.1, 122.6, 121.9, 121.3, 120.6, 119.0, 118.7, 118.5, 111.7, 109.2,
76.3, 73.4, 71.5, 71.3, 66.7, 50.5, 32.1, 29.3, 1.4; FAB HRMS m/e
calcd for (M+) C43H35N4O7I1 846.1556, found 846.1600.
1-[(Benzyloxy)methyl]-3,4-dihydro-4-([3-[[(benzyloxy)methyl]-
amino]-3-N,4-O-carbonyl-2-deoxy-r-D-allopyranosyl]-1H-indol-3-
yl)-3-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (50). A red solution of
1.7674 g (1.786 mmol) of indole glycoside 49 in 125 mL of THF was
treated with 1.77 g of 4 Å molecular sieves and 2.7 mL (2.7 mmol,
1.0 M in THF) of TBAF. The reaction was heated to reflux and every
30 min for 2.5 h 1.4 mL of TBAF was added. The reaction turned
purple and was cooled to ambient temperature. After quenching with
brine the crude products were diluted with EtOAc. The organic layer
was then dried over Na2SO4, filtered, and concentrated in Vacuo to
provide 1.2011 g (91%) of 50 as a red solid: mp 76-78 °C (sublimes);
Rf 0.60 (EtOAc); [R]20D +38.7° (c 0.76, CH2Cl2); IR (film) 3386, 2930,
6-[(Benzyloxy)methyl]-12-(3-[[(benzyloxy)methyl]amino]-3-N,4-
O-carbonyl-2,6-dideoxy-5,6-anhydro-r-D-allopyranosyl)indolo[2,3-
a]pyrrolo[3,4-c]carbazole-5,7-dione (53a). To a green solution of
1.092 g (1.29 mmol) of indolocarbazole glycoside 52 in 100 mL of
THF at 0 °C was added 0.58 mL (3.869 mmol) of DBU. The reaction
turned from green to red and after 10 min was diluted with EtOAc and
extracted with H2O (2×). The organic layer was rinsed with brine,
dried over Na2SO4, filtered, and concentrated in Vacuo. Purification
by flash chromatography (3:1 EtOAc:hexane) provided 0.8250 g (89%)
of 53a as a yellow solid: mp 98-99 °C (sublimes); Rf 0.40 (3:1 Et2O:
EtOAc); [R]20 +2.74° (c 0.84, CH2Cl2); IR (film) 3400, 2910, 1750,
D
1
1
1760, 1705, 1610, 1530, 1420, 1350, 1075, 750 cm-1; H NMR (400
1700, 1570, 1325, 1065, 745 cm-1; H NMR (400 MHz, CDCl3)
MHz, acetone-d6) 10.92 (s, 1H), 7.93 (s, 2H), 7.55 (d, J ) 10.1 Hz,
1H), 7.15-7.43 (m, 10H), 7.07-7.12 (m, 2H), 6.92-7.02 (m, 1H),
6.83 (m, 1H), 6.74 (m, 1H), 6.64 (m, 2H), 6.32 (dd, J ) 11.3, 4.1 Hz,
1H), 5.18 (s, 2H), 4.90 (d, J ) 11.0 Hz, 1H), 4.81 (d, J ) 11.0 Hz,
1H), 4.69 (s, 2H), 4.68 (m, 1H), 4.60 (d, J ) 12.1 Hz, 1H), 4.56 (d, J
) 12.1 Hz, 1H), 4.43 (m, 1H), 4.01 (m, 1H), 3.74 (m, 1H), 3.64 (m,
1H), 2.71 (m, 1H), 2.53 (m, 1H); 13C NMR (75.4 MHz, acetone-d6)
9.50 (s, 1H, N12H), 9.22 (d, J ) 8.0 Hz, 1H, H8), 9.07 (d, J ) 8.0 Hz,
1H, H4), 7.58 (d, J ) 8.1 Hz, 1H, H11), 7.51 (m, 2H, ArH), 7.21-
7.42 (m, 8H, ArH), 7.12 (m, 3H, ArH), 7.01 (m, 2H, ArH), 6.17 (dd,
J ) 11.8, 2.5 Hz, 1H, H1), 5.46 (d, J ) 2.0 Hz, 1H, H6), 5.27 (d, J )
2.0 Hz, 1H, H6′), 5.19 (d, J ) 10.9 Hz, 1H, CH2OBn), 5.13 (d, J )
10.9 Hz, 1H, CH2OBn), 4.82 (d, J ) 11.4 Hz, 1H, CH2OBn), 4.78 (d,
J ) 6.8 Hz, 1H, H4), 4.72 (s, 2H, CH2Ph), 4.62 (d, J ) 11.4 Hz, 1H,