ConVergent Synthesis of (+)-Dynemicin A and Analogs
J. Am. Chem. Soc., Vol. 119, No. 26, 1997 6091
6.76 (dd, 1H, J ) 8.6, 2.3 Hz), 5.87 (m, 1H), 5.83 (br s, 1H), 5.70 (dd,
1H, J ) 1.11, 1.6 Hz), 5.66 (br d, 1H, J ) 11.3 Hz), 5.19 (m, 2H),
4.67 (m, 1H), 4.64 (d, 1H, J ) 10.9 Hz), 4.50 (br dd, 1H, J ) 13.0,
4.1 Hz), 3.41 (s, 3H), 3.27 (s, 3H), 3.16 (d, 1H, J ) 1.7 Hz), 2.94 (br
d, 1H, J ) 10.5 Hz), 2.34 (m, 1H), 1.95 (dd, 1H, J ) 14.5, 4.3 Hz),
1.57 (dd, 1H, J ) 14.4, 11.3 Hz), 1.46 (d, 3H, J ) 7.6 Hz), 0.98 (s,
9H), 0.23 (s, 3H), 0.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.0,
153.0, 132.2, 129.7, 128.6, 128.2, 120.3, 119.7, 119.3 (2C), 117.4, 98.4,
92.6, 84.8, 81.9, 80.4, 76.0, 70.1, 66.8, 62.9, 50.7, 48.4, 46.1, 36.8,
30.3, 25.7, 18.2, 17.3, -4.4; FTIR (neat), cm-1 3552 (sh, w, OH), 3474
(br, m, OH), 3298 (m, CtCH), 2252 (w, CtC), 2090 (w, CtC), 1711
(vs, CdO); [R]22D (CHCl3), +230.2, c ) 0.41; HRMS (FAB) m/z calcd
for C32H41NO7Si (M)+ 579.2652, found 579.2633. Anal. Calcd for
C32H41NO7Si: C, 66.29; H, 7.13; N, 2.42. Found: C, 65.99; H, 7.09;
N, 2.31.
Anal. Calcd for C32H39NO7Si: C, 66.53; H, 6.80; N, 2.42. Found:
C, 66.60; H, 6.89; N, 2.14.
Hydroxy Ketone 68. A solution of the cyclization product 67 (5.43
g, 9.40 mmol, 1 equiv) in acetone (300 mL) was stirred with
p-toluenesulfonic acid monohydrate (7.15 g, 37.6 mmol, 4.00 equiv)
at 23 °C for 2 h. The reaction solution was partitioned between
saturated aqueous sodium bicarbonate solution (300 mL) and ethyl
acetate (300 mL). The aqueous layer was separated and extracted
further with ethyl acetate (2 × 300 mL). The combined organic layers
were dried over sodium sulfate and were concentrated. The residue
was purified by flash column chromatography (25% ethyl acetate in
hexanes) to afford the hydroxy ketone 68 as a pale yellow foam (4.03
1
g, 81%): Rf 0.52, 40% ethyl acetate-hexanes; H NMR (300 MHz,
CDCl3) δ 8.01 (d, 1H, J ) 2.7 Hz), 7.19 (br d, 1H, J ) 8.7 Hz), 6.80
(dd, 1H, J ) 8.7, 2.7 Hz), 5.95 (m, 1H), 5.87 (d, 1H, J ) 9.8 Hz), 5.79
(dd, 1H, J ) 10.3, 1.5 Hz), 5.78 (br s, 1H), 5.21 (m, 2H), 4.69 (s, 1H),
4.65 (m, 1H), 4.58 (br m, 1H), 3.00 (m, 1H), 2.90 (m, 2H), 1.54 (d,
3H, J ) 7.1 Hz), 0.97 (s, 9H), 0.21 (s, 3H), 0.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.7, 154.7, 152.7, 131.9, 130.1, 127.5, 127.1,
123.9, 123.4, 121.9, 120.0, 117.6, 97.9, 95.7, 94.3, 91.0, 74.5, 74.3,
70.8, 66.8, 48.3, 41.0, 33.8, 25.7, 19.8, 18.2, -4.5, -4.6; FTIR (neat),
cm-1 3420 (br, m, OH), 2280 (w, CtC), 2187 (w, CtC), 1714 (vs,
CdO); [R]22D (CHCl3), +904.6, c ) 0.35; HRMS (FAB) m/z calcd for
C30H33NO6Si (M)+ 531.2077, found 531.2106. Anal. Calcd for
C30H33NO6Si: C, 67.77; H, 6.26; N, 2.63. Found: C, 68.11; H, 6.36;
N, 2.33.
Ketone 66. Dimethyl sulfoxide (4.22 mL, 59.5 mmol, 15.0 equiv)
was added to a solution of oxalyl chloride (3.46 mL, 39.7 mmol, 10.0
equiv) in dichloromethane (75 mL) at -78 °C. After the resulting
solution was stirred at -78 °C for 20 min, a solution of the
tert-butyldimethylsilyl phenyl ether 65 (2.30 g, 3.97 mmol, 1 equiv)
in dichloromethane (75 mL) was added over 10 min via cannula. The
reaction mixture was warmed to -40 °C and was held at that
temperature for 10 h. The reaction mixture was then cooled to -78
°C, triethylamine (16.6 mL, 119 mmol, 30.0 equiv) was added, and
the resulting solution was stirred in an ice bath for 30 min. The product
solution was poured into aqueous phosphate buffer solution (pH 7, 0.05
M in sodium hydrogen phosphate and 0.05 M in potassium dihydrogen
phosphate, 150 mL). The aqueous layer was separated and extracted
further with dichloromethane (2 × 150 mL). The combined organic
layers were dried over sodium sulfate and were concentrated. The
residue was purified by flash column chromatography (2% ethyl acetate
in dichloromethane initially, grading to 5% ethyl acetate in dichlo-
romethane) to afford the ketone 66 as a light brown foam (2.10 g, 92%).
Due to its instability to storage, product 66 was typically carried directly
on to the next step in the sequence: Rf 0.51, 5% ethyl acetate-
dichloromethane; 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H, J ) 2.6
Hz), 7.17 (br d, 1H, J ) 8.3 Hz), 6.80 (dd, 1H, J ) 8.6, 2.5 Hz), 5.86
(m, 1H), 5.82 (br s, 1H), 5.68 (br s, 2H), 5.20 (m, 2H), 4.67 (br dd,
1H, J ) 13.0, 4.7 Hz), 4.52 (br d, 1H, J ) 13.4 Hz), 3.29 (s, 3H), 3.28
(s, 3H), 3.14 (d, 1H, J ) 1.0 Hz), 2.77 (m, 1H), 2.19 (dd, 1H, J )
14.0, 6.1 Hz), 1.98 (dd, 1H, J ) 14.0, 3.2 Hz), 1.51 (d, 3H, J ) 7.5
Hz), 0.96 (s, 9H), 0.22 (s, 3H), 0.22 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 195.5, 154.9, 152.9, 132.0, 129.9, 128.6, 123.8, 120.3 (2C),
120.1, 119.8, 117.6, 97.8, 91.6, 85.0, 82.7, 80.1, 77.3, 66.9, 58.4, 49.7
(2C), 47.2, 35.6, 30.6, 25.6, 19.2, 18.1, -4.5; FTIR (neat), cm-1 3297
(m, CtCH), 2094 (w, CtC), 1713 (vs, CdO).
Thionocarbonate 69. (Thiocarbonyl)diimidazole (4.19 g, 23.5
mmol, 5.00 equiv) and 4-(dimethylamino)pyridine (862 mg, 7.05 mmol,
3.00 equiv) were added sequentially to a solution of the hydroxy ketone
68 (1.25 g, 2.35 mmol, 1 equiv) in dichloromethane (100 mL) at 23
°C. The reaction mixture was heated at a gentle reflux for 7 h. A
second portion of (thiocarbonyl)diimidazole (838 mg, 4.70 mmol, 2.00
equiv) and 4-(dimethylamino)pyridine (287 mg, 2.35 mmol, 1 equiv)
was added, and the reaction mixture was heated at a gentle reflux for
an additional 14 h. The reaction mixture was then cooled to 23 °C,
and volatiles were removed in vacuo. The residue was purified by
flash column chromatography (30% hexanes in dichloromethane) to
afford the thionocarbonate 69 as an off-white foam (1.15 g, 85%): Rf
1
0.44, dichloromethane; H NMR (300 MHz, CDCl3) δ 7.54 (d, 1H, J
) 2.7 Hz), 7.23 (br s, 1H), 6.86 (dd, 1H, J ) 8.8, 2.7 Hz), 5.95 (m,
1H), 5.83 (d, 1H, J ) 10.0 Hz), 5.78 (br s, 1H), 5.77 (dd, 1H, J )
10.3, 1.3 Hz), 5.57 (d, 1H, J ) 6.7 Hz), 5.21 (m, 2H), 4.70 (br dd, 1H,
J ) 14.4, 7.2 Hz), 4.62 (br d, 1H, J ) 15.2 Hz), 3.44 (quin, 1H, J )
7.3 Hz), 1.44 (d, 3H, J ) 7.5 Hz), 0.99 (s, 9H), 0.26 (s, 3H), 0.25 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 184.3, 154.8, 153.2, 142.9, 131.8,
129.3, 127.8, 125.8, 125.0, 122.6, 120.8, 120.2, 117.8, 105.9, 95.4,
94.8, 94.6, 90.5, 81.6, 71.5, 67.1, 65.7, 47.6, 34.6, 25.7, 18.3, 17.6,
-4.4, -4.5; FTIR (neat), cm-1 2280 (w, CtC), 2195 (w, CtC), 1724
Cyclization Product 67. A suspension of anhydrous cerium(III)
chloride (1.70 g, 6.90 mmol, 4.93 equiv) and the ketone 66 (810 mg,
1.40 mmol, 1 equiv) in tetrahydrofuran (30 mL) was stirred at 23 °C
for 30 min. The suspension was then cooled to -78 °C, and a solution
of potassium N,N-bis(trimethylsilyl)amide in toluene (0.5 M, 4.50 mL,
2.25 mmol, 1.61 equiv) was added dropwise over 5 min causing the
yellow suspension to turn initially light brown, darkening to a deep
gray-brown. The reaction flask was transferred to an ice bath, and
saturated aqueous ammonium chloride solution (150 mL) was added
carefully. The biphasic mixture was extracted with ethyl acetate (3 ×
150 mL). The combined organic layers were dried over sodium sulfate
and were concentrated. The residue was purified by flash column
chromatography (25% ethyl acetate in hexanes) to afford the cyclization
product 67 as a pale yellow foam (761 mg, 94%): Rf 0.14, 20% ethyl
acetate-hexanes; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 1H, J ) 2.7
Hz), 7.11 (br s, 1H), 6.73 (dd, 1H, J ) 8.6, 2.7 Hz), 5.85 (m, 1H),
5.78 (d, 1H, J ) 10.0 Hz), 5.70 (br s, 1H), 5.65 (dd, 1H, J ) 9.9, 1.6
Hz), 5.20 (m, 2H), 4.68 (br dd, 1H, J ) 13.2, 5.2 Hz), 4.58 (br m,
1H), 3.51 (s, 3H), 3.49 (s, 1H), 3.36 (s, 3H), 2.50 (m, 1H), 2.07 (m,
2H), 1.40 (d, 3H, J ) 7.3 Hz), 0.96 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 154.7, 152.1, 132.1, 130.2, 129.5, 126.9,
123.9, 122.5 (2C), 119.2, 117.5, 100.5, 100.3, 94.8, 93.5, 89.7, 77.6,
73.6, 67.1, 66.8, 51.6, 50.0, 47.0, 36.8, 30.6, 25.8, 18.2, 17.4, -4.4,
-4.5; FTIR (neat), cm-1 3465 (br, m, OH), 2280 (w, CtC), 2192 (w,
(sh, s, CdS), 1714 (vs, CdO); [R]22 (CHCl3), +750.7, c ) 0.43;
D
HRMS (FAB) m/z calcd for C31H31NO6SiS (M)+ 573.1641, found
573.1660. Anal. Calcd for C31H31NO6SSi: C, 64.90; H, 5.45; N, 2.44.
Found: C, 64.57; H, 5.66; N, 2.37.
Ketone 70. Tributyltin hydride (722 µL, 2.68 mmol, 1.40 equiv)
and azobis(isobutyronitrile) (75.0 mg, 457 µmol, 0.238 equiv) were
added sequentially to a solution of the thionocarbonate 69 (1.10 g, 1.92
mmol, 1 equiv) in toluene (75 mL). The resulting pale yellow solution
was deoxygenated by three consecutive freeze-pump-thaw cycles;
then the reaction vessel was placed in an oil bath preheated to 70 °C.
The reaction mixture was heated at 70 °C for 30 min and then was
allowed to cool to 23 °C. Volatiles were removed in vacuo. The
residue was purified by flash column chromatography (dichloromethane
initially, then 1% ethyl acetate in dichloromethane) to furnish the ketone
70 as an off-white foam (957 mg, 97%): Rf 0.21, dichloromethane;
1H NMR (300 MHz, CDCl3) δ 7.22 (br s, 1H), 6.89 (d, 1H, J ) 2.6
Hz), 6.81 (dd, 1H, J ) 8.7, 2.6 Hz), 5.90 (m, 1H), 5.77 (dd, 1H, J )
9.7, 1.5 Hz), 5.70 (dd, 1H, J ) 9.5, 0.4 Hz), 5.70 (br s, 1H), 5.22 (m,
2H), 4.75 (br dd, 1H, J ) 14.6, 7.2 Hz), 4.60 (br d, 1H, J ) 15.2 Hz),
4.21 (d, 1H, J ) 0.9 Hz), 3.07 (m, 1H), 2.85 (dd, 1H, J ) 16.8, 8.1
Hz), 2.50 (dd, 1H, J ) 17.2, 3.4 Hz), 1.51 (d, 3H, J ) 7.5 Hz), 0.96
(s, 9H), 0.18 (s, 3H), 0.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
200.5, 154.6, 152.9, 131.9, 139.7, 128.5, 127.7, 124.0, 123.6, 120.2,
117.9, 117.7, 96.2, 95.1, 91.3, 91.2, 72.1, 67.0, 63.8, 47.9, 43.5, 42.9,
CtC), 1705 (vs, CdO); [R]22 (CHCl3), +579.8, c ) 0.48; HRMS
D
(FAB) m/z calcd for C32H39NO7Si (M)+ 577.2496, found 577.2527.