7936 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Cook et al.
4.68 (1H, d, J ) 11.6 Hz), 4.23 (1H, d, J ) 9.3Hz), 3.36 (1H, ddd, J
) 9.8, 9.8, 4.6 Hz), 1.96 (1H, m), 1.65-1.52 (3H, m), 1.25 (3H, s),
1.22 (3H, s), 0.17 (9H, s). 13C NMR (125 MHz, CDCl3): δ 128.3
ppm, 127.8, 127.6, 105.0, 77.6, 72.8, 72.3, 65.9, 35.1, 30.6, 26.5, 21.7,
4.3, -0.1. HRMS (FAB): C19H28O2Si (M + Na)+ calcd 339.1756,
found 339.1763.
Transformation of Alcohols 9 and 10 to Hydroxy Ketones 11
and 12. Selective Hydrogenation. To a solution of alkynes, 9 and
10 (384 mg, 0.639 mmol), in EtOAc (10 mL) was added Lindlar catalyst
(3.60 g), and the mixture was vigorously stirred at room temperature
under a H2 atmosphere for 16 h. The catalyst was filtered off through
Celite washing with EtOAc, and the filtrate was concentrated to give
a 1:1 mixture of saturated alcohols as a colorless oil (0.338 g, 87%).
Data for the 1:1 mixture of saturated alcohols. IR: 3555 cm-1(br),
3090, 3064, 3028, 2959, 2928, 2855, 1461, 1380, 1363. 1H NMR (500
MHz, C6D6): δ 7.37 ppm (4H, m), 7.18 (6H, m), 4.48 (2H, d, J )
11.8 Hz), 4.33 (4H, m), 3.66 (4H, m), 3.35 (2H, ddd, J ) 11.5 3.4, 1.2
Hz), 3.21 (1H, m), 3.06 (2H, dddd, J ) 10.1, 10.1, 10.0, 4.6 Hz), 3.00
(1H, br d, J ) 2.9 Hz) 2.76 (1H, m), 2.34 (1H, m), 2.15 (2H, m), 2.03
(3H, m), 1.88 (2H, ddd, J ) 11.6, 11.6, 11.6 Hz), 1.83 (4H, m), 1.72
(2H, m), 1.54-1.44 (8H, m), 1.41 (3H, s), 1.40 (3H, s), 1.38-1.27
(8H, m), 1.26 (3H, s), 1.24 (3H, s), 1.22 (3H, s), 1.21 (3H, s), 1.15
(3H, s), 1.14 (3H, s), 1.12 (3H, s), 1.04 (3H, s), 1.03 (3H, s), 0.94 (9H,
s), 0.93 (9H, s), 0.43 (3H, s), 0.11 (3H, s), 0.10 (3H, s), 0.03 (3H, s).
13C NMR (125 MHz, C6D6): δ 139.7 ppm, 128.5 (×2), 128.3, 128.1,
127.9, 127.5, 116.2, 80.9, 80.8, 79.8, 79.5, 78.6 (×2), 74.3, 74.0, 72.7,
72.6 (×2), 71.2 (×2), 71.1, 70.9, 70.9, 36.0, 35.9, 34.9, 33.0, 31.6 (×2),
31.3, 27.6, 27.5, 26.2, 22.9, 22.0, 21.9, 19.9, 19.7, 18.2, 18.0, -3.0.
HRMS (FAB): C35H60O6Si (M + Na)+ calcd 627.4057, found
627.4073.
TMS Deprotection. To a 0 °C solution of the alkyne (4.25 g, 13.0
mmol) in EtOH/H2O (4:1, 200 mL) was added AgNO3 (5.00 g, 2.00
equiv) in EtOH/H2O (3:1, 50 mL). The mixture was stirred for 25
min, then was treated with NaI (9.00 g, 4.00 equiv) in H2O (50 mL),
stirred for an additional 1 h, and then filtered through Celite with Et2O
(250 mL). The water layer was separated and washed with Et2O (3 ×
100 mL). The combined organic layers were dried over MgSO4 and
concentrated. SGC (5:1 hexanes/EtOAc) yielded the terminal alkyne
(2.60 g, 84%). Data for the terminal alkyne: IR: 3287 cm-1, 3101,
3071, 3041, 2974, 2939, 2871, 1454, 1372, 1352, 1254. 1H NMR (500
MHz, CDCl3): δ 7.37 (2H, d, J ) 7.3 Hz), 7.32 (2H, t, J ) 7.2 Hz),
7.26 (1H, t, J ) 7.2 Hz), 4.75 (1H, d, J ) 11.6 Hz), 4.67 (1H, d, J )
11.6 Hz), 4.21 (1H, dd, J ) 9.4, 1.9 Hz), 3.38 (1H, ddd, J ) 10.6, 9.5,
4.7 Hz), 2.44 (1H, d, J ) 2.2 Hz), 1.98 (1H, m), 1.65-1.50 (3H, m),
1.25 (3H, s), 1.23 (3H, s). 13C NMR (125 MHz, CDCl3): δ 138.4
ppm, 128.3, 127.9, 127.7, 77.4, 72.8, 72.7, 72.2, 65.2, 35.0, 30.6, 26.3,
21.6. HRMS (CI): C16H20O2 (M + NH4)+ calcd 262.1807, found
262.1806.
Swern Oxidation. DMSO (2.38 mL, 60.0 equiv) was slowly added
to a solution of (COCl)2 (1.46 mL, 30.0 equiv) in CH2Cl2 (20 mL) at
-78 °C, and the resultant mixture was stirred for 10 min. A solution
of the alcohols (338 mg, 0.559 mmol) in CH2Cl2 (10 mL) was added
dropwise, and the resultant mixture was stirred at -35 °C for 1 h and
then warmed to -15 °C for 40 min. The reaction mixture was cooled
again to -78 °C, and Et3N (9.34 mL, 120 equiv) was slowly added to
the mixture. After having been stirred at -78 °C for 10 min, the
mixture was warmed up to 0 °C and stirred for additional 10 min. Et2O
(100 mL) and saturated NaHCO3 aqueous (20 mL) were added to the
mixture, and the aqueous layer was extracted with Et2O (3 × 20 mL).
The organic extracts were combined, dried over MgSO4, filtered, and
concentrated. The residue was purified by SGC (95:5 f 90:10 hexanes/
EtOAc) to give a 1:1 mixture of ketones as a colorless oil (408 mg,
100%). Data for a 1:1 mixture of the ketones: IR: 2923 cm-1, 2852,
1721, 1462, 1453, 1379, 1363. 1H NMR (500 MHz, C6D6): δ 7.33
ppm (4H, m), 7.15 (6H, m), 4.44 (2H, m), 4.40 (1H, dd, J ) 9.0, 6.2
Hz), 4.27 (2H, t, J ) 12.5 Hz), 3.59 (2H, m), 3.48 (2H, ddd, J ) 12.2,
4.2, 1.0 Hz), 3.24 (1H, ddd, J ) 17.9, 9.7, 4.8 Hz), 3.07 (2H, m), 2.97
(4H, m), 2.63 (1H, m), 2.49 (1H, m), 2.14 (3H, m), 1.86 (3H, m), 1.79
(1H, dddd, J ) 12.9, 4.3, 4.3, 4.3 Hz), 1.72 (1H, ddd, J ) 13.3, 13.3,
4.3 Hz), 1.61 (2H, br d, J ) 10.4 Hz), 1.49 (3H, s), 1.48 (8H, m), 1.48
(3H, s), 1.36 (3H, s), 1.34 (3H, s), 1.30 (6H, m), 1.17 (3H, s), 1.16
(3H, s), 1.16 (4H, m), 1.14 (6H, s), 1.09 (3H, s), 1.08 (3H, s), 0.94
(9H, s), 0.94 (9H, s), 0.40 (3H, s), 0.10 (3H, s), 0.10 (3H, s), 0.03 (3H,
s), 0.02 (3H, s). 13C NMR (125 MHz, C6D6): δ 128.5 ppm, 128.3,
128.1, 127.9, 127.6, 84.0, 73.5, 73.5, 73.4, 73.1, 72.5, 71.8, 71.5, 70.7,
69.9 (×2), 56.1, 41.8, 36.0, 35.9, 35.7, 35.0, 33.1, 33.1, 32.4, 32.2,
31.5, 31.3, 28.1, 26.1 (×2), 26.0, 22.8, 22.0 (×3), 21.2, 18.5, 18.4,
18.2, -4.5. HRMS (FAB): C35H58O6Si (M + Na)+ calcd 625.3900,
found 625.3901.
Benzyl Deprotection. A suspension of the 1:1 mixture of the
ketones (408 mg crude, 0.559 mmol) and 20% Pd(OH)2 on C (1.40 g)
in EtOAc (6 mL) was stirred under H2 at room temperature for 2 h.
The reaction mixture was filtered through Celite washing with EtOAc
(15 mL), and the filtrate was concentrated to give a 1:1 mixture of
alcohols, 11 and 12, as a colorless oil (290 mg, 100% overall yield for
two steps), which was used for the next step without further purification.
Transformation of Hydroxyl Ketones 11 and 12 to Me-A and
Me-B. Reductive Cyclization.11 To a mixture of ketoalcohols, 11
and 12 (86.1 mg, 0.168 mmol), and Et3SiH (0.540 mL, 20.0 equiv) in
CH3CN (10 mL) at -20 °C was slowly added BF3‚OEt2 (0.100 mL,
5.00 equiv), and the mixture was stirred at -20 °C for 1 h. To the
reaction mixture was added saturated NaHCO3 aqueous (10 mL) at 0
°C, and the mixture was stirred vigorously for 10 min. The resultant
mixture was extracted with Et2O (3 × 5 mL), and the organic extracts
were washed with brine, dried over MgSO4, filtered, and concentrated.
The residue was subjected to SGC (95:5 f 70:30 hexanes/EtOAc) to
Iodoacetylene Formation. To a solution of morpholine (13.0 mL,
10.0 equiv) in benzene (130 mL) was added iodine (4.60 g, 1.20 equiv),
and the mixture was heated at 45 °C for 1.3 h. A solution of the
terminal alkyne (2.60 g, 11.0 mmol) in benzene (60 mL) was added
Via canula, and the reaction was stirred at 45 °C overnight. The reaction
was cooled to room temperature, diluted with Et2O (200 mL), and
filtered through cotton wool. The filtrate was washed with saturated
Na2SO3 aqueous (100 mL), H2O (100 mL), and saturated NH4Cl
aqueous (100 mL) and then dried over Na2SO4. The organic layers
were concentrated and SGC (9:1 hexanes/EtOAc) yielded the io-
doacetylene 8 (2.50 g, 63%). Data for 8: IR: 3087 cm-1, 3062, 3029,
2973, 2938, 2869, 2190, 1496, 1454, 1371. 1H NMR (500 MHz,
CDCl3): δ 7.37-7.25 ppm (5H, m), 4.70 (1H, d, J ) 11.7 Hz), 4.66
(1H, d, J ) 11.7 Hz), 4.34 (1H, d, J ) 9.3 Hz), 3.35 (1H, ddd, J )
9.9, 9.6, 4.6 Hz), 1.99 (1H, m), 1.64-1.48 (3H, m), 1.24 (3H, s), 1.21
(3H, s). 13C NMR (125 MHz, CDCl3): δ 138.3 ppm, 128.4, 128.0,
127.7, 93.5, 77.4, 73.0, 72.1, 66.8, 34.9, 30.5, 26.3, 21.6. HRMS
(FAB): C16H19IO2 (M + Na)+ calcd 393.0328, found 393.0324.
Coupling of Aldehyde 5 with Iodoacetylene 8. NiCl2-CrCl2
Coupling. This coupling was carried out in a drybox. To a mixture
of aldehyde 5 (crude 323 mg, 0.688 mmol) and iodoacetylene 8 (1.27
g, 5.00 equiv) in THF/DMF (7:3, 8.0 mL) was added 0.05% NiCl2-
CrCl2 (750 mg, 8.94 equiv) in one portion, and the mixture was stirred
at room temperature for 24 h. The reaction mixture was taken out
from the drybox, quenched with 1.0 M serin potassium salt aqueous
(20 mL)27 at 0 °C, and diluted with EtOAc (50 mL). After stirring 20
min at room temperature, the aqueous layer was extracted with EtOAc
(3 × 40 mL). Then the aqueous layer was acidified with 2.0 M HCl
aqueous, and the solution was extracted again with EtOAc (40 mL).
The organic extracts were combined, washed with water and brine,
dried over MgSO4, filtered, and concentrated. The residue was purified
by SGC (95:5 f 80:20 hexanes:EtOAc) to give a 1:1 mixture of two
isomers, 9 and 10, as colorless oil (384 mg, 93%). Data for the 1:1
mixture of 9 and 10: IR: 3450 cm-1 (br), 3092, 3060, 2980, 2964,
2924, 2853, 2343, 1467, 1379, 1244. 1H NMR (400 MHz, C6D6): δ
7.48 ppm (4H, br d, J ) 7.3 Hz), 7.26-6.94 (6H, m), 4.85 (2H, d, J
) 11.9 Hz), 4.67 (2H, d, J ) 11.9 Hz), 4.48 (6H, m), 3.64 (2H, ddd,
J ) 12.5, 12.5, 3.4 Hz), 3.43 (2H, m), 2.67 (2H, t, J ) 10.7 Hz), 2.02
(4H, ddd, J ) 11.8, 5.1, 3.4 Hz), 1.92 (4H, ddd, J ) 11.8, 11.8, 11.8
Hz), 1.84 (2H, m), 1.76 (4H, ddd, J ) 13.0, 4.2, 4.2 Hz), 1.52 (3H, s),
1.52 (4H, m), 1.35 (2H, m), 1.25 (3H, s), 1.25 (5H, m), 1.24 (3H, s),
1.20 (3H, s), 1.19 (3H, s), 1.19 (6H, m), 1.17 (3H, s), 0.97 (3H, s),
0.87 (9H, s), 0.86 (9H, s), 0.10 (3H, s), 0.09 (3H, s), 0.02 (3H, s),
-0.02 (3H, s). 13C NMR (125 MHz, C6D6): 128.5 ppm, 128.3, 128.1,
127.9, 127.7, 80.5, 78.1, 78.0, 73.2, 72.6, 72.5, 72.2, 72.0, 71.8, 66.1,
35.6, 35.0, 35.0, 32.6, 31.6, 30.7, 30.6, 25.9, 23.1, 22.1, 22.0, 20.4,
18.0, 17.8. HRMS (FAB): C35H56O6Si (M + Na)+ calcd 623.3744,
found 623.3739.