Synthesis and Cycloaromatization of a Cyclic Enyne-Allene Prodrug
was stirred for 4 h, a 7:1 mixture of 10% aqueous Na2S2O4
ability of these systems and their derivatives to effect
DNA cleavage in vitro.
and10% aqueous NaHCO3 and additional CH2Cl2 were added.
This biphasic mixture was vigorously stirred until the organic
phase became clear. The mixture was then poured into
saturated aqueous NH4Cl. The aqueous phase was separated
and extracted twice with CH2Cl2. The combined organic phase
was dried over Na2SO4, decanted, and concentrated in vacuo.
The resulting residue was purified by flash chromatography
(10:90 EtOAc/petroleum ether) to afford 18 as a colorless oil
(0.045 g, 86%): 1H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H),
7.38-7.29 (m, 5H), 4.63 (s, 2H), 3.84 (m, 1H), 2.78 (d, J ) 5.4
Hz, 2H), 2.54 (d, J ) 5.9 Hz, 2H), 2.32 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 184.3, 176.7, 137.1, 128.6, 128.2, 127.9, 93.6,
88.3, 83.1, 73.9, 71.9, 32.7, 24.5, 24.3; IR (neat) νmax 2926, 2869,
2279, 2207, 1673, 1420, 1357, 1230, 1139, 1092, 1026, 828
Exp er im en ta l Section
(1-Meth yl-4-oxir an ylbu t-2-yn yloxy)tr iph en ylsilan e (12).
To a solution of 11 (4.00 g, 12.9 mmol) in dry THF (75 mL) at
-78 °C was added BuLi as a 2.71 M solution in hexanes (6.23
mL, 16.9 mmol). After the mixture was stirred for 10 min, BF3‚
OEt2 (2.40 mL, 19.5 mmol) was added. The reaction was stirred
for 15 min before epibromohydrin (1.67 mL, 19.5 mmol) was
added. The reaction was slowly warmed to 25 °C, diluted with
Et2O, and poured into saturated aqueous NH4Cl. The aqueous
phase was separated and extracted twice with Et2O. The
combined organic phase was dried over Na2SO4, decanted, and
concentrated in vacuo. The residue was redissovled in dry THF
(75 mL). To this solution was added sodium hexamethyldis-
ilizane (2.36 g, 12.9 mmol) as a solution in THF (20 mL). The
reaction was diluted with Et2O and poured into saturated
aqueous NH4Cl. The aqueous phase was separated and
extracted twice with Et2O. The combined organic phase was
dried over Na2SO4, decanted, and concentrated in vacuo. The
resulting residue was purified by flash chromatography (20:
80 Et2O/pentane) to afford 12 as a colorless oil (2.10 g 74%
based on recovered 11): 1H NMR (300 MHz, CDCl3) δ 7.79
(m, 2H), 7.74 (m, 2H), 7.74-7.36 (m, 6H), 4.51 (m, 1H), 2.95
(m, 1H), 2.71 (m, 1H), 2.52 (m, 2H), 2.32 (m, 1H), 1.40 (d, J )
6.3 Hz, 3H), 1.09 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 136.0,
135.8, 135.6, 133.9, 133.8, 129.7, 127.8, 127.5, 84.9, 78.4, 78.3,
60.1, 60.0, 49.9, 49.8, 46.5, 46.3, 26.9, 26.7, 25.4, 25.3, 22.6,
22.4, 19.2; IR (neat) νmax 3051, 2932, 2859, 2254, 1473, 1428,
cm-1
.
5-Eth oxyn a p h th a len -2-ol (19). Simultaneously, a solution
of 18 (0.045 g, 0.2 mmol) in 98% EtOH (19 mL) and a separate
solution of LiOH‚H2O (0.014 g, 0.3 mmol) in 98% EtOH (19
mL) were combined by slow dropwise addition via cannula to
a stirring volume of EtOH (10 mL). Upon complete of addition,
glacial acetic acid (0.019 mL, 0.3 mmol) was added to the
reaction vessel. The reaction mixture was concentrated in
vacuo and purified by flash chromatography (15:85 EtOAc/
petroleum ether) to afford 19 as a waxy yellow solid (0.07 g,
22%): 1H NMR (500 MHz, CDCl3) δ 8.2 (d, J ) 8.8 Hz, 1H),
7.32 (dd, J ) 8.3, 7.3 Hz, 1H), 7.24 (d, J ) 8.3 Hz, 1H), 7.10
(d, J ) 2.4 Hz, 1H), 7.05 (dd, J ) 8.8, 2.4 Hz, 1H), 6.66 (d, J
) 7.3 Hz, 1H), 4.87 (s, 1H), 4.19 (q, J ) 6.8 Hz, 2H), 1.53 (t, J
) 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.0, 153.8,
135.9, 126.9, 124.4, 121.0, 118.6, 116.5, 109.3, 102.7, 63.6, 14.9;
IR (neat) νmax 3384, 2980, 2929, 2207, 1629, 1584, 1514, 1439,
1386, 1970, 1218, 1174, 1114, 1095, 1072, 955 cm-1; MS m/z
(CI) 188 (M+) 189.
1161, 1106, 1024, 955, 823 cm-1
.
5-Ben zyloxy-1,9-bis(ter t-bu tyld ip h en ylsila n yloxy)-2,7-
d eca d iyn e (16). To a suspension of NaH, used as a 60%
dispersion in mineral oil (0.126 g, 3.16 mmol), in THF (6 mL)
were added BnBr (0.47 mL, 3.9 mmol) and tetrabutylammo-
nium iodide (0.19 g, 0.53 mmol). Compound 15 (1.73 g, 2.6
mmol) was then added as a solution in THF (2 mL). The
reaction was stirred for 4 h, diluted with Et2O, and poured
into saturated aqueous NH4Cl. The aqueous phase was
separated and extracted twice with Et2O. The combined
organic phase was dried over Na2SO4, decanted, and concen-
trated in vacuo. The resulting residue was purified by flash
chromatography (10:90 Et2O/pentane) to afford 16 as a color-
less oil (1.62 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.78-7.69
(m, 8H), 7.46-7.24 (m, 17H), 4.58 (m, 2H), 4.49 (m, 1H), 4.33
(m, 2H), 3.48 (m, 1H), 2.43 (m, 4H), 1.39 (d, J ) 6.3 Hz, 3H),
1.07 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 138.3, 136.0, 135.9,
135.7, 133.9, 133.3, 129.8, 129.7, 129.6, 128.4, 127.8, 127.7,
127.6, 127.5, 84.5, 81.9, 81.8, 80.3, 75.9, 75.8, 71.6, 71.5, 60.2,
53.0, 26.9, 26.8, 25.5, 24.0, 23.9, 23.8, 19.3; IR (neat) νmax 3071,
2932, 2859, 1958, 1472, 1428, 1363, 1262, 1145, 1109, 1028,
955, 823, 739, 703 cm-1. Anal. Calcd for C49H56Si2O3: C, 78.56;
H, 7.53. Found: C, 78.29; H, 7.39.
5-Ben zyloxyd eca -2,7-d iyn e-1,9-d iol (17). To a solution of
16 (1.62 g, 2.2 mmol) in THF (6 mL) was added tetrabutyl-
ammonium fluoride as a 1.0 M solution in THF (4.30 mL, 4.3
mmol) and the mixture stirred for 2 h. The reaction was diluted
with EtOAc and poured into saturated aqueous NH4Cl. The
aqueous phase was separated and extracted twice with EtOAc.
The combined organic phase was dried over Na2SO4, decanted,
and concentrated in vacuo. The resulting residue was purified
by flash chromatography (50:50 EtOAc/petroleum ether) to
afford 17 as a pale yellow oil (0.532 g, 90%): 1H NMR (300
MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.61 (s, 2H), 4.46 (m, 1H),
4.19 (t, J ) 2.2 Hz, 2H), 3.66 (qt, J ) 5.6 Hz, 1H), 2.61-2.56
(m, 6H), 1.40 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 137.8, 128.5, 127.9, 84.6, 81.9, 80.8, 80.3, 75.5, 71.5, 58.4,
51.1, 24.5, 23.9, 23.8.
2,7-Non a d iyn ed ia l (25). To a solution of 1,6-heptadiyne
24 (1.00 g, 10.9 mmol) in THF (40 mL) at 0 °C was added
n-BuLi as a 2.6 M solution in hexanes (8.80 mL). After 20 min,
DMF (4.21 mL, 54.2 mmol) was added and the reaction stirred
for 12 h. The reaction was diluted with EtOAc and poured into
saturated aqueous NH4Cl. The aqueous phase was separated
and extracted twice with EtOAc. The combined organic phase
was dried over Na2SO4, decanted, and concentrated in vacuo.
The resulting residue was purified by flash chromatography
(25:75 EtOAc/petroleum ether) to afford 25 as a pale yellow
oil (0.986 g, 61%): 1H NMR (200 MHz, CDCl3) δ 9.1 (s, 2H),
2.49 (t, J ) 7.0 Hz, 4H), 1.79 (qt, J ) 7.0 Hz, 2H); 13C NMR
(50 MHz, CDCl3) δ 177.4, 97.1, 82.6, 25.9, 18.5; IR (neat) νmax
3649, 2533, 3307, 2945, 2868, 2746, 2278, 2202, 1666, 1425,
1390, 1346, 1329, 1138, 1034, 964, 859, 814, 750 cm-1
.
9-Hyd r oxy-2,7-d eca d iyn a l (26). To a solution of 25 (0.51
g, 3.4 mmol) in dry CH2Cl2 (12 mL) at -50 °C was added Me3-
Al as a 2 M solution in PhCH3 (0.34 mL, 0.68 mmol) and the
mixture slowly warmed to 25 °C. The reaction was diluted with
CH2Cl2 and poured into saturated aqueous NH4Cl. The aque-
ous phase was separated and extracted twice with Et2O. The
combined organic phase was dried over Na2SO4, decanted, and
concentrated in vacuo. The resulting residue was purified by
flash chromatography (20:80 Et2O/pentane) to afford 26 as a
pale yellow oil (0.073 g, 65% based on recovered starting
material): 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 4.47 (m,
1H), 2.51 (m, 2H), 2.31 (m, 3H), 1.75 (m, 2H), 1.38 (d, J ) 2.7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 98.1, 83.7, 82.5,
82.0, 58.4, 26.5, 24.7, 18.2, 17.9; IR (neat) νmax 3404, 2981,
2936, 2870, 2278, 2202, 1665, 1430, 1391, 1330, 1138, 1076,
1013, 884, 812, 768 cm-1
.
2-Br om ocyclop en t-1-en eca r ba ld eh yd e (34).19 A solution
of DMF (6.90 mL, 90 mmol) in CH2Cl2 at 0 °C was slowly
treated with PBr3 (7.0 mL, 75 mmol) and stirred for 1 h. A
solution of cyclopentanone (2.40 mL, 30 mmol) in CH2Cl2 (12.5
mL) was added dropwise to the reaction mixture and the
reaction stirred for 24 h at 25 °C. The reaction was quenched
by pouring it into ice and adding NaHCO3 until a pH of 7 was
5-Ben zyloxy-9-oxod eca -2,7-d iyn a l (18). To a solution of
17 (0.053 g, 0.2 mmol) in dry CH2Cl2 (3 mL) was added the
Dess-Martin periodinane (0.33 g, 0.8 mmol). After the mixture
J . Org. Chem, Vol. 68, No. 22, 2003 8477