Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4851
0.75 g), copper(I) iodide (15 mol %, 1.95 mmol, 0.37 g), and
n-butylamine (5.0 equiv, 0.065 mol, 4.75 g, 6.41 mL). The
resulting suspension was degassed by four freeze-thaw cycles
and was gently stirred at room temperature until it became a
pale, yellow clear solution (10-20 min). After degassing by four
freeze-pump-thaw cycles, the alkyne solution was cannulated
dropwise to the yellow solution of cis-1,2-dichloroethylene and
catalysts, and the reaction mixture was allowed to stir for 12 h
under nitrogen. It was then poured into saturated aqueous
ammonium chloride (50 mL) and extracted with diethyl ether.
The combined organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure, and the residue was purified by gradient flash chro-
matography (diethyl ether/hexane mixtures) to afford enyne
ester 11 (2.69 g) as a light yellow oil in 79% yield: Rf (25%
diethylether/75% hexane) 0.3; IR (neat) 2252.2, 1732.5, 1589.2;
1H NMR (CDCl3) δ 6.33 (d, J ) 6.96, 1H), 5.80 (dd, J ) 7.51, J
) 1.65, 1H), 4.89 (d, J ) 6.78, 1H), 4.48 (dd, overlapping, J )
7.14, J ) 1.65, 1H), 4.50 (d, J ) 6.78, 1H), 4.05 (q, J ) 7.15,
2H), 3.29 (s, 3H), 2.46 (t, J ) 7.88, 2H), 2.03 (dt, J ) 7.51, J )
7.14, 2H), 1.17 (t, J ) 7.15, 3H); 13C NMR (CDCl3) δ 172.66,
129.00, 111.20, 95.06, 93.84, 79.66, 64.47, 60.17, 55.51, 30.33,
1a and 1b as a mixture of two diastereomers in 82% yield (1.54
g): Rf (50% diethyl ether/50% hexane) 0.60. The mixture was
separated by preparative HPLC. Diastereoisomer 1a : 1H NMR
(CDCl3) δ 7.31-6.86 (m, 5H), 6.80 (dd, J ) 6.60, J ) 3.85, 1H),
5.82 (dd, J ) 10.99, J ) 1.83, 1H), 5.79 (d, J ) 10.99, 1H), 4.81
(dd, J ) 6.60, J ) 14.11, 1H), 4.76 (d, J ) 6.59, 1H), 4.75 (dt,
overlapping, 1H), 4.49 (d, J ) 6.59, 1H), 4.12 (dd, J ) 3.85, J )
14.11, 1H), 3.28 (s, 3H), 2.59-1.78 (m, 4H), 1.63 (s, 3H), 0.80 (s,
9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3) δ 171.72, 141.28,
136.36, 133.33, 128.21, 127.24, 125.44, 120.25, 118.89, 98.28,
94.85, 94.30, 84.63, 83.90, 73.01, 65.43, 62.45, 55.56, 30.75, 30.64,
30.22, 25.70, 18.17, -3.19, -3.58; mp 84-85 °C; HRMS calcd
for C29H38O5SSi 526.2209, found 526.2218. Diastereoisomer
1b: IR (neat) 2251.0, 1739.6, 1582.1; 1H NMR (CDCl3) δ 7.32-
6.93 (m, 5H), 6.81 (dd, J ) 6.41, J ) 4.21, 1H), 5.79 (s, 2H), 4.84
(d, J ) 6.78, 1H), 4.73 (t, J ) 6.22, 1H), 4.53 (dd, J ) 4.21, J )
14.28, 1H), 4.48 (d, J ) 6.78, 1H), 4.44 (dd, J ) 6.41, J ) 14.28,
1H), 3.29 (s, 3H), 2.58-2.3 (m, 2H), 2.18-1.98 (m, 2H), 1.65 (s,
3H), 0.78 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3) δ
171.77, 140.73, 136.21, 133.29, 128.21, 127.10, 125.43, 119.15,
118.54, 98.56, 95.16, 94.12, 84.73, 83.84, 73.31, 65.20, 62.40,
55.59, 31.06, 30.73, 30.59, 25.63, 18.14, -3.02, -3.36; HRMS
calcd for C29H38O5SSi 526.2209, found 526.2206.
29.67, 13.95; HRMS calcd for
260.0822.
C12H17ClO4 260.0815, found
(6Z)-2-Eth yn yl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-3-m eth -
yl-10-[(m eth oxym eth yl)oxy]-2-(p h en ylth io)-1-[[(tr iisop r o-
p ylsilyl)oxy]ca r bon yl]-cyclou n d ecen e-(4,8)-d iyn es (3a a n d
3b). To a stirred solution of lactone 1a (350 mg, 0.69 mmol) in
dry THF (12 mL) containing HMPA (3.5 equiv, 2.3 mmol, 0.42
g, 0.40 mL) at -100 °C (hexane-liquid nitrogen bath) was added
lithium bis(trimethylsilyl)amide (LHMDS, 1.2 equiv, 0.8 mmol,
0.80 mL from a 1.0 M solution in THF) immediately followed
by triisopropylsilyl trifluoromethansulfonate (1.2 equiv, 0.8
mmol, 0.245 g, 0.22 mL). Subsequently the reaction mixture
was warmed quickly to 23 °C and allowed to stir for 5 min (TLC
analysis). Gradual replacement of almost all THF with dry
hexane under high vacuum while stirring was continued induced
the precipitation of insoluble salt (LiOTf) which was removed
(7Z,12Z)-Eth yl-14-h yd r oxy-11-[(ter t-bu tyld im eth ylsilyl)-
oxy]-11-m et h yl-4-[(m et h oxym et h yl)oxy]-12-(p h en ylt h io)-
tetr a d eca d ien e-(5,9)-d iyn oa te (13). According to the above
procedure for the synthesis of 11, palladium (0)-catalyzed
coupling of free alkyne 12 (8.0 mmol, 2.8 g) with chloroenyne
ester 11 (1.1 equiv, 8.8 mmol, 2.3 g) in a benzene solution (10
mL) containing palladium tetrakis(triphenylphosphine) (5 mol
%, 0.4 mmol, 0.46 g), copper(I) iodide (10 mol %, 0.8 mmol, 0.152
g), and n-butylamine (3 equiv, 0.024 mol, 1.75 g, 2.4 mL)
generated enediyne 13 (3.2 g) in 93% isolated yield (flash
chromatography) as a mixture of two diastereomers: Rf (50%
diethyl ether/50% hexane) 0.20; IR (neat) 3450.1, 2247.4, 1732.3,
1582.2; 1H NMR (CDCl3) δ 7.23-6.92 (m, 5H), 6.81 (dd, J ) 6.95,
J ) 5.49, 1H for one diastereomer), 6.79 (dd, J ) 6.96, J ) 5.49,
1H for other diastereomer), 5.78 (s, 2H for one diastereomer),
5.75 (s, 2H for other diastereomer), 4.89 (d, J ) 3.66, 1H), 4.87
(d, J ) 3.66, 1H), 4.48 (ddd, J ) 6.95, J ) 5.4, J ) 3.1, 2H), 4.06
(t, J ) 7.51, 1H), 4.02 (q, J ) 7.15, 2H), 3.28 (s, 3H for one
diastereomer), 3.26 (s, 3H for other diastereomer), 2.42 (t, J )
7.51, 2H), 2.03 (dt, J ) 7.51, J ) 1.28, 2H), 1.63 (s, 3H for one
diastereomer), 1.61 (s, 3H for other diastereomer), 1.14 (t, J )
7.15, 3H), 0.77 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR
(CDCl3) δ 172.90, 137.61, 137.49, 137.21, 136.85, 136.83, 128.67,
126.46, 124.95, 119.25, 99.04, 94.29, 83.52, 82.97, 72.93, 64.65,
61.13, 60.35, 55.42, 30.84, 30.44, 29.86, 25.60, 18.04, 13.99,
-3.00, -3.32.
(4Z,9Z)-6-[(t er t -Bu t yld im e t h ylsilyl)oxy]-6-m e t h yl-13-
[(m et h oxym et h yl)oxy]-5-(p h en ylt h io)t et r a d eca d ien e-(7,-
11)-d iyn olid es (1a a n d 1b). To a solution of water (64 mL) in
methanol (100 mL) was added n-butyllithium (5 equiv, 0.028
mol, 12.17 mL from a 2.3 M solution in hexane) dropwise while
stirring. To the resulting lithium hydroxide solution was added
ester 13 (3.2 g, 5.6 mmol) in methanol (100 mL) slowly at room
temperature. The reaction mixture was allowed to stir vigor-
ously until hydrolysis was complete (5 h) as indicated by TLC
analysis. Concentration under reduced pressure and treatment
of the residue with HCl solution (0.5 M) was followed by
extraction with diethyl ether. The combined ether layer was
washed with water and brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo to furnish the desired hydroxy
acid in quantitative yield (3.05 g). This material was used for
the macrolactonization without further purification. To a solu-
tion of DCC (4 equiv, 0.014 mol, 2.96 g), pyridine (6 equiv, 0.021
mol, 1.7 g, 1.74 mL), and pyridinium p-toluenesulfonate (4 equiv,
0.14 mol, 3.52 g) in dry, ethanol-free chloroform (350 mL) was
infused a solution of crude hydroxy acid (1.95 g, 3.5 mmol) in
dry chloroform (40 mL) via a syringe pump during 50 h. After
this time, methanol (10 equiv, 0.035 mol, 1.15 g, 1.45 mL) and
acetic acid (8 equiv, 0.028 mol, 1.72 g, 1.64 mL) were added and
stirring was continued for 30 min, until no DCC was detected
by TLC analysis. The mixture was concentrated to about 30
mL, diluted with 30 mL of diethyl ether, filtered and concen-
trated. The residual oil was purified by flash chromatography
with diethyl ether/hexane to furnish the desired macrolactones
by filtration through
a triethylamine pretreated silica gel
microcolumn (Pasteur pipette). The filtrate was concentrated
in vacuo to give uncomplexed (Z)-ketene acetal 2a as the only
isomer in quantitative yield: Rf (50% diethyl ether/50% hexane)
0.80; 1H NMR (CDCl3) δ 7.38-7.05 (m, 5H), 6.97 (dd, J ) 5.86,
J ) 4.4, 1H), 5.92 (dd, J ) 10.81, J ) 1.46, 1H), 5.82 (d, J )
10.81, 1H), 4.93 (d, J ) 6.77, 1H), 4.63 (d, J ) 6.77, 1H), 4.61
(dt, J ) 4.03, J ) 1.46, 1H), 4.47 (dd, overlaping, 1H), 4.42 (dd,
J ) 15.94, J ) 4.40, 1H), 4.38 (dd, J ) 15.94, J ) 5.86, 1H),
3.39 (s, 3H), 3.38 (t, J ) 7.03, 1H), 2.77-2.31 (m, 2H), 1.70 (s,
3H), 1.08 (m, 3H), 1.05 (dd, J ) 6.22, J ) 1.25, 18H), 0.90 (s,
9H), 0.22 (s, 3H), 0.20 (s, 3H); 13C NMR (CDCl3) δ 155.63, 138.57,
136.15, 134.34, 128.77, 126.25, 125.02, 120.83, 117.38, 97.77,
96.93, 93.74, 83.87, 82.45, 72.56, 69.51, 67.05, 64.94, 55.03, 31.39,
30.12, 25.54, 17.68, 12.47, 11.20, -3.26, -3.57. To a carbon
monoxide-purged solution of the (Z)-ketene acetal (450 mg, 0.66
mmol) in dry hexane (10 mL) was added Co2(CO)8 (1.3 equiv,
0.85 mmol, 293 mg) at 23 °C. After stirring for 24 h, the
resulting solution was passed through a silica gel microcolumn
(Pasteur pipette). Concentration of the appropriate fractions
provided Co2(CO)6-complexed 3a as a deep crimson oil in 81%
yield (518 mg): Rf (5% diethyl ether/95% hexane) 0.80; IR (neat)
1725.1; 1H NMR (CDCl3) δ 7.69-7.19 (m, 5H), 6.72 (d, J ) 10.45,
1H), 5.75 (d, J ) 10.45, 1H), 5.70 (d, J ) 17.6, 1H), 5.67 (dd, J
) 17.60, J ) 9.16, 1H), 5.30 (d, J ) 9.16, 1H), 5.27 (t, overlaping,
1H), 5.01 (d, J ) 6.78, 1H), 4.68 (d, J ) 6.78, 1H), 4.03 (t, J )
3.48, 1H), 3.67 (dd, J ) 15.94, J ) 3.48, 1H), 3.47 (s, 3H), 2.33
(m, 1H), 1.45 (s, 3H), 1.32 (m, 3H), 1.12 (d, J ) 7.15, 18H), 0.91
(s, 9H), 0.24 (s, 3H), 0.18 (s, 3H); 13C NMR (CDCl3) δ 199.06,
173.89, 138.45, 137.74, 135.73, 132.63, 128.64, 128.42, 119.79,
108.55, 100.33, 97.25, 95.79, 84.62, 82.32, 80.04, 76.22, 66.86,
56.25, 51.12, 43.54, 27.92, 25.86, 18.49, 17.91, 12.10, -2.19,
-2.64. To a solution of Co2(CO)6-complexed 3a (450 mg, 0.46
mmol) in dry benzene (6 mL) was added N-methylmorpholine
N-oxide (5 equiv, 2.3 mmol, 0.272 g) at 23 °C in two equal
portions with a time interval of 1.5 h. After this time, the
resulting reaction mixture was passed through a silica gel
microcolumn and the filtrate was directly purified by flash
chromatography (6% diethyl ether/94% hexane) to provide 11-
membered enediyne 3a in 74% yield (232 mg): Rf (25% diethyl
ether/75% hexane) 0.40; IR (neat) 2091.6, 2054.5, 2027.8, 1709.9;