A R T I C L E S
Trost et al.
in THF containing 2.11 mL (36.9 mmol) of acetic acid at room
temperature. The resulting golden yellow solution was stirred at room
temperature for 24 h and partitioned between saturated NaHCO3 and
Et2O. The aqueous portion was extracted with Et2O (3×), and the
combined organic extracts were washed with brine (1×), dried over
MgSO4, filtered, and concentrated. Purification by flash column
chromatography on silica gel (45% Et2O in petroleum ether) gave 51
(4.13 g, 96%) as a pale yellow oil: Rf ) 0.34 (50% Et2O in petroleum
the correct structure of amphidinolide A will be discussed in
the following paper in this issue.
Experimental Section
tert-Butyl(dimethyl)({(1S,2E,4R)-4-methyl-1-[(1R)-1-methyl-4-
(trimethylsilyl)but-3-yn-1-yl]hept-2-en-1-yl}oxy)silane (11). Alcohol
72 (860 mg, 2.73 mmol) was dissolved in 8 mL of CH2Cl2. Dess-
Martin periodinane (1.39 g, 3.28 mmol) was then added. After
approximately 90 min, the reaction was diluted with petroleum ether
and filtered through a plug of silica gel (20% Et2O/petroleum ether).
Aldehyde 12 was concentrated and dissolved in 6 mL of DME. In a
separate flask, KN(TMS)2 (499 mg, 2.5 mmol) was dissolved in 6 mL
of DME and cooled in a dry ice/acetone bath. Sulfone 13 (736 mg, 2.5
mmol) was then added in 6 mL of DME. The solution turned bright
yellow. After being stirred for approximately 90 min, the solution of
aldehyde 12 in DME was added over approximately 10 min. The
reaction was allowed to slowly warm to room temperature and stirred
overnight (approximately 16 h). The reaction was then poured into brine
and extracted with Et2O (4×), and the combined organic extracts were
dried (MgSO4) and concentrated. Purification by silica gel chromatog-
raphy (3-6% Et2O/petroleum ether) provided 11 (685 mg, 72%, >20:1
E/Z by 1H NMR) as a colorless oil: Rf ) 0.34 (2% Et2O in petroleum
ether); IR (film) 2959, 2171 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.42
(dd, J ) 15.6, 7.3 Hz, 1H), 5.32 (dd, J ) 15.6, 6.8 Hz, 1H), 4.05 (t,
J ) 6.3 Hz, 1H), 2.29 (dd, J ) 16.6, 6.1 Hz, 1H), 2.01-2.15 (m, 2H),
1.56-1.72 (m, 1H), 1.21-1.33 (m, 4H), 0.95 (d, J ) 6.6 Hz, 3H),
0.85-0.90 (s br, 15H), 0.15 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 137.6, 129.7, 107.0, 85.3, 75.8, 39.7, 39.2,
36.1, 25.9, 23.7, 20.6, 20.4, 18.2, 14.3, 14.1, 0.2, -4.1, -4.9; optical
1
ether); IR (film) 3474, 3285, 2124, 1646 cm-1; H NMR (300 MHz,
CDCl3) δ 5.44 (s, 1H), 5.42 (s, 1H), 4.34 (d, J ) 8.3 Hz, 1H), 4.28 (d,
J ) 7.8 Hz, 1H), 4.09-3.99 (m, 2H), 3.84 (dd, J ) 12.2, 2.9 Hz, 1H),
3.66 (dd, J ) 11.7, 3.9 Hz, 1H), 2.64 (ddd, J ) 17.1, 4.4, 2.4 Hz, 1H),
2.48 (ddd, J ) 17.1, 5.4, 2.4 Hz, 1H), 2.03 (t, J ) 2.4 Hz, 1H), 1.99
(s br, 1H), 1.88-1.77 (m, 8H), 1.76-1.61 (m, 8H); 13C NMR (75 MHz,
CDCl3) δ 142.1, 119.1, 119.1, 116.9, 94.0, 80.9, 80.5, 79.7, 77.7, 70.8,
61.5, 37.6, 37.5, 37.2, 37.2, 23.6, 23.4, 23.4, 23.4, 22.0; optical rotation
[R]24D ) +17.4 (c 2.26, CH2Cl2). Anal. Calcd for C20H28O5: C, 68.94;
H, 8.10. Found: C, 69.14; H, 7.91.
tert-Butyl(2-{(2S,3S)-3-[1-((2R,3R)-3-{[(4-methoxybenzyl)oxy]-
methyl}-1,4-dioxaspiro[4.4]non-2-yl)vinyl]-1,4-dioxaspiro[4.4]-
non-2-yl}ethoxy)dimethylsilane (60). To a mixture of K3Fe(CN)6
(17.96 g, 54.5 mmol), K2CO3 (7.57 g, 54.8 mmol), NaHCO3 (4.62 g,
55.0 mmol), methanesulfonamide (1.720 g, 18.1 mmol), and (DHQ)2-
PHAL (369 mg, 0.47 mmol) at room temperature were added water
(85 mL) and tert-butyl alcohol (45 mL). The reaction mixture was
cooled to 0 °C, and K2OsO4‚2H2O (171 mg, 0.46 mmol) was added
followed by a solution of alkene 57 (8.871 g, 18.1 mmol) in tert-butyl
alcohol (40 mL). The reaction mixture was stirred at 0 °C for 22 h,
quenched with Na2SO3 (80 g), warmed to room temperature, stirred
for 1 h, and diluted with EtOAc and water. The aqueous phase was
extracted with EtOAc (4×), and the combined organic extracts were
washed with 2 M NaOH (1×) and brine (1×), dried over MgSO4, and
concentrated to give diol 58, which was used in the next step without
further purification. Data for 58: Rf ) 0.46 (30% EtOAc in petroleum
rotation [R]23 ) +1.4 (c 1.0, CH2Cl2).
D
((2R,3R)-3-{1-[(2R,3R)-3-Prop-2-yn-1-yl-1,4-dioxaspiro[4.4]non-
2-yl]vinyl}-1,4-dioxaspiro[4.4]non-2-yl)methanol (51). To a solution
of 4.23 g (6.09 mL, 43.1 mmol) of (trimethylsilyl)acetylene in 100
mL of THF at -78 °C was added 23.1 mL (36.9 mmol) of a 1.6 M
solution of n-BuLi in hexanes, and the resulting mixture was stirred at
-78 °C for 30 min and then at 0 °C for 1 h. During this time, in a
separate flask was prepared a solution of 1.46 g (1.49 mL, 18.4 mmol)
of pyridine in 55 mL of CH2Cl2, and the solution was cooled to -50
°C whereupon 4.51 g (2.69 mL, 16.0 mmol) of Tf2O from a freshly
opened ampule was added followed by stirring at -50 °C for 15 min,
giving a cloudy white, heterogeneous mixture. To this mixture was
then added a solution of 5.59 g (12.3 mmol) of alcohol 50 in 44 mL of
CH2Cl2 via cannula, and the resulting mixture was stirred at -50 °C
for 40 min. The mixture was then diluted with 100 mL of petroleum
ether at -50 °C, and the cold solution was poured directly onto a
column of silica gel (6 × 16 cm) which had been equilibrated with
30% Et2O in petroleum ether. The cold reaction solution was rapidly
eluted through the silica gel column, washing the column with an
additional 600 mL of 30% Et2O in petroleum ether. The resulting clear
filtrate was concentrated on a rotary evaporator to provide the crude
triflate intermediate as a pale yellow oil (Rf ) 0.81, 30% Et2O in
petroleum ether). The sensitive triflate was then immediately dissolved
in 30 mL of anhydrous THF. At this time, to the previously prepared
solution of the lithium acetylide at 0 °C was added 25.8 mL of DMPU,
the mixture was cooled to -78 °C, and the crude triflate solution was
transferred via cannula into the lithium acetylide solution at -78 °C.
The resulting mixture was stirred at -78 °C for 45 min and quenched
at -78 °C by the addition of 3 mL of MeOH followed by 40 mL of
saturated NH4Cl. After being warmed to room temperature, the mixture
was partitioned between water and Et2O. The aqueous portion was
extracted with Et2O (3×). The combined organic extracts were washed
with water (4×) and brine (1×), dried over MgSO4, filtered, and
concentrated to deliver approximately 6.5 g of a yellow oil as the crude
intermediate containing residual DMPU. This material was dissolved
in 30 mL of THF, and the solution was transferred via cannula into a
well-stirred mixture of 36.9 mL (36.9 mmol) of a 1 M solution of TBAF
1
ether); H NMR (500 MHz, CDCl3) δ 7.27 (d, J ) 7.8 Hz, 2H), 6.87
(d, J ) 8.5 Hz, 2H), 4.55 (s, 2H), 4.52 (d br, J ) 7.3 Hz, 1H), 4.48 (d,
J ) 6.8 Hz, 1H), 4.34 (ddd, J ) 5.9, 5.9, 3.2 Hz, 1H), 3.95-3.85 (m,
3H), 3.80 (s, 3H), 3.75 (dd, J ) 11.0, 3.2 Hz, 1H), 3.62 (dd, J ) 10.8,
5.9 Hz, 1H), 3.45 (d, J ) 6.8 Hz, 1H), 3.14 (d, J ) 4.9 Hz, 1H), 2.03-
1.66 (m, 10H), 0.89 (s, 9H), 0.08 (s, 6H). To a solution of diol 58,
prepared in the previous step, and 1,1-dimethoxycyclopentane (25 mL)
in CH2Cl2 (190 mL) at 0 °C was added TsOH‚H2O (562 mg, 2.95
mmol). The reaction mixture was stirred at 0 °C for 2 h, diluted with
ether, washed with saturated NaHCO3 (1×) and brine (1×), dried over
MgSO4, and concentrated to give ketal 59, which was used in the next
step without further purification. Data for 59: Rf ) 0.68 (30% EtOAc
1
in petroleum ether); H NMR (500 MHz, CDCl3) δ 7.27 (d, J ) 8.8
Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 4.57-4.51 (m, 3H), 4.41 (d, J )
7.1 Hz, 1H), 4.26 (ddd, J ) 9.3, 6.1, 3.2 Hz, 1H), 4.18 (ddd, J ) 8.8,
7.1, 3.7 Hz, 1H), 3.80 (s, 3H), 3.79-3.72 (m, 3H), 3.62 (dd, J ) 10.7,
6.1 Hz, 1H), 2.07-1.63 (m, 20H), 0.87 (s, 9H), 0.04 (s, 6H). To a
suspension of methyltriphenylphosphonium bromide (13.08 g, 36.6
mmol) in THF (150 mL) at 0 °C was added NaHMDS (37 mL, 1.0 M
in THF, 37 mmol), the resulting mixture was stirred at 0 °C for 15
min, warmed to room temperature, stirred for 1 h, and cooled to 0 °C,
and a solution of ketone 59, prepared in the previous step, in THF
(150 mL) at 0 °C was added via cannula. The reaction mixture was
stirred at 0 °C for 11 h and diluted with ether and water. The aqueous
phase was extracted with ether (3×), and the combined organic extracts
were washed with brine (1×), dried over MgSO4, and concentrated.
Purification by flash column chromatography on silica gel (5-10%
EtOAc in petroleum ether) gave alkene 60 (6.351 g, 60%) as a colorless
oil: Rf ) 0.38 (10% EtOAc in petroleum ether); IR (film) 2949, 1614,
1
1510, 1334, 1103 cm-1; H NMR (400 MHz, CDCl3) δ 7.26 (d, J )
8.2 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 5.34 (s, 2H), 4.55-4.49 (m,
2H), 4.25 (d, J ) 7.9 Hz, 1H), 4.11 (d, J ) 8.1 Hz, 1H), 4.03 (ddd, J
9
13596 J. AM. CHEM. SOC. VOL. 127, NO. 39, 2005