Synthesis of the Annonaeous Acetogenin (+)-Asimicin
J . Org. Chem., Vol. 62, No. 17, 1997 5993
resulting slurry was cooled to 0 °C, and 4.06 g (88.2 mmol) of
EtOH (freshly distilled) was added dropwise over a period of
15 min. After 20 min, 25.3 g (88.2 mmol) of (S)-1,1′-bi-2-
naphthol in THF (80 mL) was added over 30 min by means of
a cannula. The resulting cloudy, milky solution was refluxed
for 2 h. The solution was then cooled to -78 °C, and the
acylstannane in THF (described above) was added over 45 min
by means of a cannula. The reaction mixture was stirred until
the reduction was judged to be complete by TLC (approxi-
mately 2 h). The reaction was quenched by the careful
addition of dilute aqueous ammonium chloride solution (satu-
rated aqueous NH4Cl-H2O 1:4) and extracted with Et2O. The
layers were separated, and the aqueous layer was acidified
by the addition of 200 mL of 1.0 M HCl and extracted with
Et2O. The organic layers were combined, dried over magne-
sium sulfate, and filtered, and the solvent was removed under
reduced pressure. Hexane (400 mL) was then added causing
the formation of a precipitate that was allowed to settle. The
solid yellow residue (recovered BINOL) was triturated and
filtered with hexanes. Solvent was removed from the filtrate
under reduced pressure, and the yellow oil was again tritu-
rated with 200 mL of hexane and filtered (occasionally a third
trituration and filtration are required). Solvent was again
removed under reduced pressure to afford crude hydroxystan-
nane as a yellow oil. The crude hydroxystannane was dis-
solved in 50 mL of CH2Cl2 and cooled to 0 °C. To the solution
was added 19.2 mL (117 mmol) of diisopropylethylamine
followed by 7.32 g (44.1 mmol) of (2-(trimethylsilyl)ethoxy)-
methyl chloride (SEMCl). After 12 h the reaction was quenched
with 100 mL of a saturated aqueous NH4Cl solution. The
layers were separated, and the aqueous layer was extracted
with Et2O. The organic layers were dried over magnesium
sulfate and filtered. The solvent was removed under reduced
pressure, and the product was purified by column chromatog-
raphy on silica gel with 1% EtOAc-hexanes as eluant afford-
p-toluenesulfonyl chloride. The progress of the reaction was
monitored by TLC. After 12 h, when the diol was no longer
present, the reaction was quenched at rt with H2O and
saturated aqueous CuSO4 and then extracted with Et2O. The
extracts were dried over MgSO4, the solvent was removed
under reduced pressure, and the product was purified by
column chromatography on silica gel. Elution with 10%
EtOAc-hexanes afforded 3.04 g (92%) of tosylate 10: IR (film)
1
1605 cm-1; H NMR δ 7.78 (d, J ) 8.1 Hz, 4H), 7.30 (d, J )
8.1 Hz, 4H), 5.71 (dq, J ) 15.4, 6.2 Hz, 2H), 5.40 (dd, J ) 15.4,
7.7 Hz, 2H), 4.60, 4.51 (ABq, J ) 6.9 Hz, 4H), 4.49-4.44 (m,
2H), 4.23 (dd, J ) 8.1, 2.4 Hz, 2H), 3.72-3.41 (m, 4H), 3.60 (t,
J ) 6.5 Hz, 4H), 3.33 (bd, J ) 9.3 Hz, 4H), 2.42 (s, 6H), 2.01
(dt, J ) 6.9, 5.8 Hz, 4H), 1.80-1.66 (m, 2H), 1.58-1.20 (m,
30H), 0.91-0.88 (m, 4H), 0.89 (s, 18H), 0.84 (s, 18H), 0.04 (s,
12H), 0.02 (s, 18H), -0.02 (s, 12H); 13C NMR δ -5.3, -4.7,
-4.1, -1.4, 17.9, 18.3, 21.6, 25.8, 26.0, 26.4, 27.0, 29.0, 29.3,
29.4, 29.5, 32.4, 32.9, 63.3, 65.1, 75.3, 77.9, 86.0, 92.1, 124.9,
127.9, 129.5, 134.8, 137.1, 143.0.
(9E,21E,11R,12S,15R,16R,19S,20R)-12,15:16,19-Diepoxy-
11,20-b is[(2-(t r im et h ylsilyl)et h oxy)m et h oxy]-9,21-t r ia -
con ta d ien e-1,30-d iol (11). To solution of 3.01 g (1.90 mmol)
of bis-TBS ether 10 in 19 mL of THF at 40 °C was added 19.3
mL (19.3 mmol) of 1 M TBAF in THF. The progress of the
reaction was monitored by TLC. During 6 h, a more polar spot
appeared which was gradually replaced with a less polar one.
The mixture was cooled to rt, quenched with H2O, and
extracted with Et2O. The organic extracts were dried over
MgSO4. The solvent was removed under reduced pressure,
and the product was purified by column chromatography on
silica gel with 60% EtOAc-hexanes as eluant affording 1.17
g (78%) of bis-tetrahydrofuran diol 11: [R]D -59.4 (c 1.4,
1
CHCl3); IR (film) 3441, 1666 cm-1; H NMR δ 5.68 (dq, J )
15.4, 7.0 Hz, 2H), 5.33 (dd, J ) 15.4, 7.7 Hz, 2H), 4.71, 4.67
(ABq, J ) 6.9 Hz, 4H), 4.07-3.92 (m, 6H), 3.74, 3.52 (ABdt, J
) 10.0, 7.7 Hz, 4H), 3.63 (t, J ) 7.0 Hz, 4H), 2.20 (bs, 2H),
2.03 (dt, J ) 7.0, 6.5 Hz, 4H), 1.97-1.65 (m, 8H), 1.61-1.13
(m, 24H), 0.92 (ABq (appt t), J ) 8.8 Hz, 4H), 0.01 (s, 18H);
13C NMR δ -1.5, 18.0, 25.6, 27.8, 27.9, 28.9, 29.0, 29.3, 32.3,
62.8, 64.8, 76.6, 78.5, 81.2, 81.5, 91.8, 126.6, 135.6. Anal. Calcd
for C42H82O8Si2: C, 65.41; H, 10.72. Found: C, 65.12; H, 10.58.
(9E,21E,11R,12S,15R,16R,19S,20R)-12,15:16,19-Diepoxy-
11,20-b is[(2-(t r im et h ylsilyl)et h oxy)m et h oxy]-9,21-t r ia -
con ta d ien e-1,30-d iol Mon o-p-tolu en esu lfon a te (12). To
a solution of 304 mg (0.40 mmol) of diol 11 in 1.5 mL of THF
at rt was added 0.20 mL (0.20 mmol) of 2.5 M butyllithium in
hexanes. The solution was heated to 40 °C for 10 min, and
0.25 mL of DMSO was added. After an additional 30 min at
40 °C, the reaction mixture was allowed to cool to rt and 75
mg (0.40 mmol) of p-toluenesulfonyl chloride was added as a
solution in THF (0.25 mL). After 1 h the reaction was
quenched with H2O and the solution extracted with Et2O. The
organic extracts were dried over MgSO4. The solvent was
removed under reduced pressure, and the product was purified
by column chromatography on silica gel with 35% EtOAc-
hexanes as eluant affording 185 mg (51%) of monotosylate 12
(86% based on 126 mg of recovered diol): [R]D -38.8 (c 1.9,
CHCl3); IR (film) 3493, 1675, 1606 cm-1; 1H NMR δ 7.79 (d, J
) 8.1 Hz, 4H), 7.34 (d, J ) 8.1 Hz, 4H), 5.74-5.61 (m, 2H),
5.32 (dd, J ) 15.4, 7.8 Hz, 2H), 4.73-4.65 (m, 4H), 4.07-3.92
(m, 8H), 3.74, 3.52 (ABdt, J ) 10.0, 7.7 Hz, 4H), 3.63 (t, J )
7.0 Hz, 4H), 2.45 (s, 3H), 2.10 (vbs, 1H), 2.07-1.98 (m, 2H),
1.95-1.45 (m, 18H), 1.40-1.17 (m, 16H), 0.92 (ABq (appt t),
J ) 8.8 Hz, 4H), 0.01 (s, 18H); 13C NMR δ -1.4, 18.1, 21.6,
25.3, 25.7, 27.8, 27.9, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 32.3,
32.8, 63.0, 64.8, 70.6, 78.6, 81.3, 81.5, 91.9, 126.6, 127.8, 129.8,
135.6, 135.6. Anal. Calcd for C49H88O10SSi2: C, 63.59; H, 9.58.
Found: C, 63.34; H, 9.49.
1
ing 9.97 g (47%) of stannane 7: [R]D 42.0 (c 1.9, CHCl3); H
NMR δ 5.54 (dt, J ) 15.4, 7.3 Hz, 1H), 5.38 (dd, J ) 15.4, 6.5
Hz, 2H), 4.68, 4.58 (ABq, J ) 6.5 Hz, 2H), 4.58 (d, J ) 7.4 Hz,
1H), 3.67, 3.50 (ABdt, J ) 10.0, 7.7 Hz, 2H), 3.60 (t, J ) 6.5
Hz, 2H), 2.00 (q, J ) 6.6 Hz, 2H), 1.56-1.44 (m, 2H), 1.38-
1.21 (m, 10H), 0.93-0.86 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H),
0.02 (s, 9H); 13C NMR δ -5.3, -4.1, 9.1, 13.7, 18.1, 25.8, 26.0,
27.4, 29.1, 29.2, 29.4, 29.6, 23.9, 63.3, 65.0, 72.3, 93.3, 125.4,
131.3.
(9E,21E,11R,12S,15R,16R,19S,20R)-1,11,20,30-Tetr a k is-
[ter t-b u t yld im et h ylsilyl)oxy]-11,20-b is[(2-(t r im et h ylsi-
lyl)eth oxy)m eth oxy]-9,21-tr ia con ta d ien e-12,19-d iol (9). A
solution of 1.23 g (5.6 mmol) of InCl3 in 135 mL of EtOAc was
placed in a sonication bath at rt for 15 min to dissolve the
InCl3. The solution was removed from the bath, and 1.13 g
(2.80 mmol) of aldehyde 8 was added with stirring. The
solution was cooled to -78 °C followed by addition of 5.96 g
(8.30 mmol) of stannane (R)-7. The reaction mixture was
allowed to slowly warm to rt as its progress was monitored by
TLC. When the aldehyde was no longer present the reaction
was quenched with cold 1 M HCl and extracted with Et2O.
The organic extracts were dried over MgSO4, and Et3N
(approximately 2 equiv) was added to remove tin byproducts.
The solvent was distilled under reduced pressure and the
product purified by column chromatography on silica gel with
10% EtOAc-hexanes as eluant to afford 2.53 g (71%) of adduct
1
9: [R]D -27.6 (c 1.5, CHCl3); IR (film) 3501 cm-1; H NMR δ
5.71 (dq, J ) 15.4, 6.9 Hz, 2H), 5.40 (dd, J ) 15.4, 8.1 Hz,
2H), 4.72, 4.65 (ABq, J ) 6.9 Hz, 4H), 3.94 (dd, J ) 8.1, 3.1
Hz, 2H), 3.77-3.47 (m, 12H), 2.20 (bs, 2H), 1.93-1.81 (m, 2H),
1.68-1.17 (m, 30H), 0.92-0.89 (m, 4H), 0.89 (s, 18H), 0.87 (s,
18H), 0.03 (s, 12H), 0.03-0.02 (m, 18H), 0.02 (s, 12H); 13C
NMR δ -5.2, -4.6, -4.0, -1.4, 18.0, 18.1, 25.8, 25.9, 26.0, 26.8,
29.1, 29.3, 29.4, 29.5, 29.9, 32.5, 32.9, 63.3, 65.3, 74.3, 75.9,
80.6, 92.1, 125.0, 137.1. Anal. Calcd for C66H142O10Si6: C,
62.70; H, 11.32. Found: C, 62.75; H, 11.29.
(9E,21E,11R,12S,15R,16R,19S,20R)-12,15:16,19-Diepoxy-
11,20-b is[(2-(t r im et h ylsilyl)et h oxy)m et h oxy]-9,21-t r ia -
con ta d ien -1-ol (13). To solution of 180 mg (0.19 mmol) of
monotosylate 12 in 0.3 mL of THF at 0 °C was added 1.94 mL
(1.94 mmol) of 1 M Super-Hydride in THF. The progress of
the reaction was monitored by TLC. After 12 h the reaction
mixture was cooled to 0 °C, quenched with H2O, and extracted
with Et2O. The organic extracts were dried over MgSO4. The
(9E,21E,11R,12S,15R,16R,19S,20R)-1,11,20,30-Tetr a k is-
[(ter t-b u t yld im et h ylsilyl)oxy]-11,20-b is[(2-(t r im et h ylsi-
lyl)eth oxy)m eth oxy]-9,21-tr ia con ta d ien e-12,19-d iol Bis-
p-tolu en esu lfon a te (10). To a solution of 2.65 g (2.10 mmol)
of diol 9 in 8 mL of pyridine was added 2.40 g (12.6 mmol) of