ozone was passed through the solution. After 75 min, the initially
yellow reaction mixture acquired the blue characteristic color of
ozone and a yellow precipitate formed. The reaction mixture was
diluted with ether and water, allowed to warm to room temperature,
and extracted with ether. The organic layer was dried over MgSO4,
and removal of the solvent by distillation under reduced pressure
gave the corresponding methyl ester, which was heated in acetic
anhydride (10 mL) at 130 °C with stirring for 6 h, concentrated,
and coevaporated with xylene. Chromatography on silica gel (8%
nately, treatment of the hydroxy acid 16 with PPh3 and DIAD
in anhydrous benzene in high dilution (1 mM) gave the desired
macrolactone 17. Deprotection of MOM group smoothly by
LiBF4 in CH3CN/H2O completed the synthesis of aspergillide
B.15 Synthetic (+)-2b was identical in all respects to the natural
product (-)-aspergillide B, with the exception of its optical
rotation, which had the opposite sign but a similar absolute value
([R]20D +84, c 0.12, MeOH; lit.1a [R]31D -97.2, c 0.27, MeOH).
On the other hand, our synthesis confirmed the report by
Uenishi.2
1
EtOAc in PE) provided 310 mg (41% yield from 12) of 13: H
1
NMR (400 MHz, CDCl3) δ H NMR (400 MHz): δ 7.68-7.69
In conclusion, we have finished a concise total synthesis of
(+)-aspergillide B. Highlights of the synthetic venture included
the C-glycosylation reaction when constructing the 2,6-trans-
disubstituted pyran core, a highly effective four-step sequence
without purification to produce the key intermediate 13, and an
advantegous E-selective Julia-Kocienski olefination on a highly
elaborate substrate. As for our total synthesis, the longest linear
sequence comprised 12 steps involving a four-step sequence
without purification and 9% overall yield. The synthetic
approaches toward aspergillides C are still under investigation
in our laboratory.
(4H, m), 7.37-7.44 (6H, m), 6.08 (1H, m), 6.01 (1H, dd, J ) 10.4
Hz, 2.4 Hz), 4.76 (1H, d, J ) 6.8 Hz), 4.65 (1H, d, J ) 6.8 Hz),
4.44 (1H, td, J ) 6.8 Hz, 3.2 Hz), 4.33 (1H, b), 3.98 (1H, t, J )
3.6 Hz), 3.77 (2H, d, J ) 5.6 Hz), 3.68 (3H, s), 3.39 (3H, s), 2.70
(2H, m), 1.07 (9H, s); 13C NMR (100 MHz) δ 171.8, 135.6, 135.6,
133.5, 133.4, 130.5, 129.7, 129.7, 127.7, 125.7, 95.8, 73.0, 69.7,
68.1, 65.0, 55.6, 51.6, 35.3, 26.8, 19.2; [R]20D -36 (c 1.2, CHCl3);
IR (KBr) νmax 3070, 3048, 1736, 1466, 1432 cm-1; HRMS (ESIMS)
m/z [M + Na]+ calcd for C27H36NaO6Si 507.2173, found 507.2182.
Alcohol (-)-7. To a solution of 13 (50 mg, 0.1 mmol) in CH3CN
(2 mL) was added Et3N·3HF (0.32 mL, 2 mmol). This mixture
was heated at 45 °C for 4 h followed by addition of ethyl acetate
(10 mL) and saturated NaHCO3 (10 mL). After being stirred for 5
min, the organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (40% EtOAc in PE) to afford alcohol (-)-7 (21
Experimental Section
Sulfone 4. Triphenylphosphine (1.76 g, 6.7 mmol), 1-phenyl-
1H-tetrazole-5-thiol (PT-SH, 1.19 g, 6.7 mmol), and 10 (1.01 g,
4.47 mmol) were dissolved in 45 mL of anhydrous THF, to which
was added DIAD (1.35 g, 6.7 mmol) at room temperature. After
being stirred for 0.5 h, the reaction mixture was diluted with 50
mL of EtOH and cooled to 0 °C. In a separate flask were mixed
30% aqueous H2O2 (10 g, 88 mmol) and ammonium molybdate
(1.09 g, 0.88 mmol), producing a bright yellow solution that was
added to the reaction via pipet. After being stirred overnight at
room temperature, the reaction mixture was diluted by the addition
of water and CH2Cl2. The layers were separated, and the aqueous
layer was extracted three times with CH2Cl2. The combined organic
layers were washed with water and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification on silica gel (10%
EtOAc in PE) provided 1.6 g (82% yield) of 4: 1H NMR (400 MHz,
CDCl3) δ 7.69-7.71 (2H, m), 7.61-7.64 (3H, m), 3.79-3.83 (1H,
m), 3.74 (2H, t, J ) 8 Hz), 1.93-2.01 (2H, m), 1.41-1.63 (4H,
m), 1.13 (3H, d, J ) 6.4 Hz), 0.89 (9H, s), 0.05 (6H, d, J ) 4 Hz);
13C NMR (100 MHz, CDCl3) δ 153.5, 133.1, 131.4, 129.7, 125.1,
1
mg, 85%) as a colorless oil: H NMR (400 MHz, CDCl3) δ 6.10
(1H, ddd, J ) 10.4 Hz, 4.8 Hz, 2 Hz), 5.91 (1H, dd, J ) 10.4 Hz,
2.8 Hz), 4.78 (1H, d, J ) 6.8 Hz), 4.65 (1H, d, J ) 6.8 Hz), 4.36
(1H, m), 4.32 (1H, m), 3.81-3.84 (2H, m), 3.73 (3H, s), 3.54 (1H,
dd, J ) 12.4 Hz, 2.6 Hz), 3.39 (3H, s), 2.87 (1H, dd, J ) 17.2 Hz,
10.4 Hz), 2.56 (1H, dd, J ) 17.2 Hz, 2.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 172.7, 129.7, 126.2, 95.6, 73.7, 68.1, 66.9, 61.3, 55.6,
52.0, 35.1; [R]D20 -152 (c 1.2, CHCl3); IR (KBr) νmax 3440, 2925,
1734, 1651, 1035, 916, 719 cm-1; HRMS (ESIMS) m/z [M + Na]+
calcd for C11H18NaO6 269.0996, found 269.0993.
Olefin 15. To a solution of sulfone 4 (147 mg, 0.35 mmol) in 4
mL of THF/HMPA (4:1 v/v) was added LiHMDS (1 M in THF,
0.22 mL, 0.22 mmol) at -78 °C. After the mixture was stirred for
15 min, a solution of the aldehyde ent-5 (57 mg, 0.23 mmol) in
0.5 mL of THF/HMPA (4:1 v/v) was added dropwise. The reaction
was stirred at -78 °C for 2 h, warmed to room temperature, and
stirred for 2 h. Saturated NH4Cl (aq) was added. The mixture was
then extracted with EtOAc (3 × 10 mL). The combined organic
layers was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (8% EtOAc in PE) to afford a mixture
of two geometrical isomers 15 (55 mg, 57% yield, E/Z ) 9 based
on 1H NMR): 1H NMR (400 MHz, CDCl3) δ 5.64-5.71(1H, dt, J
) 15.6 Hz, 6.8 Hz), 5.49 (1H, dd, J ) 15.6 Hz, 4.8 Hz), 4.70 (1H,
d, J ) 7.2 Hz), 4.63 (1H, d, J ) 7.2 Hz), 4.32-4.36 (1H, m),
4.27-4.29 (1H, m), 3.76-3.81 (1H, m), 3.70-3.73 (1H, m), 3.70
(3H, s), 3.38 (3H, s), 2.75 (1H, dd, J ) 15.4 Hz, 8.4 Hz), 2.61
(1H, dd, J ) 15.4 Hz, 5.6 Hz), 1.93-2.09 (2H, m), 1.75-1.86
(2H, m), 1.33-1.53 (6H, m), 1.12 (3H, d, J ) 6.4 Hz), 0.89
(9H, s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ
172.0, 133.1, 129.2, 95.3, 71.9, 71.3, 70.3, 68.5, 55.7, 51.6, 39.2,
34.6, 32.5, 26.2, 25.9, 25.3, 25.2, 23.9, 23.8, 18.1, -4.4, -4.7;
[R]20D +19 (c 1.0, CHCl3); IR (KBr) νmax 3424, 2931, 1740, 1036
cm-1; HRMS (ESIMS) m/z [M + Na]+ calcd for C23H44NaO6Si
467.2799, found 467.2795.
67.9, 56.1, 38.8, 25.9, 24.3, 23.8, 22.1, 18.1, - 4.4, - 4.8; [R]20
D
+8 (c 1.7, CHCl3); IR (KBr) νmax 2955, 2929, 2857, 1732, 1596,
1498, 1462 cm-1; HRMS (ESIMS) m/z [M + H]+ calcd for
C19H33N4O3SSi 425.2037, found 425.2033.
Compound 13. To a stirred mixture of 12 (700 mg, 1.58 mmol)
and trimethyl orthoformate (1.75 mL, 16 mmol) in CH2Cl2 (8 mL)
was added d-camphorsulfonic acid (18 mg, 0.08 mmol). The
mixture was stirred at room temperature for 1 h and then diluted
with ether, washed with saturated NaHCO3 solution, water, and
brine, dried, and concentrated to give the corresponding ortho ester,
which was used directly in the next step. To a solution of the
resulting ortho ester in CH2Cl2 (16 mL) at 0 °C were added
diisopropylethylamine (2.8 mL, 16 mmol), chloromethyl methyl
ether (0.78 mL, 10 mmol,) and NaI (12 mg, 0.08 mmol). The
reaction mixture was immediately allowed to warm to 40 °C. After
6 h, saturated NaHCO3 (aq) was added. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 three
times. The combined organic layers was washed with water and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was filtrated through a shot pad of Celite to
provide MOM ether. A solution of MOM ether in 12 mL of CH2Cl2
and 3 mL of 2.5 M methanolic NaOH was stirred at -78 °C as
Macrolactone 17. PPh3 (83 mg, 0.3 mmol) and DIAD (60 µL,
63 mg, 0.3 mmol) were dissolved in benzene (10 mL). After 30
min of stirring, a slight yellow color remained. The crude hydroxy
acid 16 (10 mg, 0.03 mmol) was dissolved in benzene (20 mL)
and slowly added to the solution during 1 h. After 5 h, the reaction
(15) Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51, 635–648.
J. Org. Chem. Vol. 74, No. 14, 2009 5065