A Total Synthesis of (
+
)-Tetronolide
A R T I C L E S
tube. The reaction tube was flushed with Ar and thoroughly degassed
using three freeze-thaw cycles under vacuum (∼0.1 Torr). The tube
was sealed under vacuum and placed in a preheated 140 °C oil bath
for 5 h. Upon cooling to ambient temperature, the xylenes were removed
by distillation under reduced pressure to afford 2.3 g of crude material
as a pale yellow oil. Purification by flash chromatography on silica
gel with gradient elution using 30-60% Et2O in hexanes provided 0.55
CaH2) was prepared in 4 mL of anhydrous THF. After cooling the
solution to -78 °C, 0.19 mL of a 0.6 M solution of NaN(TMS)2 in
toluene (115 µmol) was added, and the resulting clear, pale yellow
reaction mixture was allowed to warm to room temperature and was
stirred for 18 h. The reaction mixture was partitioned between 20 mL
of Et2O and 3 mL of 1 N aqueous HCl solution. The phases were
separated, and the aqueous phase was extracted with three 5 mL portions
of Et2O. The combined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuo to afford 0.14 g of the crude product as a
pale yellow oil. The crude material was used in the next transformation
without further purification. An analytical sample of spirotetronic acid
was obtained by further purification by flash chromatography on silica
gel with elution by 33% acetone in hexanes to afford a white solid.
This material was freed of metal ions by partitioning between 3 mL of
CH2Cl2 and 3 mL of 1 N HCl. The phases were separated, and the
acidic aqueous phase was extracted with two 3 mL portions of CH2-
Cl2. The combined organic phases were dried over Na2SO4, filtered,
and concentrated in vacuo to afford pure hydroxy spirotetronic acid as
a clear, colorless oil: IR (film) 3406, 3072, 2933, 1748, 1614, 1514,
1250, 1113, 1039 cm-1; UV (90% aq MeOH) λmax (ꢀ) 230 nm
g of recovered alcohol 5 and 0.99 g (69%) of â-ketoester 43 as a clear,
1
colorless oil having [R]25 -5.41° (c 2.20, CH2Cl2) that by H NMR
D
analysis exists as a 9:1 equilibrium mixture of keto and enol forms.
The keto form of 43 has the following spectroscopic characteristics:
1
IR (film) 2932, 1738, 1708, 1614, 1513, 1248, 1105, 1040 cm-1; H
NMR (300 MHz, CDCl3) δ 7.68 (m, 4 H), 7.47-7.40 (m, 6 H), 7.24
(d, J ) 8.5 Hz, 2 H), 6.84 (d, J ) 8.5 Hz, 2 H), 6.42 (dd, J1 ) 14.2
Hz, J2 ) 6.8 Hz, 1 H), 6.03 (d, J ) 10.3 Hz, 1 H), 5.85 (s, 1 H),
5.48-5.39 (m, 2 H), 4.95 (sept, J ) 6.2 Hz, 1 H), 4.74 (d, J ) 6.6 Hz,
1 H), 4.70-4.61 (m, 3 H), 4.36 (m, 2 H), 4.21-3.80 (m, 9 H), 3.79 (s,
3 H), 3.62 (dd, J1 ) 9.9 Hz, J2 ) 5.6 Hz, 1 H), 3.48 (dd, J1 ) 10.9 Hz,
J2 ) 5.6 Hz, 1 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 3.35 (m, 2 H), 2.96 (d,
J ) 18.0 Hz, 1 H), 2.66 (m, 1 H), 2.50 (m, 2 H), 2.30 (m, 1 H), 2.06
(m, 1 H), 1.92 (m, 1 H), 1.50 (m, 2 H), 1.45 (s, 3 H), 1.26 (s, 3 H),
1.23 (d, J ) 6.2 Hz, 3 H), 1.19 (d, J ) 6.2 Hz, 3 H), 1.08 (s, 9 H),
1.00 (d, J ) 7.0 Hz, 3 H), 0.60 (d, J ) 6.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 205.0, 169.5, 166.2, 159.6, 151.9, 139.1, 138.2, 136.0,
134.03, 133.98, 131.2, 130.1, 129.8, 128.2, 127.3, 126.4, 117.8, 114.2,
95.8, 87.3, 81.4, 81.2, 72.3, 72.2, 69.8, 66.8, 66.4, 65.0, 57.5, 56.2,
56.1, 55.7, 53.4, 47.8, 46.2, 44.5, 41.8, 38.2, 32.3, 32.2, 30.9, 27.3,
23.5, 22.1, 21.9, 19.8, 19.2, 13.8. HRMS (FAB-). Calcd for C62H83O13-
Si [M - H+]: m/z 1063.5603. Found: m/z 1063.5632.
1
(∼17000), 257 nm (∼10000), 276 nm (9000); H NMR (300 MHz,
CDCl3) δ 7.66 (d, J ) 6.8 Hz, 4 H), 7.45-7.35 (m, 6 H), 7.26 (d, J )
8.9 Hz, 2 H), 6.87 (d, J ) 8.9 Hz, 2 H), 6.03 (d, J ) 10.2 Hz, 1 H),
5.94 (s, 1 H), 5.44-5.41 (m, 2 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.69 (d,
J ) 7.0 Hz, 1 H), 4.66 (d, J ) 6.7 Hz, 1 H), 4.56 (d, J ) 6.9 Hz, 1 H),
4.40 (s, 2 H), 4.10-4.04 (m, 4 H), 3.90-3.80 (m, 1 H), 3.82 (s, 3 H),
3.61-3.55 (m, 2 H), 3.42 (s, 3 H), 3.35 (s, 3 H), 3.27 (d, J ) 6.4 Hz,
2 H), 2.64 (d, J ) 17.5 Hz, 1 H), 2.42-2.30 (m, 2 H), 2.18 (m, 1 H),
2.08 (m, 1 H), 1.90 (d, J ) 17.7 Hz, 1 H), 1.65-1.50 (m, 3 H), 1.57
(s, 3 H), 1.45 (s, 3 H), 1.28 (d, J ) 4.3 Hz, 1 H), 1.07 (s, 9 H), 1.05
(m, 3 H), 0.60 (br s, 3 H); 13C NMR (75 MHz, CDCl3) δ 204.4, 200.1,
167.5, 159.4, 138.1, 135.4, 133.9, 133.2, 133.1, 130.1, 129.7, 129.0,
127.6, 126.3, 125.8, 125.5, 121.7, 113.7, 100.7, 96.6, 95.2, 83.0, 80.9,
73.4, 73.0, 67.6, 65.8, 58.0, 55.61, 55.59, 52.6, 50.8, 45.6, 43.3, 41.3,
38.0, 35.1, 31.9, 31.1, 26.7, 21.8, 19.2, 15.4, 14.1, 13.5. HRMS (FAB+).
Calcd for C57H74NaO12Si (M+ + Na): m/z 1001.4847. Found: m/z
1001.4860. Calcd for C57H73Na2O12Si (M+ - H + 2Na): 1023.4667.
Found: 1023.4682.
Methyl Spirotetronate 45. Removal of the Vinyl Ether: Prepara-
tion of the Hydroxy â-Ketoester. To a solution of 0.375 g (0.353
mmol) of â-ketoester 43 in 20 mL of methanol was added 9 mg (0.035
mmol) of pyridinium p-toluenesulfonate, and the mixture was allowed
to stir at 40 °C for 14 h. After cooling to ambient temperature, the
reaction mixture was concentrated in vacuo, and the resulting residue
was dissolved in 25 mL of Et2O. The cloudy solution was filtered
through a plug of silica gel eluting with additional Et2O, and the clear
filtrate was concentrated in vacuo to afford 0.39 g of the crude product
mixture as a clear, colorless oil. The crude material was purified by
flash chromatography on silica gel with gradient elution using 80-
100% Et2O in hexanes to yield 0.315 g (86%) of pure hydroxy
â-ketoester as a white solid having [R]25D -17.0° (c 3.10, CH2Cl2). 1H
NMR analysis revealed that the hydroxy â-ketoester exists as a ∼9:1
equilibrium mixture of keto and enol forms. The keto form of the
primary alcohol had the following spectroscopic characteristics: IR
Methylation of the Spirotetronic Acid: Preparation of Methyl
Hydroxy Spirotetronate 45. A solution of 0.14 g (∼96 µmol) of the
crude hydroxy spirotetronic acid, prepared as immediately above, in
1.25 mL of benzene and 0.5 mL of methanol was cooled to 0 °C. To
this mixture was added dropwise 0.15 mL of a 2.0 M solution of
TMSCHN2 in hexanes (300 µmol) with the concomitant evolution of
gas. The resulting clear, bright yellow solution was allowed to warm
to ambient temperature and was stirred for 30 min. The reaction mixture
was concentrated in vacuo to afford the crude material as a yellow oil.
Purification by flash chromatography on silica gel with elution by 70%
Et2O in hexanes afforded 0.060 g (62% overall from 43) of pure methyl
hydroxy spirotetronate 45 as a clear, colorless oil: IR (film) 3454, 2932,
1746, 1682, 1613, 1504, 1248, 1038 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.67 (d, J ) 5.9 Hz, 4 H), 7.43-7.38 (m, 6 H), 7.24 (d, J ) 8.5 Hz,
2 H), 6.88 (d, J ) 8.5 Hz, 2 H), 6.04 (d, J ) 10.3 Hz, 1 H), 5.91 (s,
1 H), 5.64 (m, 1 H), 5.52 (m, 1 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.72 (d,
J ) 6.9 Hz, 1 H), 4.66 (d, J ) 6.8 Hz, 1 H), 4.62 (d, J ) 6.9 Hz, 1 H),
4.41 (dd, J1 ) 17.4 Hz, J2 ) 11.0 Hz, 2 H), 4.25 (s, 3 H), 4.20-4.08
(m, 2 H), 4.06 (s, 2 H), 4.00-3.87 (m, 2 H), 3.82 (s, 3 H), 3.50 (dd,
J1 ) 10.9 Hz, J2 ) 5.2 Hz, 1 H), 3.42-3.38 (m, 2 H), 3.42 (s, 3 H),
3.38 (s, 3 H), 3.19 (br s, 1 H), 2.68 (d, J ) 17.9 Hz, 1 H), 2.40-2.23
(m, 2 H), 2.17 (m, 1 H), 2.03 (m, 1 H), 1.89 (d, J ) 17.9 Hz, 1 H),
1.60-1.50 (m, 3 H), 1.52 (s, 3 H), 1.46 (d, J ) 2.8 Hz, 3 H), 1.06 (s,
9 H), 1.03 (d, J ) 7.0 Hz, 3 H), 0.55 (d, J ) 6.0 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 204.2, 195.2, 184.5, 169.4, 159.5, 138.8, 135.4,
135.0, 133.3, 130.2, 129.6, 129.0, 127.6, 126.4, 126.1, 120.9, 113.8,
99.9, 96.4, 95.3, 86.9, 80.9, 73.9, 73.1, 67.3, 65.9, 65.3, 59.1, 55.6,
55.1, 52.5, 51.2, 46.2, 45.7, 41.1, 37.6, 35.7, 31.8, 30.2, 30.1, 26.7,
(film) 3478, 2931, 1738, 1710, 1613, 1514, 1248, 1106, 1039 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.78-7.65 (m, 4 H), 7.45-7.38 (m, 6
H), 7.26 (d, J ) 8.5 Hz, 2 H), 6.85 (d, J ) 8.5 Hz, 2 H), 6.04 (d, J )
10.3 Hz, 1 H), 5.91 (s, 1 H), 5.51-5.40 (m, 2 H), 5.09 (sept, J ) 6.2
Hz, 1 H), 4.78 (d, J ) 6.7 Hz, 1 H), 4.78-4.74 (m, 2 H), 4.66 (d, J )
6.6 Hz, 1 H), 4.46-4.37 (m, 3 H), 4.22-3.79 (m, 6 H), 3.79 (s, 3 H),
3.72-3.65 (m, 1 H), 3.55-3.46 (m, 1 H), 3.43 (s, 3 H), 3.41 (s, 3 H),
3.41-3.38 (m, 2 H), 2.90 (d, J ) 18.1 Hz, 1 H), 2.66-2.60 (m, 2 H),
2.48 (m, 1 H), 2.30 (m, 1 H), 2.16 (m, 1 H), 2.07 (m, 1 H), 1.94 (m,
1 H), 1.55-1.45 (m, 2 H), 1.50 (s, 3 H), 1.30 (d, J ) 6.3 Hz, 3 H),
1.26 (s, 3 H), 1.24 (d, J ) 6.3 Hz, 3 H), 1.09 (s, 9 H), 1.02 (d, J ) 7.0
Hz, 3 H), 0.62 (d, J ) 5.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
205.0, 169.9, 166.2, 159.6 139.3, 136.8, 136.0, 134.0, 133.9, 131.1,
130.1, 129.8, 128.1, 127.4, 127.2, 126.3, 119.6, 114.2, 96.4, 95.9, 83.3,
81.4, 72.9, 72.2, 70.2, 66.9, 66.4, 60.5, 57.5, 56.2, 56.1, 55.7, 53.5,
48.5, 47.6, 44.6, 41.7, 38.1, 32.3, 31.4, 30.9, 27.3, 23.33, 22.1, 22.0,
19.8, 19.4, 13.8. HRMS (FAB-). Calcd for C60H81O13Si (M - H+):
m/z 1037.5446. Found: m/z 1037.5424.
Dieckmann Condensation of the Hydroxy â-Ketoester: Prepara-
tion of the Spirotetronic Acid. A solution of 0.10 g (96 µmol) of the
preceding primary alcohol and 0.2 mL of freshly distilled HMPA (from
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J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10585