phase was removed, and the ether phase was washed with 10 mL
of brine and dried on sodium sulfate. The ether solution was filtered
and concentrated under vacuum to yield 2.39 g of product (84%).
The crude product was used in the next step without further
purification: 1H NMR (CDCl3) 4.13 (1 H, dd), 3.04 (1 H, d), 2.68
(1 H, s, OH), 2.41 (1 H, d), 2.3-2.1 (2 H, M), 1.71 (3 H, s), 1.52
(1 H, t of d), 1.46 (1 H, d of t), 1.08 (3 H, s), 1.01 (3 H, s); 13C
NMR (CDCl3) 21.0, 22.0, 26.5, 32.7, 37.2, 37.3, 39.4, 40.8, 90.7,
174.0, MS 306, 179, 137, 109; mp 102-103 °C. A sample was
crystallized from hexane/ethyl acetate for elemental analysis. Anal.
Calcd for C11H17IO3: C, 40.76; H, 5.29. Found: C, 40.73; H, 4.87.
Synthesis of (()-7r-Iodo-4,4,7r-trimethyl-5,6,7,7r-tetrahy-
dro-1-benzofuran-2(4H)-one (9). Compound 8 (2.05 g, 6.32 mmol)
was dissolved in 30 mL of pyridine. The reaction mixture was
treated with 3.76 g of thionyl chloride (31.6 mmol, 5.0 equiv) and
heated in a 60 °C oil bath for 1 h. The reaction was transferred to
a 100 mL flask, and the excess pyridine was removed under
vacuum. The crude product was dissolved in 50 mL of ethyl acetate
and washed with 50 mL of 10% aqueous hydrochloric acid. The
ethyl acetate layer was washed with 10 mL of saturated sodium
hydrogen carbonate and 10 mL of brine and dried over anhydrous
sodium sulfate. The ethyl acetate solution was filtered and
concentrated under vacuum to give 1.72 g of product as a solid, an
89.1% yield: 1H NMR (CDCl3) 5.73 (1 H, s), 3.97 (1 H, d of d),
2.37 (1 H, m), 2.28 (3 H, s), 1.65 (1H, t of d), 1.47 (1H, t of d),
1.29 (3 H, s), 1.27 (3 H, s); 13C NMR (CDCl3) 24.2, 24.8, 29.5,
33.5, 35.6, 36.2, 43.3, 87.7, 113.5, 170.2,178.8. MS 307, 179.
A sample was crystallized from hexane/ethyl acetate as fine plates
for elemental analysis: mp 167 °C. Anal. Calcd for C11H15IO2: C,
43.16; H, 4.94. Found: C, 43.54; H, 4.84. The crude material was
carried to the next step without further purification.
Synthesis of (()-Actinidiolide (4). Compound 9 (1.13 g, 3.69
mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 4.49 g, 29.5
mmol) were combined in a glass sealed reactor and heated in a
150 °C oil bath for 24 h. The reaction was cooled, diluted with 50
mL of ethyl acetate, and washed with 3 × 50 mL of 10% aqueous
hydrochloric acid. The ethyl acetate solution was washed with 25
mL of saturated sodium bicarbonate solution and 25 mL of saturated
sodium chloride solution and dried on anhydrous sodium sulfate.
The ethyl acetate solution was filtered and concentrated to give
0.65 g of (()-actinidiolide in 98% yield. The product was purified
by a simple filtration through a silica gel plug to remove color.
The spectral data of the product was identical to previously
published data for 4:9 1H NMR (CDCl3) 5.90 (1H, bd), 5.7 (1H, d
of q), 5.73 (1 H, s), 2.29 (1 H, d of d), 2.15 (1 H, d of t), 1.61 (3
H, s), 1.34 (3 H, s), 1.31 (3 H, s); 13C NMR (CDCl3) 26.1, 26.2,
28.2, 35.8, 44.5, 85.5, 112.7, 128.4, 128.9,171.5, 180.9; MS 180,
178, 163, 150, 135, 107.
Synthesis of (()-7â-Bromo-6r-hydroxy-4,4,7r-trimethyl-
5,6,7,7r-tetrahydro-1-benzofuran-2(4H)-one (11). The reaction
was run in a 50 mL reactor. Compound 4 (0.459 g, 2.58 mmol)
was dissolved in 10 mL of 1,4-dioxane and treated with N-
bromoacetamide (0.533 g, 3.86 mmol). The resulting solution was
treated with 10 mL of 10% aqueous trifluoroacetic acid. The
reaction was stirred at 25 °C for 2 h until the reaction was judged
to be complete by TLC analysis. The reaction was diluted with 25
mL of ethyl acetate and washed with 50 mL of 10% aqueous sodium
thiosulfate to quench the excess N-bromoacetamide. The ethyl
acetate phase was washed with 50 mL of saturated sodium
bicarbonate solution and 50 mL of saturated sodium chloride
solution and dried over anhydrous sodium sulfate. The solution was
filtered and concentrated under vacuum to give 0.600 g of crude
product (81% yield). The crude product was washed with 5 mL of
hexane to remove the nonpolar byproducts and excess reagents.
The product was dissolved in a minimal amount of acetone, filtered,
and crystallized by the addition of 5 volumes of hexane. The
crystallized compound was identical by NMR spectroscopy to the
previously published reference:9 1H NMR (CDCl3) 5.84 (1 H, s),
4.62 (1 H, bs), 4.50 (1 H, bm), 2.8-3.1 (1 H, OH), 2.14 (1H d of
d), 1.95 (3 H, s), 1.90 (1 H bd), 1.46 (3 H, s), 1.29 (3 H, s); 13C
NMR (CDCl3) 26.0, 26.9, 30.7, 35.5, 40.7, 59.3, 85.9, 115.4, 172.1,
178.3; MS 276, 195, 177, 149, 139.
Synthesis of (()-Loliolide (1). The reaction was run in a 50
mL reactor with a condenser, stir bar, and a nitrogen inlet. The
reactor was charged with 0.43 g of compound 11 (1.55 mmol),
tri-n-butyltin hydride (0.906 g, 3.12 mmol), 10 mL of hexane, and
catalytic 1,1-azobis(cyclohexanecarbonitrile) (0.077 mmol, 5 mol
%). The reaction was flushed with nitrogen and then heated to reflux
for 4 h. The reaction was monitored by GC analysis and was
determined to be complete by absence of 11. The reaction was
cooled to 25 °C, and the white solid was allowed to precipitate.
The hexane solution was removed, and the white solid was washed
with 10 mL of additional hexanes and dried to give 0.263 g of 1,
an 86% yield. The product was dissolved into 5 mL of ethyl acetate,
filtered, and crystallized by the addition 20 mL of hexane. Loliolide
(1) was recovered as fine prisms and was identical by NMR
spectroscopy to previously reported samples;9 1H NMR (CDCl3)
5.69 (1 H, s), 4.35 (1 H, bm), 2.50 (1 H, d of t), 2.27 (1 H, OH),
1.78 (3 H, s), 1.77 (1 H, d of d), 1.54 (1 H, d of d), 1.47 (3 H, s),
1.27 (3 H, s); 13C NMR (CDCl3) 26.3, 26.9, 30.6, 36.1, 45.4, 47.1,
66.6, 87.1, 112.6, 172.3, 183.3; MS 196, 178, 140, 111.
Synthesis of (()-Aeginetolide (2). The reaction was run in a
50 mL reaction flask with a reflux condenser, stir bar, and a nitrogen
inlet. The iodo lactone 8 (2.00 g, 6.10 mmol) was suspended in 30
mL of THF and treated with tri-n-butyltin hydride (1.97 g, 6.78
mmol) and a catalytic amount of 1,1-azobis(cyclohexanecarboni-
trile) (0.075 g, 5 mol %) as a free-radical initiator. The reaction
was heated to reflux for 4 h. The reaction was cooled, and the THF
was removed under vacuum. The product was suspended in 30 mL
of hexane, and the precipitated white solid was filtered and washed
with 50 mL of additional hexane. The product was dried and found
to weigh 1.21 g, a 99.6% crude yield. The (()-aeginetolide (2)
was purified by crystallization from ether and hexane to yield
material identical by NMR spectroscopy to previously reported
samples:11 1H NMR (CDCl3) 2.95 (1 H, d), 2.45 (1 H, OH), 2.38
(1 H, d), 2.10 (1 H, bd), 1.37-1.65 (5 H, bm), 1.50 (3 H, s), 1.05
(3 H, s), 0.98 (3 H, s); 13CNMR (CDCl3) 18.5, 19.8, 22.1, 26.8,
37.3, 37.6, 38.7, 41.3, 81.8, 89.5, 175.3; MS 180, 179, 137, 111,
98.
Synthesis of (()-Dihydroactinidiolide (3). (()-Aeginetolide (2,
0.238 g, 1.20 mmol) was dissolved in 2.0 mL of pyridine and treated
with thionyl chloride (0.283 g, 2.40 mmol). The mixture was heated
to 60 °C for 2 h. The reaction was poured into 50 mL of 10%
aqueous hydrochloric acid and was extracted with two, 50 mL
portions of ethyl acetate. The ethyl acetate layer was washed with
saturated sodium bicarbonate solution and saturated sodium chloride
solution and was dried over anhydrous sodium sulfate. The ethyl
acetate solution was filtered and concentrated under vacuum to give
0.156 g of crude 3. The product was purified by bulb-to-bulb
distillation to give 0.151 g, a 70% yield. The product is a waxy
solid that was identical by NMR spectroscopy to previously reported
samples:9 1H NMR (CDCl3), 5.63 (1 H, s), 2.24 (1 H, d of q), 1.62-
1.82 (3 H, bm), 1.55 (3 H, s), 1.46 (1 H, t of d), 1.28 (1 H, t of d),
1.27 (3 H, s), 1.23 (3 H, s); 13CNMR (CDCl3) 19.6, 24.2, 24.3,
29.8, 36.5, 40.1, 41.6, 87.2, 112.3, 171.9 182.5; MS 180, 137, 111
109.
Supporting Information Available: General experimental
1
conditions, analytical information, and H NMR, 13C NMR, and
MS data for compounds 1-4 and 7-11. This material is available
JO0611566
(11) (a) See ref 1a. (b) Goyau, B.; Rouessac, F. Bull. Soc. Chim. Fr.
1978, 590-592.
9516 J. Org. Chem., Vol. 71, No. 25, 2006