Pestalotiopsin A: Construction of Potential Building Blocks
1
1H), 5.32 (ddd, J ) 17.0, 1.3, 1.2 Hz, 1H), 5.14 (ddd, J ) 10.2,
1.3, 1.2 Hz, 1H), 4.57 (s, 2H), 4.50 (s, 1H), 4.46 (m, 1H), 3.41 (s,
3H), 3.28 (d, J ) 4.9 Hz, 1H), 1.11 (s, 3H), 1.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 137.6, 128.3, 127.7, 127.6, 116.3, 111.4, 89.2,
84.4, 72.6, 55.5, 46.2, 26.9, 16.7; HRMS (ES) m/z (M + Na)+
calcd 285.1461, obsd 285.1448; [R] 2D1 +45.0 (c 1.0, CHCl3).
(2S,4R,5R)- and (2R,4R,5R)-4-Benzyloxy-2-methoxy-3,3-di-
methyl-5-vinyltetrahydrofuran (18R and 18â). IBX oxidation of
16R and 16â (1.00 g, 3.76 mmol), following the previous example,
afforded the crude aldehyde, which was used directly in the next
reaction.
as a colorless oil: IR (film, cm-1) 3458, 1637, 1498; H NMR
(300 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 5.93 (ddd, J ) 17.5,
10.5, 7.2 Hz, 1H), 5.24 (ddd, J ) 10.5, 1.6, 1.0 Hz, 1H), 5.17 (ddd,
J ) 17.5, 1.6, 1.0 Hz, 1H), 4.48 (s, 2H), 3.84 (d, J ) 6.9 Hz, 1H),
3.82 (d, J ) 8.0 Hz, 1H), 3.05 (ddt, J ) 15.3, 7.2, 1.0 Hz, 1H),
1.52 (br s, OH), 1.15 (s, 3H), 1.10 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.5, 134.6, 128.3 (2 C), 127.5 (3 C), 117.9, 82.1, 72.2,
71.4, 47.4, 42.3, 21.4, 20.9; [R] 1D9 -34 (c 1.25, CHCl3).
(1S,5S,6S)-6-Benzyloxy-7,7-dimethyl-2-oxabicyclo[3.2.0]heptan-
3-one (8). A stirred solution of 21 (100 mg, 0.4 mmol) and
N-methylmorpholine N-oxide monohydrate (216 mg, 1.6 mmol) in
10% MeCN/CH2Cl2 (5 mL) was treated with 4 Å molecular sieves
(200 mg) under N2. After 10 min, TPAP (14 mg, 40 µmol) was
added, and the reaction mixture was stirred for a further hour and
evaporated under reduced pressure to leave a residue that was
diluted with CH2Cl2 (10 mL) and passed through a pad of silica
gel. The latter was washed with ethyl acetate (20 mL) to provide
8 (96 mg, 98%) as a colorless oil: IR (film, cm-1) 1778, 1605,
1413; 1H NMR (300 MHz, CDCl3) δ 7.41-7.27 (m, 5H), 4.51 (d,
J ) 11.8 Hz, 1H), 4.41 (d, J ) 6.2 Hz, 1H), 4.40 (d, J ) 11.8 Hz,
1H), 3.49 (d, J ) 5.7 Hz, 1H), 2.98 (m, 1H), 2.60 (dd, J ) 18.3,
8.9 Hz, 1H), 2.36 (dd, J ) 18.3, 1.1 Hz, 1H), 1.19 (s, 3H), 1.13 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 137.8, 128.5, 128.0 (2
C), 127.6 (2 C), 84.8, 82.0, 71.9, 43.9, 38.9, 33.5, 21.5, 19.8; HRMS
(ES) m/z (M + Na)+ calcd 269.1154, obsd 269.1163; [R] 1D9 -13.0
(c 0.3, CHCl3).
A suspension of methyltriphenylphosphonium bromide (2.02 g,
5.64 mmol) in anhydrous THF (10 mL) was cooled to 0 °C under
N2 and treated with n-butyllithium (3.3 mL, 1.6 M in hexanes, 5.26
mmol). The orange mixture was stirred at rt for 1 h, agitation was
stopped, and the solids were allowed to settle. A solution of
unpurified aldehydes in anhydrous THF (10 mL) and DMSO (1
mL) was cooled to -78 °C under N2 and treated slowly with the
supernatant ylide solution via cannula. The reaction mixture was
allowed to warm slowly to rt over 4 h. The reaction mixture was
treated with saturated NH4Cl solution (20 mL) and extracted with
ether (3 × 20 mL). The combined organic extracts were washed
with brine (20 mL), then dried. The solvent was evaporated under
reduced pressure and the residue was purified by column chroma-
tography (elution with 2-10% ethyl acetate in hexanes) to yield
18R and 18â (1:3) (699 mg, 71%) as colorless oils.
1
For 18R: IR (film, cm-1) 1468, 1363, 1102, 1030; H NMR
(1S,5S,6S)-7,7-Dimethyl-6-hydroxy-2-oxabicyclo[3.2.0]heptan-
3-one (22). A stirred solution of 8 (120 mg, 0.49 mmol) in
anhydrous THF (2 mL) was treated with 5% Pd on carbon (20 mg,
excess) and placed under 500 psi of hydrogen for 48 h. The reaction
mixture was filtered through a pad of Celite which was washed
with ethyl acetate (10 mL). The solvent was evaporated under
reduced pressure to yield the crude product which was purified by
column chromatography on silica gel (elution with 1:1 ethyl acetate/
hexanes) to afford 22 (75 mg, 99%) as a white solid: mp 68-
(500 MHz, CDCl3) δ 7.36-7.26 (m, 5H), 6.14-6.07 (m, 1H),
5.33-5.29 (m, 1H), 5.25-5.23 (m, 1H), 4.64-4.58 (m, 2H), 4.44
(d, J ) 12.9 Hz, 1H), 4.42 (s, 1H), 3.52 (d, J ) 5.5 Hz, 1H), 3.41
(s, 3H), 1.09 (s, 3H), 1.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.3, 136.5, 128.1 (3 C), 127.6 (2 C), 117.5, 111.4, 86.0, 83.6,
73.4, 55.7, 47.4, 26.1, 17.4; [R] 2D0 -18.3 (c 1.63, CHCl3).
1
For 18â: IR (film, cm-1) 1467, 1362, 1097, 1028; H NMR
(500 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 6.10-6.03 (m, 1H),
5.38-5.34 (m, 1H), 5.27-5.25 (m, 1H), 4.63-4.58 (m, 2H), 4.54
(s, 1H), 4.46 (d, J ) 11.8 Hz, 1H), 3.91 (d, J ) 7.8 Hz, 1H), 3.37
(s, 3H), 1.11 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.4, 135.6, 128.3 (2 C), 127.5 (3 C), 118.0, 110.5, 86.4, 80.4,
73.1, 55.5, 46.2, 21.2, 20.6; [R] 2D0 +112.6 (c 2.61, CHCl3).
(1S,3S,4R)-3-Benzyloxy-2,2-dimethyl-4-vinylcyclobutanol ((+)-
11). A stirred solution of Cp2ZrCl2 (0.7 g, 2.39 mmol) in anhydrous
THF (7.5 mL) was cooled to -78 °C under N2 and treated with
n-butyllithium (2.5 mL, 1.9 M in hexanes, 4.77 mmol). The yellow
solution was stirred for 2 h and transferred via cannula into a stirred
solution of 17 (250 mg, 0.95 mmol) and Cp2ZrCl2 (28 mg, 95 µmol)
at -78 °C under N2. After the addition was complete, the reaction
mixture was allowed to warm slowly to rt overnight, and BF3‚
OEt2 (0.12 mL, 0.95 mmol) was slowly introduced. The stirring
was continued for 2 h, and the reaction mixture was filtered through
a short pad of silica gel which was rinsed with ether (50 mL). The
filtrate was passed through another fresh pad of silica gel which
was washed with ether (50 mL). The solvent was evaporated under
reduced pressure and the residue was purified by column chroma-
tography (elution with an increasing proportion of ethyl acetate in
hexanes from 5 to 10%) to yield (+)-11 (163 mg, 74%) as a
69 °C; IR (film, cm-1) 3438, 1754, 1466; H NMR (300 MHz,
1
CDCl3) δ 4.43 (d, J ) 6.6 Hz, 1H), 3.76 (d, J ) 5.6 Hz, 1H), 2.94
(m, 1H), 2.68 (dd, J ) 18.5, 8.5 Hz, 1H), 2.56 (dd, J ) 18.5, 1.6
Hz, 1H), 1.90 (br s, OH), 1.13 (s, 3H), 1.10 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 177.9, 81.8, 78.8, 44.1, 40.8, 33.4, 20.6, 19.2;
HRMS (ES) m/z (M + Na)+ calcd 179.0684, obsd 179.0685;
[R] 1D9 -72.8 (c 1.15, CHCl3).
Thiocarbonic Acid [(1S,3S,4S)-3-(tert-Butyldimethylsiloxy)-
4-(2′-methoxymethoxyethyl)-2,2-dimethylcyclobutyl] Ester p-
Tolyl Ester (26). A stirred solution of 25 (20 mg, 63 µmol) in
anhydrous CH2Cl2 (0.5 mL) was treated with freshly distilled
pyridine (0.5 mL), O-p-tolyl thiochloroformate (29 µL, 0.19 mmol),
and DMAP (cat) under N2. The reaction mixture was stirred for 16
h, quenched with water (2 mL), and extracted with CH2Cl2 (3 ×
10 mL). The combined extracts were washed with water (2 × 2
mL), then dried. The solvent was evaporated under reduced
pressure, and the residue was purified by column chromatography
on silica gel (elution with 5% ethyl acetate in hexanes) to afford
26 (26.2 mg, 89%) as a pale yellow oil: IR (film, cm-1) 1730,
1
1612, 1506; H NMR (300 MHz, CDCl3) δ 7.20 (d, J ) 8.3 Hz,
2H), 6.97 (d, J ) 8.3 Hz, 2H), 5.19 (d, J ) 7.7 Hz, 1H), 4.62 (s,
2H), 3.91 (d, J ) 7.7 Hz, 1H), 3.54 (tq, J ) 6.4, 2.8 Hz, 2H), 3.37
(s, 3H), 2.78 (tt, J ) 15.1, 7.5 Hz, 1H), 2.37 (s, 3H), 1.88 (qd, J )
6.4, 3.3 Hz, 2H), 1.16 (s, 3H), 1.14 (s, 3H), 0.92 (s, 9H), 0.04 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 195.2, 151.4, 136.2, 130.0 (2
C), 121.5 (2 C), 96.5, 87.7, 72.0, 65.9, 55.2, 44.6, 40.8, 27.5, 25.8
(3 C), 22.1, 21.6, 20.9, 18.3, -4.7, -5.1; HRMS (ES) m/z (M +
Na)+ calcd 491.2263, obsd 491.2276; [R] D19 +20.7 (c 0.3, CHCl3).
1
colorless oil: IR (film, cm-1) 3458, 1637, 1498; H NMR (300
MHz, CDCl3) δ 7.34-7.25 (m, 5H), 5.93 (ddd, J ) 17.5, 10.5, 7.2
Hz, 1H), 5.24 (ddd, J ) 10.5, 1.6, 1.0 Hz, 1H), 5.17 (ddd, J )
17.5, 1.6, 1.0 Hz, 1H), 4.48 (s, 2H), 3.84 (d, J ) 6.9 Hz, 1H), 3.82
(d, J ) 8.0 Hz, 1H), 3.05 (ddt, J ) 15.3, 7.2, 1.0 Hz, 1H), 1.52 (br
s, OH), 1.15 (s, 3H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.5, 134.6, 128.3 (2 C), 127.5 (3 C), 117.9, 82.1, 72.2, 71.4,
47.4, 42.3, 21.4, 20.9; HRMS (ES) m/z (M + Na)+ calcd 255.1356,
obsd 255.1360; [R] 2D1 +32 (c 1.00, CHCl3).
tert-Butyl((1S,4R)-4-(2-(methoxymethoxy)ethyl)-2,2-dimeth-
ylcyclobutoxy)dimethylsilane (27). A solution of 26 (15 mg, 0.032
mmol), tributyltin hydride (69 µL, 0.25 mmol), and AIBN (4.2 mg,
0.025 mmol) in freshly distilled benzene (6 mL) was deoxygenated
thoroughly with argon. The reaction mixture was heated at 80 °C
(1R,3R,4S)-3-Benzyloxy-2,2-dimethyl-4-vinylcyclobutanol
((-)-11). Zirconocene ring contraction of 18 (800 mg, 3.05 mmol),
following the previous example, afforded (-)-11 (474 mg, 67%)
J. Org. Chem, Vol. 72, No. 19, 2007 7131