SYNTHESIS
April 1998
625
at r.t. for 24 h. After dilution with CH2Cl2, the mixture was washed
with H2O (50 mL × 2) and brine and was dried (MgSO4). Removal of
the solvent under reduced pressure yielded 90.1 mg (96%) of pure 26.
IR (neat) ν = 2958, 1734, 1674, 1624, 1241, 1174, 1097 cm–1.
1H NMR (300 MHz, CDCl3) δ = 7.10 (1H, d, J = 1 Hz), 5.15 (1H, dd,
J = 10, 5 Hz), 3.98–3.91 (4H, m), 3.74 (3H, s), 2.45–2.35 (1H, m),
2.13 (1H, dd, J = 14, 10 Hz), 1.96–1.88 (2H, m), 1.68 (3H, d, J = 1
Hz), 1.65–1.57 (2H, m).
13C NMR (75 MHz, CDCl3) δ = 208.3, 172.4, 143.5, 132.5, 94.9,
90.3, 87.2, 79.6, 57.0, 54.8, 52.3, 41.4, 37.7, 27.1, 12.0.
MS m/z = 296 (M+), 278, 264, 214, 205, 179, 154, 142, 125 (100%),
111, 85, 82.
HRMS 297.1340 (calcd for C15H21O6 297.1340).
Anal. Calcd for C15H20O6: C, 60.80; H, 6.80. Found: C, 60.71; H,
6.65.
13C NMR (75 MHz, CDCl3) δ = 189.2, 170.5, 157.2, 112.0, 107.7,
78.9, 64.5, 64.3, 56.1, 52.9, 34.8, 31.1, 24.9, 10.7.
5-Acetoxy-9,9-ethylenedioxy-4-methyl-15-oxo-4,15-epoxyapotri-
chothec-2-ene (32):
MS m/z = 282 (M+), 251, 223, 198, 183, 167, 99, 86 (100%).
HRMS 282.1098 (calcd for C14H18O6Si 282.1103).
A solution of 27 (70.3 mg, 0.23 mmol) in glacial HOAc (3 mL) was
stirred at r.t. overnight. The solvent was evaporated under reduced
pressure and the residue was chromatographed on silica gel with hex-
ane/EtOAc (1:1) as eluent to give 19.6 mg (26%) of 32.
IR (neat) ν = 2980, 1768, 1755, 1230, 1105, 1082, 1043 cm–1.
1H NMR (300 MHz, CDCl3) δ = 6.09 (1H, d, J = 6 Hz), 5.87 (1H, br
s), 5.63 (1H, br s), 4.20 (1H, t, J = 4 Hz), 3.47 (4H, m), 2.15 (3H, s),
2.18–2.01 (6H, m), 1.48 (3H, s).
cis-anti-cis-8-Carbomethoxy-11,11-ethylenedioxy-6-methyl-7-
oxo-2-oxatricyclo[6.4.4.03,6]dodec-4-ene (27):
A solution of 26 (87 mg, 0.3 mmol) in acetone (120 mL) was flushed
with Ar for 0.5 h and with acetylene for 0.5 h. The solution was irradi-
ated with a 450 Hanovia medium pressure mercury lamp through a
Pyrex filter for 1.5 h while acetylene was passed continuously through
the solution. After the solvent was evaporated under reduced pressure,
a yellow oil was obtained which was chromatographed on silica gel
with hexane/EtOAc (6:1) as eluent to yield 43.4 mg (44%) of 27.
IR (neat) ν = 2957, 1745, 1700, 1248, 1183, 1098, 1048, 1009 cm–1.
1H NMR (300 MHz, CDCl3) δ = 6.28, (1H, d, J = 3 Hz), 6.09 (1H, d,
J = 3 Hz), 4.90 (1H, dd, J = 4, 3 Hz), 4.76 (1H, s), 4.13–4.05 (1H, m),
4.01–3.85 (3H, m), 3.72 (3H, s), 2.11–1.74 (6H, m), 1.35 (3H, s).
13C NMR (75 MHz, CDCl3) δ = 206.9, 169.8, 141.2, 139.2, 107.0,
79.8, 69.2, 65.1, 63.8, 60.8, 56.9, 52.6, 37.0, 31.6, 24.7, 19.3.
MS m/z = 308 (M+, 100%), 307, 295, 291, 277, 265, 228, 211, 200,
199, 167, 156, 140, 112, 100, 60.
13C NMR (75 MHz, CDCl3) δ = 175.4, 169.8, 137.4, 131.1, 106.8,
99.6, 93.4, 87.7, 78.0, 64.9, 64.0, 55.9, 34.6, 29.7, 21.8, 21.1, 19.6.
MS m/z = 336 (M+), 232, 165, 153, 115, 99 (100%), 86.
HRMS 336.1209 (calcd for C17H20O7 336.1209).
Anal. Calcd for C17H20O7: C, 60.71; H, 5.99. Found: C, 60.99; H, 5.95.
4,9-Dimethyl-5-hydroxy-15-oxo-4,15-epoxyapotrichothec-2,9-di-
ene (34):
To a solution of 28 (26 mg, 0.10 mmol) in anhyd Et2O (25 mL) at 0°C
was added dropwise a 3M solution of MeMgBr in Et2O (0.07 mL,
0.22 mmol). The mixture was stirred at 0°C for 2 h, poured onto
cracked ice, and acidified to pH 5 with dilute HCl. The mixture was
extracted with Et2O and the extract was dried (Na2SO4). Removal of
the solvent left 21 mg of crude 33 (mixture of epimers) which was
used in the next step without purification.
HRMS 309.1337 (calcd for C16H21O6 309.1338).
9,15-Dioxo-5-hydroxy-4-methyl-4,15-epoxyapotrichothec-2-ene
(28):
A solution of 27 (12 mg, 0.039 mmol) in anhyd benzene (2.5 mL)
containing p-TsOH (3 mg) was stirred at r.t. for 48 h. The solvent was
evaporated under reduced pressure to leave a solid which was taken
up in a small volume of EtOAc and chromatographed on silica gel
with hexane/EtOAc (1:1) as eluent. This afforded 5.5 mg (57%) of 28:
mp 214–215°C.
To a solution of crude 33 (21 mg) in pyridine (8 mL) was added
POCl3 (30 mg, 0.2 mmol), and the mixture was stirred at r.t. for 4 h.
The mixture was poured onto cracked ice and extracted with Et2O.
The ethereal extract was washed with dilute HCl, sat. aq. CuSO4, and
brine, and was dried (Na2SO4) Removal of the solvent under reduced
pressure left an oily residue which was chromatographed on silica gel
with hexane/EtOAc (1:1) as eluent to give 15 mg (60% based on 28)
of 34 as an oil.
IR (KBr) ν = 3429, 2937, 2908, 1759, 1733, 1710, 1689, 1406, 1354,
1264, 1253, 1105, 1088, 1049, 1019 cm–1
.
1H NMR (300 MHz, CDCl3) δ = 6.11 (1H, d, J = 6 Hz), 5.82 (1H, dd,
J = 6, 2 Hz), 4.94 (1H, d, J = 2 Hz), 4.37 (1H, dd, J = 3, 3 Hz), 2.70
(2H, d, J = 3 Hz), 2.53 (1H, s; D2O exchange), 2.48–2.30 (4H, m),
1.55 (3H, s).
IR (neat) ν = 3340, 2895, 1765, 1433, 1281, 1070, 1022 cm–1.
1H NMR (300 MHz, CDCl3) δ = 6.10 (1H, d, J = 6 Hz), 5.85 (1H, dd,
J = 6, 2 Hz), 5.56 (1H, br s), 4.92 (1H, d, J = 2 Hz), 4.76 (1H, br s),
2.94 (1H, s, exchanged with D2O), 2.25–1.85 (4H, m), 1.68 (3H, s),
1.52 (3H, s).
13C NMR (75 MHz, CDCl3) δ = 208.4, 176.3, 138.6, 130.8, 95.0,
93.8, 93.2, 79.1, 57.0, 40.6, 34.7, 21.3, 19.3.
13C NMR (75 MHz, CDCl3) δ = 179.2, 141.1, 133.3, 129.9, 126.7,
94.2, 92.8, 89.6, 82.5, 55.3, 37.7, 26.8, 18.4, 13.5.
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.34; H, 6.29.
MS m/z = 251 (M+1, 100%), 233, 205, 169, 141, 111.
HRMS 251.0915 (calcd for C13H15O5 251.0919):
Anal. Calcd for C13H14O5: C, 62.39; H, 5.64. Found: C, 62.08; H, 5.57.
5,14-Dimethyl-2,10-dioxa-9,13-dioxotetracyclo[6.4.2.03,8.011,14]-
tetradecan-4-ene (35):
Compound 28 crystallized from hexane–EtOAc in the space group
Pbca (#61) with a = 17.600 (9) Å, b = 13.242 (9) Å, c = 9.803 (9) Å,
and dcalcd = 1.455 g/cm3. The intensity data were measured on a
Rigaku AFC6R diffractometer (Mo radiation). There were 1763 inde-
pendent reflections of which 835 were considered observed (F >3 σ
(F)). The structure was solved by direct methods; final discrepancy
indices were R = 0.0701 and wR = 0.0850.
A solution of 34 (14.0 mg, 0.056 mmol) in THF (7 mL) containing tet-
rakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) and triphe-
nylphosphine (15 mg, 0.057 mmol) was heated at reflux for 2 h. The
solvent was evaporated and the residue was taken up into Et2O. The
ethereal suspension was filtered and the filtrate was dried (MgSO4).
After removal of the solvent under reduced pressure, the residual oil
was chromatographed on silical gel with hexane/EtOAc (1:1) as elu-
ent to give 8.1 mg (58%) of 35 as a solid which crystallized from
Et2O: mp 146–148°C.
7-Hydroxy-4-methoxy-8-(methoxycarbonyl)-6-methyl-11-oxo-2-
oxatricyclo[6.4.0.03,7]dodec-5-ene (31):
To a solution of 27 (10 mg, 0.03 mmol) in anhyd MeOH (1.5 mL) was
added a catalytic amount of p-TsOH. The mixture was heated at reflux
overnight and the solvent was evaporated under reduced pressure to
leave a light brown oil, which was chromatographed on silica gel with
hexane/EtOAc (1:1–1:2) as eluent to give 3.3 mg (38%) of 31 as an oil.
IR (neat) ν = 3340, 2897, 1723, 1265, 1096, 1062, 1020 cm–1.
1H NMR (300 MHz, CDCl3) δ = 5.82 (1H, m), 4.45 (1H, m), 4.18
(1H, s), 3.97 (1H, t, J = 2 Hz), 3.82 (3H, s), 3.39 (3H, s), 2.68–2.12
(6H, m), 1.94 (1H, br s), 1.68 (3H, m).
IR (KBr) ν =2970, 1772, 1755, 1445, 1353, 1212, 1190, 1130, 1078,
1055, 1020 cm–1
.
1H NMR (300 MHz, CDCl3) δ = 5.36 (1H, d, J = 1 Hz), 4.53 (1H, dd,
J = 7, 1 Hz), 4.43 (1H, br s), 4.10 (1H, br s), 2.29 (1H, d, J = 15 Hz),
1.85–2.20 (5H, m), 1.68 (3H, s), 1.37 (3H, s).
MS m/z 248 (M+), 154 (100%) 136, 121, 111, 105, 95.
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.51; H,
6.40.