Studies toward the Total Synthesis of Clavulactone
J . Org. Chem., Vol. 66, No. 8, 2001 2697
) -31.7 (c 1.6, EtOH). 1H NMR (CDCl3, 300 MHz): δ 6.93
(dt, 1H, J ) 15.7, 7.0 Hz), 5.84 (dt, 1H, J ) 15.6, 1.6 Hz), 5.51
(m, 1H), 4.79 (q, 1H, J ) 5.1 Hz), 4.29 (dd, 1H, J ) 13.1, 1.5
Hz), 4.19 (q, 2H, J ) 7.2 Hz), 3.91 (dd, 1H, J ) 13.2, 1.7 Hz),
3.85 (m, 1H), 2.61 (s, 3H), 2.30 (m, 2H), 1.65 (m, 1H), 1.86 (m,
1H), 1.39 (d, 3H, J ) 5.1 Hz), 1.29 (t, 3H, J ) 7.1 Hz). IR
(film): 1717, 1655, 1216, 1071 cm-1. EIMS m/z: 335, 301, 245,
183, 137. Anal. Calcd for C14H22O5S2: C, 50.29; H, 6.64.
Found: C, 50.24; H, 6.76. Data for 17 follow. [R]15D ) -20.3 (c
1.70 (m, 1H), 1.35 (d, 3H, J ) 5.2 Hz), 1.27 (t, 6H, J ) 7.4
Hz). IR (film): 1722, 1637, 1447, 1248, 1216 cm-1. EIMS m/z:
421, 376, 358, 330, 223. Anal. Calcd for C18H28O7S2: C, 51.41;
H, 6.71. Found: C, 51.78; H, 6.95.
Cyclop en ta -1,3-d ioxin -5-a cetic Acid , Hexa h yd r o-2,5-
d im eth yl-, Eth yl Ester , (2S,4a R,5S,7a R) (4a ) a n d (2S,-
4a R,5R,7a R) (4b). A solution of Bu3SnH (0.54 mL, 2.00 mmol)
in benzene (5 mL) was added dropwise to a solution of 25 (560
mg, 1.33 mmol) in benzene (20 mL) containing a catalytic
amount of AIBN at reflux under nitrogen. The resulting
mixture was refluxed for 10 h before being cooled to room
temperature. Aqueous NaF (20 mL) was added. Stirring was
continued for a few more hours before the reaction mixture
was diluted with ethyl ether (100 mL), washed with brine, and
dried over Na2SO4. After concentration, the residue was
purified by column chromatography to yield 334 mg of the
mixture of a pair of inseparable diastereomers of 26 (80%).
A mixture of 25 (4.92 g, 15.67 mmol), LiCl (666 mg, 15.67
mmol), water (564 mg, 31.34 mmol), and DMSO (50 mL) was
heated at 190 °C under argon for 5 h. After the mixture was
cooled to room temperature, ether (300 mL) was used to extract
the product. The organic layer was washed successively with
water and brine and dried over Na2SO4. Concentration and
column chromatography gave 4a (1.72 g) and 4b (0.73 g) in
1
1.42, EtOH). H NMR (CDCl3, 300 MHz): δ 6.29 (dt, 1H, J )
11.5, 7.6 Hz), 5.77 (dt, 1H, J ) 11.5, 1.7 Hz), 5.55 (m, 1H),
4.87 (q, 1H, J ) 5.1 Hz), 4.20 (dd, 1H, J ) 13.1, 1.5 Hz), 4.12
(q, 2H, J ) 7.2 Hz), 4.02 (dd, 1H, J ) 13.2, 1.6 Hz), 4.10 (m,
1H), 2.70 (m, 2H), 2.62 (s, 3H), 1.64 (m, 1H), 1.75 (m, 1H),
1.26 (d, 3H, J ) 5.1 Hz), 1.26 (t, 3H, J ) 7.1 Hz). IR (film):
1718, 1645 cm-1. EIMS m/z: 335, 245, 183, 137, 91. Anal.
Calcd for C14H22O5S2: C, 50.29; H, 6.64. Found: C, 50.02; H,
6.75.
Cyclop en t a -1,3-d ioxin -5-a cet ic a cid , H exa h yd r o-2-
m eth yl-, Eth yl Ester , (2S,4a R,5R,7a R) (18a ) a n d (2S,-
4a R,5S,7a R) (18b). To a gently refluxing solution of 16 (838
mg, 2.51 mmol) and AIBN (40 mg) in benzene (10 mL) under
nitrogen was added dropwise a solution of Bu3SnH (1.0 mL,
3.77 mmol) in benzene (10 mL) over 30 min. The reaction was
refluxed for another 3 h. After the mixture was cooled to room
temperature, saturated aqueous NaF solution (20 mL) was
introduced. Stirring was continued for an additional 1 h before
the reaction mixture was diluted with ether (100 mL), washed
with brine, and dried over Na2SO4. Column chromatography
gave 18a (420 mg) and 18b (101 mg) in 73% and 18% yield,
respectively. When compound 17 (182 mg, 0.55 mmol) was
used as substrate in this reaction, 18a and 18b were isolated
65% yield. Data for 4a follow. [R]23 ) -20.4 (c 1.85, EtOH).
D
1H NMR (CDCl3, 300 MHz): δ 4.61 (q, 1H, J ) 5.1 Hz), 4.21
(m, 1H), 4.09 (q, 2H, J ) 7.0 Hz), 4.08 (d, 1H, J ) 12.9 Hz),
3.96 (dd, 1H, J ) 12.5, 4.3 Hz), 2.21 (d, 1H, J ) 13.8 Hz), 2.32
(d, 1H, J ) 13.8 Hz), 1.88-1.68 (m, 4H), 1.54 (t, 1H, J ) 4.3
Hz), 1.29 (s, 3H), 1.26 (d, 3H, J ) 5.1 Hz), 1.23 (t, 3H, J ) 7.1
Hz). 13C NMR (CDCl3, 75 MHz): δ 172.23, 97.23, 79.96, 64.89,
60.08, 47.35, 44.90, 41.50, 38.83, 30.56, 24.61, 21.34, 14.28.
IR (film): 1733, 1462, 1408, 1370 cm-1. EIMS m/z: 243, 227,
199, 181. Anal. Calcd for C13H22O4: C, 64.42; H, 9.16. Found:
C, 64.14; H, 9.40. Data for 4b: see ref 2f.
in 45.5% and 52.7% yield, respectively. Data for 18a follow.
1
[R]19 ) +23.8 (c 1.80, EtOH). H NMR (CDCl3, 300 MHz): δ
D
4.66 (q, 1H, J ) 5.1 Hz), 4.16 (q, 2H, J ) 7.1 Hz), 4.16 (m,
1H), 4.10 (d, 1H, J ) 11.4 Hz), 4.01 (dd, 1H, J ) 11.4, 3.8 Hz),
2.60 (m, 2H), 2.75 (m, 1H), 2.05-1.60 (m, 5H), 1.30 (d, 3H, J
Cyclop en t a -1,3-d ioxin -5-a cet ic Acid , H exa h yd r o-2-
(p -m et h oxyb en zylid en e)-5-m et h yl,
Met h yl
E st er ,
) 5.1 Hz), 1.28 (t, 3H, J ) 7.1 Hz). IR (film): 1733 cm-1
.
(2S,4R,5S,7R) (28) a n d La cton e (30). A mixture of 4a and
4b (45.0 g, 2.2:1 by NMR) and p-TsOH (70 g) was dissolved in
methanol (1 L) and heated to reflux for 13 h. After removal of
the solvent, diethoxy p-methoxybenzylidene acetal (58.3 g),
pyridine (29.8 mL), and DMF (50 mL) were added. The
resulting mixture was stirred at 50 °C under reduced pressure
(10-15 mmHg) for 3 h. After being cooled to room temperature,
the reaction mixture was diluted with ethyl ether (1000 mL),
washed in turn with saturated NaHCO3 and brine, and dried
over Na2SO4. After concentration, column chromatography
separated unreacted diol 27 from desired PMP-acetal. The
aqueous layer was saturated with sodium chloride, and CH2-
Cl2 (500 mL) was used to extract the unreacted diol 27. Taken
together, the recovered 27 was subjected to the same proce-
dure. After two cycles, acetal 28 (26.5 g) was finally obtained
in 65% total yield. The extract from the last portion of the
aqueous phase was dried (Na2SO4) and esterified with acetic
anhydride and pyridine system. Normal workup and chro-
matographic purification gave 8.3 g of the bridged lactone 30
EIMS: 229, 213, 185, 167. Anal. Calcd for C12H20O4: C, 63.14;
H, 8.83. Found: C, 63.26; H, 8.92. Data for 18b follow. [R]19
D
) -46.8 (c 2.45, EtOH). 1H NMR (CDCl3, 300 MHz): δ 4.62
(q, 1H, J ) 5.1 Hz), 4.11 (q, 2H, J ) 7.1 Hz), 4.11 (m, 1H),
3.94 (m, 2H), 2.70 (m, 1H), 2.50 (dd, 1H, J ) 14.8, 4.9 Hz),
2.21 (m, 1H), 2.20 (m, 1H), 1.90-1.60 (m, 3H), 1.35 (m, 1H),
1.28 (d, 3H, J ) 5.1 Hz), 1.24 (t, 3H, J ) 7.1 Hz). IR: 1735
cm-1
. EIMS m/z: 227, 213, 184, 167. Anal. Calcd for
C
12H20O4: C, 63.14; H, 8.83. Found: C, 63.36; H, 8.94.
P r op a n ed ioic Acid , [1-Meth yl-3-[(2S,4R,5R)-2-m eth yl-
5-[(m et h ylt h io)t h ioxom et h oxy]-1,3-d ioxa n -4-yl]p r op y-
lid en e]-, Dieth yl Ester (25). n-BuLi (21 mL, 52.5 mmol) was
added to a stirring solution of (i-Pr)2NH (6.7 mL, 51.45 mmol)
and HMPA (12 mL, 68.6 mmol) in freshly distilled THF (150
mL) stirred at -78 °C under nitrogen. After 15 min, a solution
of 22 (11.32 g, 34.3 mmol) in THF (30 mL) was introduced
dropwise. The resulting mixture was stirred at -78 °C for 2 h
before ethyl chloroformate (4.0 mL, 41.16 mmol) was added.
The reaction mixture was warmed to room temperature
gradually and stirred for another 45 h. Ether (200 mL) was
then added, and the reaction mixture was washed with
saturated aqueous NH4Cl and brine. The organic layer was
concentrated, and the residue was taken up into THF (50 mL)
with 1 N HCl. When TLC showed that the EE was removed
completely, ether (200 mL) was added. The combined organic
layer was washed with brine and then dried over Na2SO4. After
concentration, the residue was carefully column chromato-
graphed to give 1.85 g of the monoester (deprotected product
of the unreacted starting material) and 7.34 g of the diester
product 24 in 65% yield for two steps.
1
as the sole product. Data for 28 follow. H NMR (CDCl3, 300
MHz): δ 7.39 (d, 2H, J ) 8.5 Hz), 6.89 (d, 2H, J ) 8.5 Hz),
5.40 (s, 1H), 4.44 (m, 1H), 4.22 (m, 2H), 3.81 (s, 3H), 3.67 (s,
3H), 2.42 (d, 1H, J ) 14.0 Hz), 2.31 (d, 1H, J ) 13.1 Hz), 1.90
(m, 3H), 1.75 (m, 1H), 1.65 (m, 1H), 1.40 (s, 3H). IR (film):
1735, 1673, 1615, 1518 cm-1. EIMS: 321, 320, 319, 289, 241,
227. HRMS: calcd for C18H23O5 319.1546, found 319.1569.
Data for 30 follow. 1H NMR (CDCl3, 300 MHz) δ 5.30 (m, 1H),
4.23 (d, 2H, J ) 6.3 Hz), 2.53 (d, 1H, J ) 14.8 Hz), 2.40 (d,
1H, J ) 14.8 Hz), 2.26 (m, 1H), 2.07 (s, 3H), 1.98 (m, 1H),
1.80 (m, 2H), 1.59 (m, 1H), 1.18 (s, 3H). IR (film): 1736, 1457,
1435, 1375, 1244 cm-1. EIMS m/z: 213, 197, 185, 170, 153,
152. HRMS m/z: calcd for C11H16O4 212.1049, found 212.1069.
Z-Tr isu bstitu ted -r,â-Un sa tu r a ted Ester (31). To a solu-
tion of 28 (26.5 g, 82.8 mmol) in CH2Cl2 (200 mL) stirred at
-78 °C under nitrogen was added DIBAL (182 mL, 1.0 M in
cyclohexane). The resulting solution was stirred at -78 °C for
another 5 h before the reaction was quenched by slow addition
of H2O (10 mL). The reaction mixture was warmed to room
Using a procedure similar to that for preparing xanthate
16, compound 25 (11.90 g) was obtained from its precursor 24
(10.5 g, 31.8 mmol) in 89% yield. Data for 25 follow. [R]20
)
D
1
+22.0 (c 1.40, EtOH). H NMR (CDCl3, 300 MHz): δ 5.48 (m,
1H), 4.77 (q, 1H, J ) 5.2 Hz), 4.28 (d, 1H, J ) 13.2 Hz), 4.21
(q, 4H, J ) 7.1 Hz), 3.89 (d, 1H, J ) 13.5 Hz), 3.85 (m, 1H),
2.58 (s, 3H), 2.50-2.30 (m, 2 H), 2.04 (s, 3H), 1.84 (m, 1H),