Total Synthesis of (()-Stemodinone
J . Org. Chem., Vol. 66, No. 21, 2001 7111
(440 mg, 70% yield): colorless crystals; mp 97-99 °C (n-
hexane); IR (KBr) cm-1 1672, 1620; 1H NMR (500 MHz, CDCl3)
δ 1.29 (m, 1H), 1.39 (ddd, J ) 14.2, 6.5, 4.3 Hz, 1H), 1.67 (m,
1H), 1.76 (m, 1H), 1.80 (dd, J ) 14.2, 6.5 Hz, 1H), 1.95 (s, 3H,
2-Me), 2.04 (ddd, J ) 14.2, 14.2, 6.5 Hz, 1H), 2.07 (d, J ) 11.8
Hz, 1H), 2.11-2.36 (m, 4H), 2.48 (dd, J ) 14.2, 5.4 Hz, 1H),
3.84-4.02 (m, 4H, OCH2CH2O), 5.80 (s, 1H, 3-H); 13C NMR
(67.8 MHz, CDCl3) δ 21.2, 29.0, 34.5, 35.4, 35.6, 39.1, 44.1,
44.2, 46.6, 64.1, 64.6, 110.1, 126.1, 164.3, 199.0; MS (EI) m/z
248 (M+). Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found:
C, 72.28; H, 8.20.
1H), 2.25 (s, 3H, COCH3), 2.38 (d, J ) 17.5 Hz, 1H, 3-CHH),
2.47 (m, 1H), 2.69 (d, J ) 17.5 Hz, 1H, 3-CHH), 3.80-3.95 (m,
4H, OCH2CH2O), 5.70 (dd, J ) 10.3, 2.1 Hz, 1H), 6.05 (dd, J
) 10.3, 2.1 Hz, 1H); 13C NMR (67.8 MHz, CDCl3) δ 19.6, 28.8,
29.0, 29.0, 34.4, 35.0, 38.1, 38.6, 42.0, 45.0, 45.7, 64.0, 64.6,
88.4, 110.0, 116.8, 140.5, 175.6, 207.3; MS (CI) m/z 333 (MH+).
Anal. Calcd for C19H24O5: C, 68.65; H, 7.28. Found: C, 68.30;
H, 7.21.
Meth yl (()-(1R,2S,3R,6S,8S)-[9,9-Eth ylen edioxy-2-m eth -
yl-3-(1-oxoeth yl)tr icyclo[6.3.1.01,6]d od ec-2-yl]a ceta te (7a )
a n d Its (1R,2S,3S,6S,8S)-Isom er (7b). To a solution of 8 (21
mg, 0.063 mmol) in a mixed solvent of THF (1 mL) and MeOH
(1 mL) was added 10% Pd/C (10 mg), and the mixture was
stirred for 6 h under hydrogen (1 atm) at room temperature.
The mixture was filtered, and the filtrate was concentrated
to give the crude acid 14, which was dissolved in MeOH (1
mL). TMSCHN2 (ca. 10 equiv) was added to the above stirred
solution until 14 disappeared on TLC. The mixture was
concentrated, and the residue was purified by column chro-
matography (1:1 n-hexane/EtOAc) to give 7a (16 mg, 72%
yield) and 7b (3.0 mg, 14% yield).
(()-(1R,2R,6S,8S,9S)-1-Meth yl-11-(1-oxoeth yl)tetr acyclo-
[7.2.2.12,6.02,8]tetr a d ec-10-en e-5,13-d ion e 5,5-Eth ylen e Ac-
eta l (9). A solution of 12 (640 mg, 2.6 mmol) in THF (10 mL)
was added dropwise to LDA [0.48 M in THF-n-hexane (2:1);
16 mL, 7.7 mmol] at -78 °C, and the mixture was stirred for
15 min. After TMSCl (0.5 mL, 3.9 mmol) was added, the
mixture was stirred with warming to 0 °C. Et3N (1.0 mL, 7.2
mmol) was added to the mixture, and the mixture was
concentrated. The residue was suspended in Et2O and filtered,
and the filtrate was concentrated to give crude silyl dienol
ether 10. 3-Butyn-2-one (1.0 mL, 13 mmol) was added to the
crude 10, and the mixture was stirred for 30 h. The mixture
was concentrated to give a residual oil, which was dissolved
in Et2O (10 mL). n-Bu4NF (1.0 M in THF; 3.0 mL, 3.0 mmol)
was added to the mixture with stirring, and the mixture was
stirred for 5 min. Water was added to the mixture, and the
whole was extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated. The concentrate was
purified by column chromatography (4:1 n-hexane/EtOAc) to
give 9 (595 mg, 73% yield): colorless crystals; mp 144-145
°C (i-Pr2O); IR (KBr) cm-1 1726, 1673, 1593; 1H NMR (200
MHz, CDCl3) δ 1.11 (m, 1H), 1.38 (s, 3H, 1-Me), 1.40-1.45 (m,
2H), 1.56-1.62 (m, 2H), 1.72-1.81 (m, 2H), 1.90 (m, 1H), 2.01
(m, 1H), 2.03 (d, J ) 18.0 Hz, 1H, 12-CHH), 2.21 (m, 1H), 2.28
(d, J ) 18.0 Hz, 1H, 12-CHH), 2.31 (s, 3H, COCH3), 3.07 (dd,
J ) 6.4, 2.4 Hz, 1H, 9-H), 3.79-3.99 (m, 4H, OCH2CH2O), 7.08
(d, J ) 6.4 Hz, 1H, CdCH); 13C NMR (67.8 MHz, CDCl3) δ:
17.9, 27.9, 30.3, 30.6, 32.6, 33.1, 44.1, 47.1, 48.4, 49.0, 49.7,
55.0, 64.4 (2C), 110.6, 140.7, 151.4, 197.9, 211.6; MS (EI) m/z
316 (M+). Anal. Calcd for C19H24O4: C, 72.13; H, 7.65. Found:
C, 72.07; H, 7.65.
1
Compound 7a : colorless oil; IR (KBr) cm-1 1730, 1709; H
NMR (500 MHz, CDCl3) δ 1.20-1.26 (m, 2H), 1.24 (s, 3H,
2-Me), 1.51-1.63 (m, 6H), 1.70-1.98 (m, 5H), 2.10 (m, 1H),
2.21 (s, 3H, COCH3), 2.47 (d, J ) 15.2 Hz, 1H), 2.61 (d, J )
15.2 Hz, 1H), 3.18 (m, 1H, 3-H), 3.60 (s, 3H, CO2CH3), 3.77-
3.96 (m, 4H, OCH2CH2O); 13C NMR (67.8 MHz, CDCl3) δ 19.5,
24.7, 28.88, 28.93, 30.8, 32.4, 35.3, 36.7, 38.2, 39.6, 40.2, 42.9,
49.0, 51.2, 52.2, 63.9, 64.5, 111.2, 173.2, 212.3; MS (EI) m/z
350 (M+). Anal. Calcd for C20H30O5: C, 68.54; H, 8.63. Found:
C, 68.57; H, 8.46.
1
Compound 7b: colorless oil; IR (KBr) cm-1 1732, 1711; H
NMR (500 MHz, CDCl3) δ: 1.08 (s, 3H, 2-Me), 1.22-1.27 (m,
2H), 1.45-1.80 (m, 9H), 1.94-2.04 (m, 2H), 2.18 (s, 3H,
COCH3), 2.35 (m, 1H), 2.40 (d, J ) 14.3 Hz, 1H), 3.05-3.09
(m, 2H), 3.59 (s, 3H, COOCH3), 3.80-3.98 (m, 4H, OCH2-
CH2O); MS (EI) m/z 350 (M+).
(()-(1R,2S,7R,10S,12S)-4-Meth oxy-2-m eth yltetr a cyclo-
[10.3.1.01,10.02,7]h exa d ec-4-en e-6,13-d ion e (16) a n d (()-
(1R ,2S ,7R ,10S ,12S )-6-Me t h o x y -2-m e t h y lt e t r a c y c lo -
[10.3.1.01,10.02,7]h exa d ec-5-en e-4,13-d ion e (17). NaH (60%
dispersion; 8.0 mg, 0.20 mmol; washed with n-hexane) and
MeOH (1 mL) were added to a mixture of 7a and 7b (10 mg,
0.029 mmol) in benzene (5 mL), and the mixture was heated
under reflux for 20 h. After cooling, the mixture was made
acidic with 10% HCl, and the whole was extracted with EtOAc.
The extract was washed with water and brine, dried, and
concentrated to give a crude triketone 15 (1:1 mixture of the
enols 22 and 23 in CDCl3).23 The crude triketone was treated
with 5% HCl in MeOH for 12 h at room temperature. The
mixture was concentrated to give a residual oil, which was
purified by preparative TLC (1:1 n-hexane/EtOAc) to give 16
(5.7 mg, 69% yield) and 17 (0.4 mg, 5% yield). The undesired
17 could be converted into 16 by the same protocol (treatment
with 5% HCl in MeOH for 12 h).
Compound 16: colorless crystals; mp 184-186 °C (n-
hexane-EtOAc); IR (KBr) cm-1 1716, 1655, 1616; 1H NMR
(500 MHz, CDCl3) δ: 1.00 (s, 3H, 2-Me), 1.17-1.33 (m, 2H),
1.56-1.73 (m, 3H), 1.84-2.04 (m, 4H), 2.10 (m, 1H), 2.24-
2.34 (m, 3H), 2.33 (d, J ) 17.3 Hz, 1H, 3-CHH), 2.53 (m, 1H),
2.55 (d, J ) 17.3 Hz, 1H, 3-CHH), 2.73 (m, 1H), 3.68 (s, 3H,
OMe), 5.35 (d, J ) 2.1 Hz, 1H, CdCH); 13C NMR (67.8 MHz,
CDCl3) δ: 17.8, 20.6, 29.9, 32.9, 33.5, 33.7, 35.7, 39.4, 40.1,
40.5, 48.2, 49.0, 49.3, 55.7, 100.7, 175.1, 200.2, 214.0; MS (EI)
m/z 288 (M+); HRMS (EI) calcd for C18H24O3 288.1726, found
288.1726. Anal. Calcd for C18H24O3‚1/7H2O: C, 74.31; H, 8.41.
Found: C, 74.32; H, 8.32.
(()-(1R ,2R ,6S ,8S ,9S )-1-Me t h y l-13-(1-o x o e t h y l)-10-
oxatetr acyclo[7.3.2.12,6.02,8]pen tadec-14-en e-5,11-dion e 5,5-
Eth ylen e Aceta l (13). To a stirred solution of 9 (372 mg, 1.2
mmol) in toluene (15 mL) were added 80% m-CPBA (800 mg,
3.7 mmol) and NaH2PO4 (800 mg, 6.7 mmol), and the mixture
was stirred overnight at room temperature, followed by
quenching with Me2S (0.27 mL, 3.7 mmol). The whole was
extracted with CHCl3, and the extract was washed with water
and brine, dried, and concentrated. The concentrate was
purified by column chromatography (3:1 n-hexane/EtOAc) to
give 13 (330 mg, 84% yield): colorless crystals; mp 150-152
1
°C (i-Pr2O-CHCl3); IR (KBr) cm-1 1724, 1686; H NMR (500
MHz, CDCl3) δ: 1.20 (s, 3H, 1-Me), 1.21 (m, 1H), 1.47 (ddd, J
) 11.9, 5.1, 5.1 Hz, 1H), 1.65-1.72 (m, 3H), 1.75 (d, J ) 11.9
Hz, 1H), 1.89-1.98 (m, 3H), 2.30 (m, 1H), 2.35 (s, 3H, COCH3),
2.76 (s, 2H, 12-H), 3.84-4.00 (m, 4H, OCH2CH2O), 4.77 (dd, J
) 6.8, 2.3 Hz, 1H, 9-H), 6.72 (d, J ) 6.8 Hz, 1H, 14-H); 13C
NMR (67.8 MHz, CDCl3) δ: 20.9, 28.6, 29.6, 30.0, 33.9, 35.0,
39.7, 45.6, 46.9, 49.5, 64.4, 64.5, 72.9, 96.1, 110.2, 132.1, 154.4,
171.3, 200.4; MS (EI) m/z 332 (M+). Anal. Calcd for C19H24O5:
C, 68.65; H, 7.28. Found: C, 68.50; H, 7.22.
(()-(1R ,2R ,6S ,9R ,11S )-2-Me t h y l-6-(1-o x o e t h y l)-5-
oxatetr acyclo[9.3.1.01,9.02,6]pen tadec-7-en e-4,12-dion e 12,12-
Eth ylen e Aceta l (8). To a stirred solution of 13 (14 mg, 0.042
mmol) in MeCN (0.8 mL) were added Pd(PPh3)4 (5.0 mg, 4.2
mmol) and PBu3 (4.2 mL, 0.017 mmol), and the mixture was
stirred at room temperature for 1 h. Concentration under
reduced pressure gave a residual oil, which was purified by
column chromatography (1:1 n-hexane/EtOAc) to give 8 (13
mg, 93% yield): colorless crystals; mp 231-233 °C (i-Pr2O-
Compound 17: colorless oil; IR (KBr) cm-1 1716, 1650, 1598;
1H NMR (500 MHz, CDCl3) δ 1.06 (s, 3H, 2-Me), 1.18-1.40
(m, 2H), 1.49-1.71 (m, 3H), 1.83-2.11 (m, 5H), 2.23-2.31 (m,
2H), 2.26 (d, J ) 15.9 Hz, 1H, 3-CHH), 2.47 (d, J ) 15.9 Hz,
1H, 3-CHH), 2.56 (m, 1H), 2.74 (m, 1H), 2.81 (m, 1H), 3.69 (s,
3H, OMe), 5.35 (d, J ) 3.0 Hz, 1H, CdCH); MS (EI) m/z 288
(M+).
1
CHCl3); IR (KBr) cm-1 1788, 1759, 1718; H NMR (500 MHz,
CDCl3) δ 1.07 (s, 3H, 2-Me), 1.47-1.69 (m, 5H), 1.79 (ddd, J
) 13.6, 13.6, 6.8 Hz, 1H), 1.87 (m, 1H), 2.10 (m, 1H), 2.18 (m,