Synthesis of d,l-Norlabdane Oxide
J . Org. Chem., Vol. 63, No. 14, 1998 4783
continued for 2 h followed by neutralization with 10% HCl.
The mixture was diluted with CH2Cl2 (300 mL) and then
washed with saturated NaHCO3, H2O, and brine. The organic
solution was dried (Na2SO4) and concentrated in vacuo to give
an oil. Chromatography on silica gel (140 g, 70-230 mesh)
eluting with ethyl acetate-hexanes gave 8.8 g (85%) of 4: 1H
NMR (CDCl3) δ 12.73 (br s, 0.15Η), 4.52-4.60 (m, 2H), 4.19
(q, 2H, J ) 7.1 Hz), 3.62(t, 2H, J ) 6.4 Hz), 3.52 (q, 0.85H, J
) 7.1 Hz), 2.24-2.49 (m, 2H), 2.09-2.20 (m, 4H), 1.96-2.08
(m, 4H), 1.64 (s), 1.60 (s) and (HO) [7H], 1.33 (d, J ) 7.1 Hz)
and 1.27 (t, J ) 7.1 Hz) [6H]; 13C NMR (CDCl3, 77.0) δ 205.5,
170.6, 138.3, 133.5, 124.8, 120.2, 62.4, 61.3, 52.9, 40.0, 39.6,
33.2, 31.4, 26.3, 16.1, 16.0, 14.1, 12.7; HRMS calc for C18 H30O4
(M+) 310.2144, found 310.2148. Anal. Calcd for C18H30O4: C,
69.64; H, 9.74. Found: C, 69.01; H, 9.93. The carbon value
for 4 was always slightly lower than the theoretical value.
(d ,l)-Eth yl 8r,12-Ep oxy-3â-h yd r oxy-13,14,15,16-tetr a -
n or la bd a n e-19-oa te (11). NaBH4 (91.1 mg, 2.40 mmol) was
added in small portions to keto ester 2 (246 mg, 0.799 mmol)
in EtOH (6 mL) at 0 °C over 10 min. The reaction mixture
was stirred for 30 min and then diluted with CH2Cl2 (10 mL)
and H2O (10 mL). After separation of the two phases, the
aqueous solution was extracted with CH2Cl2. The combined
CH2Cl2 solution was washed with brine, dried (Na2SO4), and
concentrated in vacuo to give a solid. Trituration of the solid
with hexanes gave 205 mg of 11: mp 139-140 °C. Recrys-
tallization of the solid from the filtrate with a 1:1 mixture of
CH2Cl2 and hexanes gave an additional 21 mg of 11 (mp
139.5-140.6 °C) for a total yield of 91%. For 11: 1H NMR
(CDCl3) δ 4.15 (q, 2H, J ) 7.1 Hz), 3.76-3.98 (m, 2H), 3.45 (d,
1H, J ) 12 Hz), 3.10 (6 line ddd, 1H, J ) 4.8, 12.0, 12.0 Hz),
1.42 (s, 3H), 1.31 (t, 3H, J ) 7.2 Hz), 1.09 (s, 3H), 0.73 (s, 3H);
13C NMR (CDCl3, 77.0) δ 177.6, 79.3, 78.4, 64.8, 60.3, 59.6,
56.3, 58.7, 39.3, 38.8, 36.3, 28.0, 23.6, 22.7, 22.2, 20.6, 14.0,
12.6; IR (KBr) 3524, 1711 cm-1. Anal. Calcd for C18H30O4: C,
69.64; H, 9.74. Found: C, 69.55; H, 9.83.
(d,l)-[1R-(1r,4ar,8aâ)]-5-(2-Hydoxyeth yl)-1,4a-dim eth yl-
6-m et h ylen e-2-oxo-1,4,4a ,5,8,8a -h exa h yd r o-1-n a p h t h yl-
ca r boxylic Acid , Eth yl Ester (3). Mn(OAc)3‚2H2O (7.54 g,
28.1 mmol) and Cu(OAc)2‚H2O (2.81 g, 14.1 mmol) were added
to keto ester 4 (4.36 g, 14.1 mmol) in deaerated HOAc (140
mL) at room temperature under Ar. The reaction mixture was
stirred for 14 h and then passed through a Celite pad by
washing with CH2Cl2 (200 mL). The organic solution was
washed with H2O and then back-washed with CH2Cl2. The
combined organic solution was neutralized with 0.1 N NaOH
(400 mL) and then washed with brine, dried (Na2SO4), and
concentrated in vacuo to give an oil. Chromatography on silica
gel (50 g, 70-230 mesh) eluting with ethyl acetate-hexanes
gave 2.5 g (58%) of 3: 1H NMR (CDCl3) δ 4.92 (s, 1H), 4.61 (s,
1H), 4.00-4.23 (m, 2H), 3.68-3.81 (m, 1H), 3.42-3.58 (m, 1H),
2.96 (6 line ddd, 1H, J ) 6.2, 14.8, 14.8 Hz), 2.34-2.52 (m,
2H), 2.13 (ddd, 1H, J ) 2.6, 6.2, 13.2 Hz), 1.34 (s, 3H), 1.23 (t,
3H, J ) 7.2 Hz), 0.82 (s, 3H); 13C NMR (CDCl3, 77.0) δ 208.7,
173.2, 146.7, 107.7, 61.8, 61.1, 57.5, 57.2, 51.0, 39.5, 38.8, 38.0,
37.1, 27.4, 26.1, 21.2, 13.6, 12.5. Anal. Calcd for C18H28O4: C,
70.10; H, 9.15. Found: C, 70.29; H, 9.48.
(d ,l)-Eth yl 13,14,15,16-Tetr a n or -8r,12-ep oxy-4-la bd en -
19-oa te (12). Trifluoromethanesulfonyl chloride (201 mg, 127
uL, 1.20 mmol) was added dropwise to alcohol 11 (149 mg,
0.481 mmol) and 4-DMAP (352 mg, 2.88 mmol) in dry CH2Cl2
(20 mL) at 0 °C under N2. The reaction mixture was stirred
for 9 h at 0 °C and then washed with saturated NaHCO3 and
brine, dried (Na2SO4), and concentrated in vacuo to give an
oil. 4-DMAP (180 mg, 1.48 mmol) was added to the oil in dry
CH2Cl2 (15 mL) and the reaction mixture was refluxed
overnight. TLC analysis showed that the reaction was incom-
plete. 4-DMAP (180 mg) was then added and refluxing was
continued for 10 h. The reaction mixture was washed with
H2O, saturated NaHCO3, and brine. After back-washing of
the aqueous solutions, the organic solution was dried (Na2-
SO4) and concentrated in vacuo to give an oil. Chromatogra-
phy on silica gel (8 g, 230-400 mesh) eluting with hexanes
and ethyl acetate-hexanes gave 116 mg (83%) of 12: mp 46.5-
1
47.9 °C; H NMR (CDCl3) δ 5.63 (s, 2H), 4.11 (q, 2H, J ) 7.1
(d ,l)-Eth yl 8r,12-Ep oxy-3-oxo-13,14,15,16-tetr a n or la b-
d a n -19-oa te (2). F r om Acid -Ca ta lyzed Cycliza tion . Keto
ester 3 (483 mg, 1.57 mmol) in CF3CO2H (12 mL) was stirred
at room temperature for 1 h and then diluted with CH2Cl2 (30
mL). The solution was washed with H2O, neutralized with
saturated NaHCO3 (pH 7), and washed with brine. After back-
washing, the organic solution was dried (Na2SO4) and concen-
trated in vacuo to give a thick oil. Chromatography on silica
gel (20 g, 230-400 mesh) eluting with ethyl acetate-hexanes
Hz), 3.78-4.01 (m, 2H), 1.32 (s, 3H), 1.25 (t, 3H, J ) 7.2 Hz)
1.09 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3, 77.0) δ 175.3, 132.0,
123.6, 79.4, 64.8, 60.3, 58.7, 53.8, 44.8, 40.9, 39.1, 35.1, 27.8,
22.9, 22.4, 20.0, 14.1, 13.9; IR (KBr) 1725, 1458 cm-1. Anal.
Calcd for C18H28O3: C, 73.93; H, 9.65. Found: C, 73.88; H,
9.80.
(d ,l)-13,14,15,16-Tet r a n or -8r-12-ep oxy-2-la b d en -19-ol
(13). Ester 12 (99.6 mg, 0.341 mmol) in dry THF (6 mL) was
added dropwise to a suspension of LAH (19.4 mg, 0.511 mmol)
in dry THF (6 mL) at room temperature. The reaction mixture
was refluxed for 40 min and cooled to 0 °C, and excess LAH
was destroyed with saturated Na2SO4 (10 mL). After extrac-
tion with CH2Cl2, back-washing, and drying (Na2SO4), the
combined organic solution was concentrated in vacuo. Chro-
matography on silica gel (2.5 g, 230-400 mesh) eluting with
ethyl acetate-hexanes gave 81.2 mg (95%) of 13: mp 116.0-
1
gave 264 mg of 2 [mp 54-56 °C; H NMR (CDCl3, 500 MHz)
δ 4.15 (m, 2H), 3.94 (m, H12ax, 1H), 3.85 (apparent dd, H12eq
,
1H, J ) 8.2, 16.5 Hz), 2.99 (6 line ddd, H2ax, 1H, J ) 6.6, 14.7,
14.7 Hz), 2.43 (dq, H2eq, 1H, J ) ∼2.2, 15 Hz), 2.07 (m, H6ax
1H), 2.00 (dt, H7eq, 1H, J ) ∼ 3.2, 11.9 Hz), 1.95 (dq, H6eq, 1H,
J ) ∼3.2, 14.4 Hz), ∼1.85 (m, H1eq, 1H), ∼1.81 (m, H11ax, H11eq
,
,
2H), 1.48 (6 line ddd, 1H, H1ax, J ) ∼ 4.7, 13.8, 13.8 Hz), 1.38
(s, C-4 Me) and 1.32-1.41 (m, H7ax, H9ax, H5ax) [6H], 1.27 (t,
3H, J ) 7.2 Hz), 1.15 (s, C-8 Me, 3H), 0.99 (s, C-10 Me, 3H);
13C NMR (CDCl3, 500 MHz, 77.0) δ 207.74 (C3), 173.43 (ester
CO), 79.43 (C8), 64.74 (C12), 61.13 (ethyl CH2), 59.17 (C9),
57.61 (C4), 57.55 (C5), 40.21 (C1), 39.05 (C7), 36.48 (C10),
36.39 (C2), 22.81 (C1), 22.47 (C6), 21.07 (4 Me), 20.73 (8 Me),
13.94 (ethyl Me), 12.52 (10 Me); IR (KBr) 1713 (br) cm-1. Anal.
Calcd for C18H28O4: C, 70.10; H, 9.15. Found: C, 69.98; H,
9.31.] and 243 mg of crude 10 along with a small amount of
isomeric material. Anhydrous K2CO3 (249 mg, 1.8 mmol) was
added to 10 (243 mg) in absolute EtOH (5 mL) and the reaction
mixture was stirred for 30 min at room temperature and then
diluted with CH2Cl2. The solution was washed with H2O and
brine, and after back-washing, the organic solution was dried
(Na2SO4) and concentrated in vacuo at 35 mm and then at 0.5
mm to give 185 mg of crude alcohol(s), which was submitted
directly to cyclization. The alcohol(s) (185 mg) in CF3CO2H
(4.5 mL) was stirred at room temperature for 1 h. Workup as
described above and chromatography on silica gel (8 g, 70-
230 mesh) eluting with ethyl acetate-hexanes gave an ad-
ditional 85 mg of 2. The total yield of 2 was 72%.
1
117.5 °C; H NMR (CDCl3) δ 5.61 (s, 2H), 3.78-4.01 (m, 2H),
3.69 (d, 1H, J ) 10.8 Hz), 3.53 (d, 1H, J ) 10.8 Hz), 1.68-
2.05 (m, 6H), 1.18-1.51 (m, 5H), 1.11 (s) and 1.10 (s) [6H],
0.91 (s, 3H); 13C NMR (CDCl3, 77.0) δ 133.1, 124.2, 79.6, 66.6,
64.8, 58.9, 53.3, 40.7, 39.3, 39.3, 35.1, 25.7, 22.8, 21.2, 20.5,
15.8. Anal. Calcd for C16H26O2: C, 76.75; H, 10.47. Found:
C, 76.51; H, 10.65.
(d ,l)-S-Meth yl 13,14,15,16-Tetr a n or -8r,12-ep oxy-2-la b-
d en -19-d ith ioca r bon a te (14). Carbon disulfide (1.6 mL) was
added dropwise to alcohol 13 (70 mg, 0.28 mmol) and DBN
(121.7 mg, 0.98 mmol) in dry DMF (2.5 mL) at room temper-
ature under N2. The red-orange reaction mixture was stirred
at room temperature for 30 min. Methyl iodide (2.7 mL) was
added dropwise and stirring was continued for 30 min. The
reaction mixture was concentrated in vacuo and then diluted
with CH2Cl2 (20 mL). The organic solution was washed with
H2O, brine, dried (Na2SO4), and concentration in vacuo gave
an oil. Chromatography on silica gel (3 g, 230-400 mesh)
eluting with hexanes and ethyl acetate-hexanes gave 89 mg
(94%) of 14: mp 105.1-106.8 °C; 1H NMR (CDCl3) δ 5.25-
5.71 (m, 2H), 4.60 (d, 1H, J ) 10.8 Hz), 4.52 (d, 1H, J ) 10.8