3304
I. S. Marcos et al.
PAPER
1H NMR (200 MHz): d = 9.41 (1 H, s, H-18), 5.42–5.27 (2 H, m, H-
1, H-14), 3.90 (2 H, d, J = 7.0 Hz, H-15), 3.30 (3 H, s, OMe), 2.49–
2.31 (1 H, m, H-5), 1.67 (3 H, s, Me-16), 2.20–1.16 (13 H, m), 0.95
(3 H, s, Me-19), 0.90 (3 H, s, Me-20), 0.79 (3 H, d, J = 7.0 Hz, Me-
17).
13C NMR (50 MHz): d = 209.7 (C-13), 141.1 (C-10), 120.2 (C-1),
43.2 (C-9), 43.2 (C-5), 39.0 (C-8), 38.9 (C-12), 33.2 (C-11), 32.2
(C-3), 31.3 (C-4), 29.9 (C-16), 28.9 (C-7), 28.0 (C-19), 25.7 (C-18),
23.4 (C-6), 23.0 (C-2), 22.2 (C-20), 22.2 (C-20), 16.6 (C-16), 15.6
(C-17), 15.6 (C-17).
13C NMR (50 MHz): d = 205.7 (C-18), 141.1 (C-13), 141.1 (C-10),
120.3 (C-14), 120.2 (C-1), 69.0 (C-15), 57.6 (OMe), 47.8 (C-4),
43.0 (C-9), 38.6 (C-8), 37.6 (C-11), 36.0 (C-5), 34.0 (C-12), 28.4
(C-3), 27.6 (C-7), 23.0 (C-6), 22.2 (C-20), 22.2 (C-2), 17.2 (C-19),
16.6 (C-16), 15.4 (C-17).
MS (EI): m/z (%) = 262 (M+, 2), 191 (100), 135 (12), 95 (8), 69 (7).
HRMS (EI): m/z calcd for C18H30O (M+): 262.2297; found:
262.2262.
Methyl-15-tetrahydropyranyloxy-ent-halima-1(10),13E-dien-
18-oate (6)
MS (EI): m/z (%) = 318 (M+, 2), 286 (23), 257 (66), 240 (60), 205
(70), 177 (100), 161 (41), 145 (32), 107 (68), 91 (75), 77 (80).
HRMS (EI): m/z calcd for C21H34O2 (M)+: 318.2559; found:
318.2564.
To a solution of 4 (2.1 g, 6.23 mmol) in benzene (25 mL), p-TsOH
(237 mg, 1.25 mmol) and DHP (1.75 mL, 18.68 mmol) were added.
After stirring for 15 min at r.t., K2CO3 (200 mg) was added. The re-
action mixture was stirred for an additional 30 min, filtered, and ex-
tracted with EtOAc (250 mL). The organic phase was washed with
an aq solution of Na2CO3 (6%; 3 × 50 mL), brine (2 × 40 mL), H2O
(2 × 40 mL), and dried over Na2SO4. The solvent was evaporated
and the residue was purified by column chromatography (hexane–
EtOAc, 95:5) to afford 6.
Yield: 2.0 g (74%); [a]D22 +24.5 (c 0.4, CHCl3).
IR (neat): 2940, 1732, 1456, 1256, 1117, 1024 cm–1.
1H NMR (200 MHz): d = 5.35–5.31 (2 H, m, H-1, H-14), 4.98–4.93,
4.66–4.60 (1 H, 2 m , H-1¢), 4.23 (1 H, dd, J = 12.1, 6.4 Hz, H-15A),
4.00 (1 H, dd, J = 12.1, 7.5 Hz, H-15B), 3.93–3.88 (1 H, m, H-5¢),
3.66 (3 H, s, COOMe), 3.58–3.53 (1 H, m, H-5¢), 2.72–2.55 (1 H,
m, H-5), 2.15–1.00 (19 H, m), 1.69 (3 H, s, Me-16), 1.11 (3 H, s,
Me-19), 0.91 (3 H, s, Me-20), 0.80 (3 H, d, J = 7.0 Hz, Me-17).
15-Methoxy-ent-halima-1(10),13E-diene (11)
NH2NH2·H2O (25%; 2 mL, 40 mmol) and KOH (297 mg, 4.95
mmol) were added to a solution of 9 (380 mg, 1.19 mmol) in dieth-
ylene glycol (10 mL), the mixture was heated at 175 °C for 18.5 h,
and then the condenser was removed. After 15 min the mixture was
warmed to 230 °C for 4.5 h. It was allowed to cool to r.t., quenched
with H2O (5 mL) and an aq solution of HCl (6 M; 5 mL), and ex-
tracted with Et2O (3 × 50 mL). The organic phase was washed with
H2O (3 × 50 mL) and dried over Na2SO4. The solvent was removed
and the residue was purified by column chromatography (hexane–
EtOAc, 98:2) to afford 11.
Yield: 307 mg (85%); [a]D22 +79.9 (c 1.2, CHCl3).
IR (neat): 1464, 1379, 1109, 953 cm–1.
1H NMR (200 MHz): d = 5.35–5.20 (2 H, m, H-1, H-14), 3.90 (2 H,
d, J = 7.0 Hz, H-15), 3.32 (3 H, s, OMe), 2.05–1.05 (14 H, m), 1.66
(3 H, s, Me-16), 0.89 (3 H, s, Me-20), 0.87 (3 H, s, Me-19), 0.82 (3
H, s, Me-18), 0.80 (3 H, d, J = 7.0 Hz, Me-17).
13C NMR (50 MHz): d = 141.7 (C-10), 141.5 (C-13), 120.1 (C-14),
119.7 (C-1), 69.0 (C-15), 57.7 (OMe), 43.4 (C-5), 42.7 (C-9), 39.1
(C-8), 37.6 (C-11), 34.2 (C-12), 33.3 (C-3), 31.4 (C-4), 29.1 (C-7),
28.2 (C-19), 25.9 (C-18), 23.6 (C-6), 23.1 (C-2), 22.2 (C-20), 16.6
(C-16), 15.6 (C-17).
13C NMR (50 MHz): d = 178.4 (C-18), 141.3 (C-13), 141.3 (C-10),
120.1 (C-14), 119.6 (C-1), 97.9 (C-1¢), 63.8 (C-15), 62.2 (C-5¢),
51.6 (CO2Me), 44.9 (C-4), 42.8 (C-9), 38.4 (C-8), 38.4 (C-5), 37.7
(C-11), 34.0 (C-12), 30.7 (C-3), 30.7 (C-2¢), 28.3 (C-7), 25.5 (C-3¢),
22.9 (C-6), 22.9 (C-2), 22.4 (C-20), 19.7 (C-4¢), 19.6 (C-19), 16.7
(C-16), 15.5 (C-17).
MS (EI): m/z (%) = 418 (M+, 1), 235 (35), 175 (35), 137 (15), 85
(100).
HRMS (EI): m/z calcd for C26H42O4 (M)+: 418.3083; found:
418.3090.
MS (EI): m/z (%) = 304 (M+, 2), 272 (6), 245 (8), 191 (100), 135
(18), 107 (19), 68 (18).
15-Tetrahydropyranyloxy-ent-halima-1(10),13E-dien-18-ol (8)
To a stirred solution of 6 (3.5 g, 8.37 mmol) at 0 °C in Et2O (80 mL),
LiAlH4 (477 mg, 12.50 mmol) was added. The mixture was stirred
at r.t. for 15 min, cooled to 0 °C, and excess LiAlH4 was decom-
posed by the slow addition of wet Et2O (150 mL). The organic
phase was dried over Na2SO4, The solvent was evaporated and the
residue was purified by column chromatography (hexane–EtOAc,
85:15) to afford alcohol 8.
14,15-Dinor-ent-halima-1(10)-en-13-one (20)
A solution of MCPBA (169 mg, 0.98 mmol) in anhyd CH2Cl2 (3
mL) was added to an ice-cooled solution of 11 (300 mg, 0.99 mmol)
in anhyd CH2Cl2 (3 mL). After 1 h the reaction mixture was diluted
with H2O (25 mL) and extracted with Et2O (3 × 25 mL). The organic
phase was washed with an aq solution of Na2SO3 (10%; 2 × 25 mL),
an aq solution of NaHCO3 (6%, 2 × 25 mL), and H2O (3 × 25 mL).
The organic phase was dried over Na2SO4. The solvent was evapo-
rated to give a mixture of epoxide derivatives (285 mg), which were
used in the next step. To a solution of the epoxide derivatives (209
mg, 0.65 mmol) in THF (2.5 mL) was added a suspension of H5IO6
(303 mg, 1.32 mmol) in THF–H2O (2:1, 4.5 mL). The reaction mix-
ture was stirred for 16 h at r.t., H2O (20 mL) was added, and extract-
ed with Et2O (3 × 25 mL). The organic phase was washed with an
aq solution of Na2SO3 (10%; 2 × 25 mL), H2O (3 × 25 mL), and
dried over Na2SO4. The solvent was evaporated and the residue was
purified by column chromatography (hexane–EtOAc, 98:2) to af-
ford ketone 20.
Yield: 3.1 g (93%); [a]D22 +36.2 (c 0.8, CHCl3).
IR (neat): 3468, 2940, 1454, 1379, 1117, 1022 cm–1.
1H NMR (200 MHz): d = 5.35–5.31 (2 H, m, H-1, H-14), 4.63–4.58
(1 H, m, H-1¢), 4.23 (1 H, dd, J = 11.8, 6.5 Hz, H-15A), 3.97 (1 H,
dd, J = 11.8, 7.5 Hz, H-15B), 3.90–3.85 (1 H, m, H-5¢), 3.53–3.47
(1 H, m, H-5¢), 3.47 (1 H, d, J = 10.8 Hz, H-18A), 3.24 (1 H, d, J =
10.8 Hz, H-18B), 2.10–1.10 (20 H, m), 1.64 (3 H, s, Me-16), 0.88 (3
H, s, Me-19), 0.83 (3 H, s, Me-20), 0.79 (3 H, d, J = 7.0 Hz, Me-17).
13C NMR (50 MHz): d = 141.5 (C-10), 141.2 (C-13), 120.2 (C-14),
120.0 (C-1), 97.9 (C-1¢), 69.6 (C-18), 63.8 (C-15), 62.2 (C-5¢), 43.0
(C-9), 39.0 (C-8), 37.8 (C-5), 37.5 (C-11), 36.5 (C-4), 34.4 (C-12),
30.7 (C-2¢), 29.0 (C-3), 28.6 (C-7), 25.5 (C-3¢), 23.3 (C-6), 22.6 (C-
2), 22.3 (C-20), 20.6 (C-19), 19.6 (C-4¢), 16.6 (C-16), 15.6 (C-17).
Yield: 167 mg (90%, two steps); [a]D22 +65.1 (c 1.24, CHCl3).
IR (neat): 2928, 1721, 1466, 1379 cm–1.
1H NMR (200 MHz): d = 5.31 (1 H, t, J = 3.8 Hz, H-1), 2.11 (3 H,
s, Me-16), 2.30–1.05 (14 H, m), 0.85 (6 H, s, Me-20, Me-19), 0.82
(3 H, s, Me-18), 0.80 (3 H, d, J = 7.0 Hz, Me-17).
MS (EI): m/z (%) = 390 (M+, 1), 257 (25), 207 (40), 177 (25), 149
(10), 85 (100).
Synthesis 2005, No. 19, 3301–3310 © Thieme Stuttgart · New York