M.P.L. Caton et al. / European Journal of Medicinal Chemistry 35 (2000) 1099–1107
1105
combined extracts were dried (MgSO4) and concentrated
under reduced pressure to give a dark brown oil (1.1 g).
An analytical sample (0.1 g) was purified by LPLC on
silica gel (16 g, 2.4×16 cm) using ether/n-hexane (1:19)
as eluant to give the isomeric 6inyl ethers 12a–d (50 mg,
85%) as a colourless oil. MS 392, C24 H44O2Si; RF
(diethyl ether) 0.61; IR wmax 1670, 1650 (CꢁCꢂOCH3),
1260 [Si(CH3)2], and 980 cm−1 (CꢁC), H-NMR lH (60
MHz) 4.5–6.5 (4H, m, HCꢁCH) 3.8–4.2 (1H, m,
CHOSi), 3.5, 3.45 (3H, 2 s, cis and trans OCH3),
1.0–2.6 (18H, m), 0.85 (12H, CꢂCH3), 0.03 [6H, s,
Si(CH3)2].
acidified to pH 2 using diluted hydrochloric acid, and
extracted with diethyl ether (2×100 mL). The combined
extracts were dried (MgSO4) and concentrated under
reduced pressure to give a yellow oil (1.5 g), which was
purified by LPLC on a silica gel (70 g) column (3.4×
16.5 cm) with diethyl ether/n-hexane (1:19) as eluant to
give the isomeric mixture of acids (14a–d) (0.25 g, 76%)
as an oil MS M+462 C20H50O3 Si RF (diethyl ether)
0.53; IR wmax 1710 (CO2H), 1260 [Si(CH3)2], and 970
cm−1 (CꢁC); H-NMR lH (80 MHz) 7.0 (1H, br, OH,
exchangeable), 5.4 (4H, m, 2×CHꢁCH), 4.1 (1H, m,
CHOSi), 0.7–2.5 (26H, m), 0.9 [12H, bs, SiC(CH3)3 and
CH2 CH3), 0.05 [6H, s, Si(CH3)2].
4.8. 3-[IE,3S,3-(t-Butyldimethylsilyloxy)oct-1-enyl-2-
( formylmethyl)bicyclo[3.1.1]heptane 13a–d
4.10. 2-(2Z-6-Carboxyhex-2-enyl)-3-(IE,3S,3-
hydroxyoct-1-enyl)bicyclo[3.1.1]heptane-trans 1,2 and
cis isomers 3,4
A stirred solution of the vinyl ethers (12a–d) (1.0 g,
2.5 mmol) in a 1:10 mixture of water–THF (13 mL) was
treated with mercury(II) acetate (2.5 g, 7.7 mmol) and
after 15 min saturated aqueous potassium iodide (33
mL) was added. After 5 min the reaction mixture was
extracted with diethyl ether (2×50 mL) and the com-
bined extracts were dried (Na2SO4) and concentrated
under reduced pressure to give a yellow oil (0.7 g),
which was purified by LPLC on a silica gel (100 g)
column (3.5×18 cm) with diethyl ether/n-hexane (5:95)
as eluant to give the mixture of isomeric aldehydes
(13a–d) (0.37g, 38%) as a colourless oil RF [diethyl
ether/n-hexane (1:19)] 0.16; IR wmax 2718 (CHO), 1728
(CHO), 1255 [Si(CH3)2] and 970 cm−1 (CꢁC); H-NMR
lH (80 MHz) 9.7 (1H, t, J=1.5 Hz, CHO), 5.45 (2H, m,
CHꢁCH), 4.05 (1H, m, CHOSi), 1.0–2.75 (32H, m),
0.11, 0.1 [together 6H, 2S, Si(CH3)2].
A solution of the acids 14a–d (0.1 g, 0.22 mmol) in a
mixture of glacial acetic acid, water, and THF (6:4:1;
11 mL) was stirred at 40–45°C for 3 h. The reaction
mixture was cooled and diluted with water (10 mL) and
extracted with diethyl ether (3×20 mL). The combined
extracts were washed with water (20 mL) several times
until the pH of the washings was 4. The ethereal solu-
tion was dried (MgSO4) and concentrated under reduced
pressure to give a yellow oil (0.8 g). (MS M+348;
C22H36O3). IR wmax 2600–3400, 1710 (CO2H), and 970
cm−1 (CꢁC); H-NMR lH (80 MHz) 6.2 (2H, b, OH,
chemical shift dependent on concentration), 5.1–5.7
(4H, m, 2×r CHꢁCH), 4.10 (1H, m, CHOH), 0.6–2.6
(29H, m). This mixture was separated by HPLC using
n-hexane/ethyl acetate/acetic acid (700:100:1) to give in
order of elution: trans isomer 2, [4] mixture of cis
isomers 3 and 4 and trans isomer 1 (CTA2) [4]. The two
components of the cis isomer mixture were then sepa-
rated by HPLC using n-hexaneꢂdichloromethaneꢂacetic
acid (700:180:1) as eluant.
4.9. 3-[1E,3S,3-(t-Butyldimethylsilyloxy)oct-1-enyl]-
2(Z,6-carboxyhex-2-enyl)bicyclo[3.1.1]heptane 14a–d
A stirred suspension of (4-carboxybutyl)triphenyl-
phosphonium bromide (1.26 g, 2.84 mmol) in dried
THF (20 mL) under argon at room temperature was
treated with a solution of potassium t-butoxide (0.81 g
7.1 mmol) in dried THF (20 mL). The mixture was
stirred for 20 min and then treated with a solution of the
aldehydes (13a–d) (0.27 g, 0.71 mmol) in dried THF (5
mL). After 2.5 h water (10 mL) was added and the
reaction mixture stirred for a further 0.5 h. The reaction
mixture was diluted with water (100 mL) then washed
with diethyl ether (50 mL) and the ether phase was
washed with saturated aqueous sodium hydrogen car-
bonate (50 mL). The combined aqueous material was
4.11. 2E,3-[1E,3S,3-(t-Butyldimethysilyloxy)oct-1-enyl]-
2-formylbicyclo[3.1.1]heptane 11c,d
Following the same procedure and scale for the
preparation of 11a–d except that before drying with
Na2SO4 the extracts were treated with DBN (1 mL, 8.1
mmol) and the mixture stirred at room temperature for
18 h. The mixture was then dried (Na2SO4) and concen-
trated under reduced pressure to give a brown oil (1.2
g), which was purified by LPLC on a silica gel (16 g)
column (2.4×15 cm) using diethyl ether: n-hexane