A. Hachem et al. / Tetrahedron Letters 43 (2002) 5217–5219
5219
relationships in these series and to design compounds
with better agonists/antagonists properties.11
References
1. For a recent review on lipoxygenases, see: Brash, A. R. J.
Biol. Chem. 1999, 34, 23679–23682 and references cited
therein.
2. Han, X.; Corey, E. J. Org. Lett. 2000, 2, 2543–2544 and
references cited therein.
3. Woolard, P. M. Biochem. Biophys. Res. Commun. 1986,
136, 169.
4. Lagarde, M.; Boutillon, M. M.; Guichardant, M.; Lel-
louche, J. P.; Beaucourt, J. P.; Vanhove, A.; Gree, R.
Biochem. Pharmacol. 1989, 38, 1863–1864.
5. For a recent example (L-6310333), see: Johnson, T. E.;
Holloway, M. K.; Vogel, R.; Rutledge, S. J.; Perkins, J.
P.; Rodan, G. A.; Schmidt, A. J. Steroid Biochem. Mol.
Biol. 1997, 63, 1–8.
6. Gree, R.; Hachem, A. M.; Gree, D.; Le Floc’h, Y.;
Rolland, Y.; Simonet, S.; Verbeuren, T. Eur. Pat. Appl.
EP 650, 953; Chem. Abstr. 1995, 123, 83092.
7. The use of wet silica gel for the deprotection of acetals
has been first reported in: Huet, F.; Lechevallier, A.;
Pellet, M.; Conia, J. M. Synthesis 1978, 63–65.
8. Experimental procedure for the preparation of 3: (a)
bisacetal 2. A mixture of isophtalaldehyde (25 g, 186
mmol), HC(OMe)3 (78 g, 4 equiv.), NH4NO3 (0.6 g) in
anhydrous MeOH (250 mL) was heated under reflux for
2 h. After evaporation of methanol under reduced pres-
sure, the crude product was dissolved in ether and the
solution was filtered. After evaporation of the solvent, the
crude bisacetal 2 was purified by distillation (yield 38 g,
90%; bp 118°C/3 mm). 1H NMR (90 MHz, CDCl3, l):
Scheme 3. Reagents and conditions: (i) Ph3P+(CH2)3CH3Br−,
n-BuLi, HMPA/THF (−80°C, 1.5 h), 82%; (ii) sec-BuLi (1.16
equiv.), THF (−80°C), then 3, 97%; (iii) imidazole (2.5 equiv.),
t-BuMe2SiCl (1.2 equiv.), DMF (rt, 15 h), 92%; (iv) SiO2,
H2SO4 2.5%, CH2Cl2 (rt, 1.5 h), quantitative; (v) Ph3P+
(CH2)4CO2HBr− (1.5 equiv.), LiHMDS (3 equiv.), HMPA/
THF (−80°C, 1.5 h), then Na2CO3, Me2SO4 (rt, 12 h), 98%
for 23, 84% for 26; (vi) n-Bu4N+F− (1.3 equiv.), THF (0°C to
rt, 15 h), 91%; (vii) LiOH, THF/H2O (rt, 15 h), acetic acid,
93%; (viii) H2–Pd/C, AcOEt (rt, 30 min), 92%.
7.6–7.35 (m, 4H, arom.); 5.40 (s, 2H, CH6 (OMe)2); 3.32 (s,
12H, CH(OMe)2); (b) monoacetal 3. To a slurry of SiO2
(40 g) in CH2Cl2 (140 mL) are added 15 drops of an
aqueous H2SO4 solution (1% weight). After stirring a few
minutes to homogenize, the bisacetal 2 (10 g, 44 mmol)
was added. The reaction mixture was stirred for 45 min
at rt. After filtration and removal of the solvent under
reduced pressure, the monoacetal 3 was purified by chro-
matography on silica gel using as eluent a 20:80 mixture
of ether and low boiling (<60°C) petroleum ether contain-
ing 1% Et3N (yield 7 g, 88%); TLC Rf=0.24 (E:PE=
20:80). IR (NaCl, film; w cm−1): 1707 (CꢀO); 1600–1575
(CꢀC arom.). 1H NMR (90 MHz, CDCl3, l): 10.04 (s,
as a (9/1) mixture by a Wittig reaction on p-
bromobenzaldehyde.
After metallation of 21 with sec-BuLi and addition to
3, the alcohol 22 was isolated (80% yield). After separa-
tion by chromatography, the Z isomer was protected as
the silyl ether 23. The latter derivative was used directly
for the preparation of the target molecules 25 and 28
following the previously described strategy. Deprotec-
tion of the aldehyde followed by the Wittig reaction led
to a 95/5 mixture of 24Z and 24E. After separation by
chromatography, desilylation and saponification, the
desired acid 25 was obtained in six steps and 74%
overall yield from 3. To prepare the next target
molecule, the intermediate 26 was first obtained by
hydrogenation of 23; then the same series of reactions
led to 28 in seven steps and 68% overall yield from 3.10
1H, CH
CH
(OMe)2); 3.35 (s, 6H, CH(OMe)2); 13C NMR (22.5
MHz, CDCl3, l): 191.5 (CHO); 139.2; 136.1; 132.3;
129.0; 128.5; 127.8 (C arom.); 101.7 (CH(OMe)2); 52.1
(CH(OMe)2).
6 O); 8.17–7.22 (m, 4H, arom.); 5.47 (s, 1H,
6
6
6
9. For the preparation and use of trimethylsulfonium
methylsulfate, see: Mosset, P.; Gree, R. Synth. Commun.
1985, 15, 749–757.
10. All new compounds have spectral and analytical data in
agreement with the indicate structures.
In conclusion, we have reported a short and efficient
synthesis of novel 12-HETE analogues. Such deriva-
tives will be used in order to establish structure–activity
11. For instance, preliminary data indicate that 11 is equipo-
tent to 12-HETE as inhibitor of platelet aggregation
induced by collagen with a IC50=2 0.1 mM.