Synthesis of aromatic analogs of 8(S)-HETE and their biological evaluation as activators of the PPAR nuclear receptors

FULL PAPER

DOI: 10.1002/ejoc.200500918

Synthesis of Aromatic Analogs of 8(S)-HETE and Their Biological Evaluation

as Activators of the PPAR Nuclear Receptors

Frédéric Caijo,^[a]Paul Mosset,*^[a]René Grée,*^[b]Valérie Audinot-Bouchez,^[d]Jean Boutin,^[d]

Pierre Renard,^[c]Daniel-Henri Caignard,^[d]and Catherine Dacquet^[c]

Keywords: PPARs / Diabetes / 8-HETE / Eicosanoids / Stereoselective synthesis

A new family of 8-HETE analogs has been synthesized as

dual PPAR α and γ agonists. A versatile strategy has been

developed to allow modulations not only around the aromatic

core but also on the side chains of these analogs. The affinity

of these compounds towards the PPARα and PPARγ receptors

is reported, together with their transactivation percentage.

The derivatives having a propargylic type side chain gave

the most promising results as dual agonists.

Germany, 2006)

disease in diabetic patients,^[6]the combined profile of dual

PPARα/γ agonists would offer a very attractive option.

Such compounds could add a hypolipidemic effect, by the

activation of subtype α,^[7]to an improvement of insulin sen-

sitivity by activation of subtype γ.^[8]Another interesting as-

pect of PPARα/γ coactivation is the limitation of side effects

observed in the actual treatment of diabetes mellitus by

TZDs, such as increase in weight and/or edema. Therefore,

a new focus for medicinal chemistry is to discover dual

PPAR α/γ agonists, and several examples of active mole-

cules have been reported recently in the literature. They

have good to excellent affinities for the PPAR receptors, but

in most cases the activity is higher on PPARγ than on sub-

type α.^[9]Several years ago, we started a program in this

field, and our goal was to develop a new family of dual

PPAR α/γ agonists with a better activity on PPARα than

on PPARγ.^[10]

Introduction

The peroxisome proliferator activated receptors (PPARs)

have been discovered in 1990 by I. Issemann and S.

Green.^[1]They are a subfamily of nuclear receptors also

comprising steroid-, thyroid-, retinoic acid-, and vitamin D₃

receptors. These nuclear receptors have three subtypes:

PPARα, PPARβ (or PPARδ), and PPARγ.^[2]The first one,

PPARα, regulates the expression of numerous genes in-

volved in lipid uptake, catabolism, and homeostasis. The

second, PPARβ, has an ubiquitous distribution and its role

is not clearly defined yet. The last one, PPARγ, has been

shown to regulate the expression of genes that mediate ad-

ipocyte differentiation, energy metabolism, and insulin ac-

tion.^[3]

Disorders of the lipid metabolism are a major threat to

human health, leading to obesity, atherosclerosis, cardiovas-

cular disease, insulin resistance, and type 2 diabetes. PPARγ

is the predominant molecular target for the insulin-sensitiz-

ing thiazolidinedione drugs (TZDs) such as pioglitazone

and rosiglitazone.^[4]TZD derivatives activate PPARγ and

improve insulin resistance by increasing the number of

small adipocytes. PPARα is the molecular target for the

fibrate class of lipid-modulating drugs.^[5]Considering the

potential benefits of fibrates in the treatment of coronary

Many fatty acids and their corresponding metabolites are

known to activate the PPAR receptors.^[11]Among them, the

8(S)-HETE appears to be a very attractive molecule, be-

cause it has an excellent activity on subtype α (EC₅₀

=

100 n), together with some activity on subtype γ.^[12]

Furthermore, the 8(R) enantiomer was found to be inac-

tive.^[13]On the basis of these data, we designed as our target

molecules various carbo- and heterocyclic analogs of the

8(S)-HETE, as indicated in Figure 1.

[a] ENSCR, Laboratoire de Synthèses et Activations de Biomolé-

cules, CNRS UMR 6052,

The conjugated E,Z diene was first replaced by an aro-

matic or a heteroaromatic core, linking carbons 9 and 14.

Simultaneously, the sp²carbon at position 15 was replaced

by an oxygen atom. These modulations, classical in the area

of fatty acid metabolites, lead to analogs which are more

stable than the polyunsaturated natural products.^[14]In this

first structure–activity relationship (SAR) study, we have

kept the three-carbon-atom chain between the acid and the

unsaturation at position 5 and we have also maintained the

Avenue du Général Leclerc, 35700 Rennes – Beaulieu, France

[b] Université de Rennes 1, Laboratoire de Synthèse et Electro-

synthèse Organiques, CNRS UMR 6510,

Avenue du Général Leclerc, 35042 Rennes – Cedex, France.

[c] Institut de Recherches Servier,

11 Rue des Moulineaux, 92150 Suresnes, France

[d] Institut de Recherches Servier,

125 Chemin de Ronde, 78290 Croissy sur Seine, France

Fax: +33 2 23 23 69 78

E-mail: rene.gree@univ-rennes1.fr

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P. Mosset, R. Grée et al.

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Therefore, the effect of methyl groups at position 2 has also

been studied.

The purpose of this publication is to report our studies

dealing with the synthesis and biological evaluation of all

these 8-HETE analogs.

Results and Discussion

Our retrosynthesis is given in Scheme 1. The propargylic

derivatives 3 were considered as the key intermediates since

they should afford easily either the Z alkenes 2 or the satu-

rated compounds 1. Furthermore, the modulations at posi-

tions 2 and 8 could be performed starting from 3. The latter

derivatives should be obtained by alkylation, with trimethyl

4-bromoorthobutyrate, of the intermediates 4. These homo-

Figure 1. Design of target molecules.

five-carbon terminal chain (C₁₆to C₂₀) which exists in the propargylic derivatives could be prepared by Grignard ad-

8-HETE. Therefore, the main variations that we have con- ditions on aldehydes 5, which are easily obtained from com-

sidered in this series of molecules dealt with four key as- pounds 6. In our target molecules, the modulations of the

pects:

aromatic system are obtained by changing the nature of the

(1) What is the effect of the nature of the aromatic (benzene, starting aldehyde 6, and in this paper we will consider three

naphthalene) or heteroaromatic ring (pyridine) on the acti- basic skeletons: benzene, naphthalene, and pyridine.

vation of the PPAR nuclear receptors?

For the benzene-derived 8-HETE analogs, the prepara-

(2) What could be the role of the alcohol function at posi- tion of the key intermediate ( )-12 is reported in Scheme 2.

tion 8? Does the absolute configuration at this stereocenter The first step was a reaction between salicylaldehyde (7)

have any effect? Is it possible to replace the OH group by a and 1-iodopentane, affording 8 in 78% yield. The reaction

methoxy group or a hydrogen atom?

of this aldehyde with the Grignard reagent prepared from

(3) What is the influence of the degree of unsaturation (tri- propargyl bromide afforded, in 78% yield, the homopro-

ple bond, double bond, or single bond) on carbons 5 and pargylic alcohol 9 which was then protected as the silyl

6?

ether 10. The alkylation of this derivative by trimethyl 4-

(4) Most of the synthetic compounds, which are presently bromoorthobutyrate was performed at –80 °C to 0 °C, af-

developed as PPAR activators have substituents at position fording 11 in 68% yield. This reaction required a good con-

2, close to the acid function (or some bioisostere of it). trol of temperature, since, above 0 °C, an elimination prod-

Scheme 1. Retrosynthetic analysis of the target molecules.

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Synthesis of Aromatic Analogs of 8(S)-HETE

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The first targeted 8-HETE analogs were obtained as

indicated in Scheme 3. Starting from 12, semihydrogenation

with Ni/P₂catalyst afforded the Z alkene 14, while the satu-

rated compound 15 was obtained by hydrogenation with

palladium on activated charcoal. Saponification of the three

methyl esters 12, 14, and 15 were performed under mild

conditions by using lithium hydroxide. Then, acidification

with oxalic acid gave the corresponding acids, which were

easily purified by flash chromatography before transforma-

tion into the desired (hygroscopic) sodium salts 13, 16, and

uct was also obtained. After cleavage of the silyl group, the

key intermediate ( )-12 was obtained in 35% overall yield

from salicylaldehyde.

17.

The activity of these six compounds towards the PPAR

receptors will be discussed in the last part of this paper.

However, it is important to note that among the three series,

the propargylic derivatives, such as ( )-12, gave the most

promising preliminary results. For this reason, several mod-

ulations around the positions 2 and 8 were performed,

starting from ( )-12.

It has been established that, in the case of the 8-HETEs,

only the 8(S) enantiomer was efficient in the activation of

the PPAR nuclear receptors. Therefore, it was of much

interest to prepare both enantiomers of 12. Towards this

goal, a resolution strategy was followed, as indicated in

Scheme 4. The reaction between homopropargylic alcohol

9 and O-methyl-L-mandelic acid afforded two diastereoiso-

mers, 18a and 18b. which could be separated by chromatog-

raphy on silica gel by gradient elution using a mixture of

tert-butyl methyl ether and petroleum ether (from 1:99 to

5:95). The less polar compound 18a was isolated in 39%

yield while the more polar diastereoisomer 18b was ob-

Scheme 2. Synthesis of the propargylic key intermediate ( )-12. (a)

KOH, 1-iodopentane, EtOH/H₂O, 80 °C, 16 h; (b) propargyl bro-

mide, Mg, Et₂O, –80 °C, 20 min; (c) tBuMe₂SiCl, imidazole, DMF,

0 °C to room temp., 24 h; (d) nBuLi/THF, –80 °C, Br(CH₂)₃-

C(OMe)₃/HMPA, –80 °C to 0 °C, aq. NH₄Cl (workup); (e)

nBu₄NF, THF, 45 °C, 3 h.

Scheme 3. Synthesis of the 8-HETE analogs 12–17 with a benzene core. (a) H₂, Ni(OAc)₂, NaBH₄, EtOH, 5 h; (b) Pd/C, H₂, MeOH; (c)

LiOH, MeOH/H₂O; (d) (CO₂H)₂, then NaOH.

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Scheme 4. Synthesis of the two enantiomers (+)-12 and (–)-12. (a) DCC, DMAP, CH₂Cl₂, room temp., 30 min; then chromatographic

separation; yields: 39% (less polar diastereoisomer 18a) and 25% (more polar diastereoisomer 18b); (b) KOH, MeOH, 0 °C, 2 h, then

room temp., 1 h; (c) tBuMe₂SiCl, imidazole, DMF, 0 °C to room temp., 24 h; (d) nBuLi/THF, –80 °C, Br(CH₂)₃C(OMe)₃/HMPA, aq.

NH₄Cl (workup); (e) nBu₄NF, THF, 45 °C, 3 h.

tained in 25% yield. After saponification of each pure dia-

stereoisomeric ester, the two enantiomers (+)-9 and (–)-9

were obtained. Then, the same sequence of reactions as that

for the racemic compound was performed on each enantio-

mer to obtain the two target enantiomers (+)-12 and (–)-

12. The absolute configuration at the carbinol center was

1

assigned by H NMR analysis of the esters 18a and 18b. It

has been clearly established in the literature that, for this

type of esters, the two hydrogen atoms vicinal to the carbi-

nol center should be more shielded in the case of the (R,S)

diastereoisomer, than in the case of the (S,S) derivative.^[15]

The chemical shifts were 2.72 ppm and 2.59 ppm in the case

Scheme 5. Synthesis of the methoxy analog 20. (a) NaH, Me₂SO₄,

THF/DMF, 0 °C then room temp., 16 h; (b) nBuLi/THF, –80 °C to

of 18a and 2.81 ppm and 2.64 ppm for 18b. Therefore, the

(R) absolute configuration has been assigned to 18a and

consequently to the alcohol (+)-12.

0 °C, Br(CH₂)₃C(OMe)₃/HMPA, aq. NH₄Cl (workup).

The next modulations involved the modifications of the coupled with propargyl bromide to give the deoxygenated

hydroxy group at position 8. It was first replaced by a meth- intermediate 23. The alkylation by trimethyl 4-bromoor-

oxy group, as indicated in Scheme 5. The homopropargylic thobutyrate afforded the target compound 24. These reac-

alcohol 9 was alkylated by dimethyl sulfate to afford 19 in tions were not optimized and the yields were poor. How-

85% yield. The same reactions as described previously gave ever, enough material could be isolated to perform the de-

the desired product 20 in racemic form.

sired biological tests.

The next modification at this position involved the re-

Many of the drugs, already used or under development

placement of the OH by a hydrogen. The direct deoxygen- and involving an activation of the PPAR receptors, have

ation of 12 was an attractive strategy for that purpose. one or two substituents vicinal to the acid group. Some rep-

However, all our experiments in this direction failed, lead- resentative examples are given in Scheme 7: They may have

ing only to decomposition products. Therefore, an alterna- a gem-dimethyl group, such as in the widely used clofibrate

tive route was designed, as indicated in Scheme 6. The ben- and fenofibrate. Alternatively, new compounds have ap-

zyl bromide 22, easily prepared in two steps from 8, was peared more recently with alkoxy groups at position 2, such

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Synthesis of Aromatic Analogs of 8(S)-HETE

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of the nature of the aromatic group. In these first SAR stud-

ies, we have considered naphthalene and pyridine deriva-

tives. The quinoline derivatives are under active study and

will be reported in a future publication.

A similar strategy was followed for the preparation of

the naphthalene-derived analogs. The synthesis of the key

intermediate 33 is described in Scheme 9. The aldehyde 29

was obtained easily in two steps from 2-naphthol (27). The

Scheme 6. Synthesis of the dehydroxylated analog 24. (a) NaBH₄,

EtOH/THF, room temp., 1 h; (b) PBr₃, pyridine, Et₂O, 0 °C, 1 h;

(c) Propargyl bromide, Mg, CuI, Et₂O, –80 °C then room temp.,

24 h; (d) nBuLi/THF, –80 °C to 0 °C, Br(CH₂)₃C(OMe)₃/HMPA,

aq. NH₄Cl (workup).

as LY-510929 and Tesaglitazar. Such substituents have been

shown to be important not only to improve the affinities

towards the receptors but also to limit the degradation by

β-oxidation. Therefore another model analog 26, bearing

two methyl groups at position 2, was prepared as indicated

in Scheme 8.

The alkylation of 11 with two equivalents of iodome-

thane gave 25 which, after deprotection, afforded the target

molecule 26 in good yield.

Scheme 9. Synthesis of intermediates with a naphthalene core. (a)

KOH, 1-iodopentane, EtOH/H₂O, 80 °C, 16 h; (b) tBuLi, THP,

0 °C then DMF room temp. 20 h; (c) propargyl bromide, Mg,

Et₂O, –80 °C, 20 min; (d) tBuMe₂SiCl, imidazole, DMF, 0 °C to

room temp., 24 h; (e) nBuLi/THF, –80 °C to 0 °C, Br(CH₂)₃-

C(OMe)₃/HMPA, aq. NH₄Cl (workup); (f) nBu₄NF, THF, 45 °C,

After performing modulations on the “upper part” of

our 8-HETE analogs, we have considered the modifications 3 h.

Scheme 7. Examples of compounds with subsituents vicinal to the acid group.

Scheme 8. Synthesis of the gem-dimethyl analog 26. (a) MeI, LDA, THF, –80 °C then room temp., 3 h; (b) nBu₄NF, THF, 45 °C, 3 h.

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O-alkylation by 1-iodopentane, followed by formylation in Scheme 11. The starting 2-chloro-3-pyridinecarbox-

with dimethylformamide, afforded 29 in 64% overall yield. aldehyde (40) was obtained by formylation of 2-chloropyri-

The four next steps were identical to the reactions per- dine (39).^[16]After protection as the dimethyl acetal 41, nu-

formed in the benzene series, and the intermediate 33 was cleophilic substitution by the pentyloxy group afforded 42,

obtained in 18% overall yield from 27.

and a final deprotection gave aldehyde 43. The next four

Starting from this propargylic intermediate, the target steps, allowing the introduction of the acid side chain, were

molecules with a naphthalene core (34–38) were prepared identical to those of the benzene and naphthalene series.

in good yields by the same sequence of reactions as before

The six target molecules of the pyridine family were ob-

(Scheme 10).

tained from 47 by hydrogenation and saponification reac-

The last series of analogs to be studied had a pyridine tions in the same manner as previously described for the

core and the synthesis of the key intermediate 47 is indicated benzene series (Scheme 12). For these pyridine derivatives,

Scheme 10. Synthesis of 8-HETE analogs with a naphthalene core. (a) H₂, Ni(OAc)₂, NaBH₄, EtOH, 5 h; (b) Pd/C, H₂, MeOH; (c)

LiOH, MeOH/H₂O; (d) (CO₂H)₂, then NaOH.

Scheme 11. Synthesis of the key intermediate with a pyridine core. (a) PhLi, iPr₂NH cat, –60 °C, then N-formylpiperidine, THF; (b)

HC(OMe)₃NH₄NO₃cat, MeOH, reflux 2.5 h; (c) NaH, 1-pentyl alcohol, NMP, 0 °C to room temp. 16 h; (d) PTSA, THF/H₂O, reflux,

3 h; (e) propargyl bromide, Mg, Et₂O, –80 °C, 20 min; (f) tBuMe₂SiCl, imidazole, DMF, 0 °C to room temp., 24 h; (g) nBuLi/THF,

–80 °C to 0 °C, Br(CH₂)₃C(OMe)₃/HMPA, aq. NH₄Cl (workup); (h) nBu₄NF, THF, 45 °C, 3 h.

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Synthesis of Aromatic Analogs of 8(S)-HETE

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Scheme 12. Synthesis of 8-HETE analogs with a pyridine core. (a) H₂, Lindlar Pd, MeOH; (b) Pd/C, H₂, MeOH; (c) LiOH, MeOH/H₂O;

(d) (CO₂H)₂, then NaOH.

the semihydrogenation did not work with NiP₂catalyst, and (2) Except for ( )-12, there is no significant difference be-

therefore we employed the classical conditions using Lind- tween the esters and the corresponding sodium salts.

lar palladium.

(3) If we now consider the propargylic derivatives with a

benzene core, several points can be noted. The alcohol

function at C₈is important: the transformation into a meth-

oxy group (derivative 20) or a hydrogen atom (compound

24) induced a complete loss in activity. However, the control

of the absolute configuration at this carbinol center af-

forded unexpected results. The racemic compound ( )-12

had a good activity, mainly on PPARα. The (R) enantiomer

(+)-12 has maintained an important percentage of trans-

activation on hPPARα (99%), as compared with the (S)

enantiomer (–)-12 (28%). It also gave a low hPPARγ bind-

ing affinity (4.13 µM), as opposed to the lack of affinity

in the case of (–)-12. The weak activity on PPARγ (14%

transactivation) was similar for both enantiomers. At this

stage, we have no clear explanation for these results. The

addition of the two methyl groups at position 2 (compound

26) also produced a derivative with a low activity.

Biological Studies on Human PPARγ and Human PPARα

The biological tests were performed on a chimera human

PPAR/Gal₄gene reporter luciferase system to determine the

maximal transactivation response and the EC₅₀for each

compound. The results are given in Table 1. Our goal was

to obtain partial dual potent PPAR agonists with a better

activity on PPARα than on PPARγ in order to reduce the

PPARγ side effects. Therefore, our 8-HETE analogs were

compared to the classical references, WY 14,643 for sub-

type α and rosiglitazone for PPARγ. We report here only

the results for these two subtypes, but each product was

also tested on PPARβ on which it showed no activity.

From the data given in Table 1, several interesting points

emerged:

(1) The most important result is that the degree of unsatu- (4) Finally, it appears that modulations of the nature of the

ration at the 5–6 position plays a key role: the propargylic aromatic core are possible: while the benzene derivative ( )-

derivatives [cf. ( )-12, 33, and 47 for instance] always exhib- 12 had the highest activity towards PPARα (173 nM), to-

ited higher affinities than the corresponding Z alkenes, gether with a very partial activity towards PPARγ and a

while the saturated compounds did not have any significant good affinity towards PPARγ (642 nM), the naphthalene

activity. More studies, including the preparation of other derivative 33 and even more so the pyridine analog 47, still

molecules, will be necessary in order to propose a tentative retained affinities in the micromolar range together with

explanation for this point. However, this is a key result for significant activities on the two receptors in terms of the

the design of more potent derivatives.

percentage of transactivation and EC₅₀values. These results

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P. Mosset, R. Grée et al.

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Table 1. In vitro activity of 8-HETE analogs in cell-based transactivation assay against human PPARα/Gal4 and PPARγ/Gal4 receptors

and binding assay PPARγ ligand binding domain. (NA = not active).

Binding Rosiglita-

zone hPPARγ

K_i[n]

Compounds

hPPARα/Gal₄

hPPARγ/ Gal₄

Transactivation [%]^[b]

EC₅₀[µ]

Transactivation [%]^[a]

EC₅₀[µ]

Rosiglitazone

WY 14,643

Ͼ10

10

15

100

81

41

20

30

35

99

28

0

42

60

112

75

122

100

80

138

148

183

121

187

155

204

4

100

15

16

32

24

42

13

29

14

0

15

23

58

100

26

34

85

51

45

25

19

13

31

27

8

NA

1050

Ͼ10 000

3 760

515

Ͼ10 000

6 690

Ͼ10

0.642

Ͼ10

0.028

Ͼ10

0.340

Ͼ10

1.356

1.503

Ͼ10

0.549

Ͼ10

( )-12

0.173

Ͼ10

1.142

0.723

1.454

1.531

1.194

1.485

1.632

1.543

Ͼ10

13

14

15

16

17

(–)-12

(+)-12

20

4 130

Ͼ10 000

2 200

695

4 390

718

579

1 030

969

Ͼ10 000

24

26

33

34

35

36

37

38

47

48

49

50

51

52

[a] Maximal signal obtained in comparison to WY 14,643: 10^–5. [b] Maximal signal obtained at 10^–5, in comparison to rosiglitazone:

10^–6.

low-boiling (Ͻ50 °C) petroleum ether (PE) and ethyl acetate

(EtOAc), with detection by UV light, or a p-anisaldehyde staining

solution. Merck silica gel (60, particle size 0.040–0.063 mm) was

used for column chromatography. Nuclear magnetic resonance

(NMR) spectra were recorded with a Bruker ARX 400 spectrome-

open the field to new types of analogs with more potent

activities.^[10]

Conclusion

1

ter. H NMR spectra: (400 MHz); δ (H) are given in ppm relative

to tetramethylsilane (TMS) [TMS, δ (H) = 0.00 ppm] as internal

reference. ¹³C NMR spectra: (100.6 MHz); δ (C) are given in ppm

relative to TMS [CDCl₃, δ (C) = 0.00 ppm] as internal reference.

Multiplicities were designated as singlet (s), doublet (d), triplet (t),

or multiplet (m).

In conclusion, we have reported an efficient and flexible

strategy towards new 8-HETE analogs with an aromatic

core. Such synthesis should allow for many modulations

around this basic skeleton. Several products exhibited al-

ready interesting properties as dual PPARα/γ agonists.

These first structure–activity relationships obtained in this

study open the route to new and more potent derivatives to

be developed in various pathologies, such as type 2 diabetes

and dislipidemia.

Pharmacological in vitro assays: These assays are described in ref.^[10]

2-Pentyloxybenzaldehyde (8): 1-Iodopentane (10.5 mL, 80 mmol)

was added to a solution of salicylaldehyde (5.3 mL, 50 mmol) and

KOH (3.6 g, 55 mmol) in DMSO (25 mL). The reaction mixture

was heated to 80 °C for 16 h. The product was extracted with

EtOAc, and the organic phase was washed with water (3×). The

aldehyde 8 was purified by Kugelrohr distillation (105 °C/2 Torr):

Experimental Section

1

yield 78% (7.45 g, 38.75 mmol). H NMR (400 MHz, CDCl₃): δ =

10.52 (s, 1 H, CHO), 7.83 (dd, J = 7.7, 1.8 Hz,1 H, 6-H), 7.52 (ddd,

J = 8.1, 7.3, 1.8 Hz, 1 H, 4-H), 6.98 (m, 2 H, 5-H, 3-H), 4.07 (t, J

= 6.5 Hz, 2 H, OCH₂CH₂), 1.90–1.80 (m, 2 H, OCH₂CH₂), 1.53–

1.35 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.1 Hz, 3 H, CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 189.96 (CHO) 161.59 (C-2),

135.94 (C-4), 128.16 (C-6), 124.86 (C-1), 120.43 (C-5), 112.48 (C-3),

68.50 (OCH₂CH₂) 28.78 (OCH₂CH₂), 28.23 (CH₂CH₂CH₃), 22.41

(CH₂CH₂CH₃), 14.02 (CH₃) ppm.

General: All reagents were obtained from Aldrich and used without

further purification. All reactions were carried out under a nitrogen

atmosphere and dry conditions. The solvents used were freshly dis-

tilled under anhydrous conditions, unless otherwise specified. The

reaction mixtures were magnetically stirred with Teflon stirring

bars, and the temperatures were measured externally. Reactions

that require anhydrous conditions were carried out by using oven-

dried (120 °C, 24 h) or flame-dried (vacuum Ͻ0.5 Torr) glassware.

Yields refer to chromatographically and spectroscopically (¹H

NMR) homogeneous materials, and the reactions were monitored

by thin layer chromatography (TLC), carried out on 0.25 mm

Merck silica gel plates (60 F₂₅₄). The eluents used were mixtures of

1-(2-Pentyloxyphenyl)-but-3-yn-1-ol (9): In a double-necked round-

bottom flask, magnesium metal turnings (175 mg, 7.2 mmol) were

flame-dried under nitrogen. After cooling to room temperature, an-

hydrous ether (9.5 mL) along with (20 mg, 0.072 mmol) mercury()

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Synthesis of Aromatic Analogs of 8(S)-HETE

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chloride were added, and then propargyl bromide (840 µL,

7.8 mmol) was added slowly dropwise until the ether started boil-

ing. If not, the solution was warmed gently with a heat gun. When

the magnesium turnings were consumed (20 to 30 min) the reaction

was cooled to –80 °C. At this temperature, a solution of aldehyde

8 (1.15 g, 6 mmol) in diethyl ether (1 mL) was added. The reaction

mixture was stirred for 20 min at this temperature, and then the

mixture was warmed to –5 °C and hydrolyzed with a NH₄Cl solu-

tion (10%) followed by extraction with EtOAc. The combined or-

ganic layers were washed with water, dried (Na₂SO₄), and evapo-

rated under reduced pressure. After purification by column

chromatography (R_f: 0.11, PE/EtOAc, 95:5) alcohol 9 was obtained

as a colorless oil. Yield 78% (1.083 g, 4.66 mmol). ¹H NMR

(400 MHz, CDCl₃): δ = 7.39 (dd, J = 7.5, 1.4 Hz, 1 H, 6-H), 7.25

(ddd, J = 8.2, 7.5, 1.4 Hz, 1 H, 4-H), 6.96 (ddd, J = 7.5, 7.5, 0.9 Hz,

1 H, 5-H), 6.86 (d, J = 8.2 Hz,1 H, 3-H), 5.07 (ddd, J = 7.5, 6.3,

5.1 Hz, 1 H, CHOH), 4.05–3.96 (m, 2 H, OCH₂CH₂), 2.99 (d, J =

6.3 Hz, 1 H, OH), 2.78 (ddd, J = 16.5, 5.1, 2.6 Hz, 1 H, CHCH₂),

2.66 (ddd, J = 16.5, 7.5, 2.6 Hz, 1 H, CHCH₂), 2.05 (t, J = 2.6 Hz,

1 H, CϵCH), 1.82–1.78 (m, 2 H, OCH₂CH₂), 1.51–1.34 (m, 4 H,

CH₂CH₂CH₃), 0.94 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 155.69 (C-2), 130.27 (C-4), 128.65 (C-6),

126.87 (C-1), 120.45 (C-5), 111.05 (C-3), 81.36 and 70.36 (CϵCH),

69.15 (OCH₂), 67.87 (CHOH), 28.93 (OCH₂CH₂), 28.34

(CH₂CH₂CH₃), 27.41 (CHCH₂), 22.41 (CH₂CH₃), 14.02 (CH₃)

ppm.

(1R)-tert-Butyldimethyl[1-(2-pentyloxyphenyl)-but-3-ynyloxy]silane

[(+)-10] and (1S)-tert-Butyldimethyl[1-(2-pentyloxyphenyl)-but-3-yn-

yloxy]silane [(–)-10]: The procedures for the preparation of (+)-10

(yield 92%, 210 mg; 0.61 mmol) and (–)-10 (yield 81%, 151 mg;

0.44 mmol) were the same as those described for the synthesis of

10. Their NMR spectroscopic data were similar to 10. (+)-10:

[α]²_D⁰: +34.2 (c = 4, CHCl₃); (–)-10: [α]²_D⁰: –36.4 (c = 2.8, CHCl₃).

Methyl 8-(tert-Butyldimethylsilanyloxy)-8-(2-pentyloxyphenyl)-oct-

5-ynoate (11): To a solution of 10 (1.276 g, 3.67 mmol) in THF

(3.7 mL), was added slowly nBuLi (4.5 mL, 4.4 mmol), and the re-

action mixture was stirred under nitrogen at –80 °C for 20 min.

Then HMPA (3.7 mL) and trimethyl 4-bromoorthobutyrate

(764 µL, 4.4 mmol) were added. The temperature of the reaction

mixture was slowly raised to 0 °C, and the mixture was kept over-

night at 0 °C. Then it was poured into a NH₄Cl solution (10%)

and extracted with PE. The organic phase was dried (Na₂SO₄) and

concentrated under reduced pressure. The residue was purified by

column chromatography, using PE as eluent, R_f: 0.23 (PE/EtOAc,

95:5), to afford 11 as a colorless oil in 68 % yield (1.115 g,

2.50 mmol). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (dd, J = 7.5,

1.7 Hz, 1 H, 6-H), 7.18 (ddd, J = 8.2, 7.8, 1.7 Hz, 1 H, 4-H), 6.92

(dd, J = 7.8, 7.5 Hz, 1 H, 5-H), 6.79 (d, J = 8.2 Hz, 1 H, 3-H), 5.15

(dd, J = 7.6, 3.8 Hz, 1 H, CHOSi), 3.94–3.84 (m, 2 H, OCH₂), 3.61

(s, 3 H, CO₂Me), 2.46 (ddt, J = 16.4, 3.8, 2.4 Hz, 1 H, CHCH₂),

2.40 (ddt, J = 16.4, 7.6, 2.3 Hz, 1 H, CHCH₂), 2.40 (t, J = 7.55 Hz,

2 H, CH₂CO₂Me), 2.20 (tdd, J = 6.9, 2.4, 2.3 Hz, 2 H, CϵCCH₂),

1.85–1.72 (m, 4 H, OCH₂CH₂and CH₂CH₂CO₂Me), 1.55–1.34 (m,

4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.2 Hz, 3 H, CH₃), 0.90 (s, 9 H,

tBuSi), 0.07 (s, 3 H, CH₃Si), –0.05 (s, 3 H, CH₃Si) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 173.87 (CO₂Me), 154.76 (C-2), 132.77 (C-

1), 127.80 (C-4), 126.80 (C-6), 120.12 (C-5), 110.56 (C-3), 79.65

and 79.06 (CϵC), 67.79 (OCH₂), 67.68 (CHOSi), 51.48 (CO₂Me),

32.83 (CH₂CO₂Me), 29.32 (CHCH₂), 28.95 (CϵCCH₂), 28.39

(OCH₂CH₂), 25.82 [3C, (CH₃)₃CSi], 24.08 (CH₂CH₂CH₃), 22.42

(CH₂CH₃), 18.35 [(CH₃)₃CSi], 18.33 (CH₂CH₂CO₂Me), 14.07

(CH₃), –4.83 and –4.99 [(CH₃)₂Si] ppm.

(1R)-1-(2-Pentyloxyphenyl)-but-3-yn-1-ol [(+)-9] and (1S)-1-(2-

Methylphenyl)-but-3-yn-1-ol [(–)-9]: To a solution of 18a (329 mg,

0.86 mmol) in MeOH (1 mL) was added KOH (241 mg, 5 equiv.,

4.3 mmol) under nitrogen at 0 °C. The reaction mixture was stirred

for 2 h at 0 °C and then for 1 h at room temperature. After addition

of water, the product was extracted with EtOAc. The alcohol (+)-

9 was purified by filtration through silica gel with PE/EtOAc (95:5)

as eluent and obtained as a yellow oil in 76% yield (212 mg,

0.66 mmol). Using the same procedure, (–)-9 was obtained from

18b in 99% yield (126 mg, 0.54 mmol). Their NMR spectroscopic

data were similar to those of 9. (+)-9: [α]²_D⁰: +21.5 (c = 4, CHCl₃);

(–)-9: [α]²_D⁰: –23.0 (c = 2, CHCl₃).

(8R)-Methyl 8-(tert-Butyldimethylsilanyloxy)-8-(2-pentyloxyphen-

yl)-oct-5-ynoate [(+)-11] and (8S)-Methyl 8-(tert-Butyldimethylsil-

anyloxy)-8-(2-pentyloxyphenyl)-oct-5-ynoate [(–)-11]: The pro-

cedures for the preparation of (+)-11 (yield 86 %, 233 mg;

0.52 mmol) and (–)-11 (yield 77%, 151 mg; 0.34 mmol) were the

same as those described for the synthesis of 11. Their NMR spec-

troscopic data were similar to 11. (+)-11: [α]²_D⁰: +35.3 (c = 4,

CHCl₃); (–)-11: [α]²_D⁰: –36.2 (c = 3, CHCl₃).

tert-Butyldimethyl[1-(2-pentyloxyphenyl)-but-3-ynyloxy]silane (10):

To a solution of 9 (1.083 g, 4.66 mmol) in DMF (4.7 mL) were

added tert-butyldimethylsilyl chloride (843 mg, 5.59 mmol) and

imidazole (793 mg, 11.65 mmol) at 0 °C under nitrogen. The reac-

tion mixture was stirred for 24 h at room temperature. The hydroly-

sis was performed with a saturated NH₄Cl solution, and the prod-

uct was extracted with PE. The combined organic layers were

washed with water, dried (Na₂SO₄), and concentrated in vacuo. The

residue was purified by column chromatography (PE), R_f: 0.42 (PE/

Methyl 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-ynoate (12): To a

solution of 11 (1.827 g, 4.06 mmol) in THF (16 mL) was added

TBAF (5.7 mL, 5.69 mmol) at room temperature. Then the reac-

EtOAc, 95:5) to afford 10 in 86% yield (1.388 g, 4.81 mmol). ¹H tion mixture was stirred under nitrogen for 3 h at 45 °C. The prod-

NMR (400 MHz, CDCl₃): δ = 7.51 (dd, J = 7.6, 1.7 Hz, 1 H, 6- uct was extracted with EtOAc. The organic phase was washed with

H), 7.19 (ddd, J = 8.2, 7.5, 1.7 Hz, 1 H, 4-H), 6.96 (dd, J = 7.6,

7.5 Hz, 1 H, 5-H), 6.86 (d, J = 8.2 Hz,1 H, 3-H), 5.26 (dd, J = 7.7,

water, dried (Na₂SO₄), and concentrated under reduced pressure.

Purification of the residue by column chromatography with PE/

3.7 Hz, 1 H, CHOSi), 4.01–3.91 (m, 2 H, OCH₂CH₂), 2.58 (ddd, J Et₃N/toluene (99:0.5:0.5) and then PE/Et₃N/toluene/EtOAc

= 16.6, 3.7, 2.7 Hz, 1 H, CHCH₂), 2.66 (ddd, J = 16.6, 7.7, 2.7 Hz,

(95:0.5:0.5:4) as eluents, R_f: 0.25 (PE/EtOAc, 80:20), afforded the

1 H, CHCH₂), 1.93 (t, J = 2.7 Hz, 1 H, CϵCH), 1.80–1.75 (m, 2 ester 12 as a colorless oil in 99% yield (1.337 g, 4.02 mmol). ¹H

H, OCH₂CH₂), 1.51–1.34 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J = NMR (400 MHz, CDCl₃): δ = 7.39 (dd, J = 7.5, 1.4 Hz, 1 H, 6-

7.2 Hz, 3 H, CH₃), 0.91 (s, 9 H, tBuSi), 0.10 (s, 3 H, CH₃Si), –0.05 H), 7.23 (ddd, J = 8.2, 7.8, 1.4 Hz, 1 H, 4-H), 6.94 (ddd, J = 7.8,

(s, 3 H, CH₃Si) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 154.75 (C-

7.5 Hz, 1 H, 5-H), 6.85 (d, J = 8.2 Hz,1 H, 3-H), 5.02 (ddd, J =

2), 132.37 (C-4), 127.99 (C-6), 126.76 (C-1), 120.13 (C-5), 110.56 7.3, 6.1, 5.8 Hz, 1 H, CHOH), 4.04–3.95 (m, 2 H, OCH₂), 3.68 (s,

(C-3), 82.52 (CϵCH), 69.12 (CϵCH), 67.69 (OCH₂), 67.41 3 H, CO₂Me), 3.00 (d, J = 6.1 Hz, 1 H, OH), 2.74 (ddt, J = 16.5,

(CHOSi), 29.05 (OCH₂CH₂), 28.94 (CH₂CH₂CH₃), 28.39 5.8, 2.3 Hz, 1 H, CHCH₂), 2.58 (ddt, J = 16.5, 7.3, 2.4 Hz, 1 H,

(CHCH₂), 25.86 [3C, (CH₃)₃CSi], 22.42 (CH₂CH₃), 18.35 [(CH₃)₃-

CSi], 14.08 (CH₃), –4.81 and –4.93 [2C, (CH₃)₂Si] ppm.

CHCH₂), 2.39 (t, J = 7.4 Hz, 2 H, CH₂CO₂Me), 2.23 (tdd, J = 6.9,

2.4, 2.3 Hz, 2 H, CϵCCH₂), 1.85–1.74 (m, 4 H, OCH₂CH₂and

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CH₂CH₂CO₂Me), 1.50–1.33 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J =

H, OCH₂CH₂), 1.68–1.58 (m, 2 H, CH₂CH₂CO₂Me), 1.53–1.31 (m,

7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.81 4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

(CO₂Me), 155.71 (C-2), 130.63 (C-1), 128.45 (C-4), 126.88 (C-6),

120.39 (C-5), 111.03 (C-3), 81.35 and 76.72 (CϵC), 69.40 (CHOH), 126.96 (HC=CH), 131.12 (C-1), 128.22 (C-4), 126.82 (C-6), 120.45

67.87 (OCH₂), 51.57 (CO₂Me), 32.83 (CH₂CO₂Me), 28.94 (C-5), 111.10 (C-3), 70.84 (CHOH), 67.85 (OCH₂), 51.50 (CO₂Me),

(100 MHz, CDCl₃): δ = 174.14 (CO₂Me), 155.90 (C-2), 131.78 and

(OCH₂CH₂), 28.34 (CH₂CH₂CH₃), 27.87 (CHCH₂), 24.01 35.33 (HC=CCH₂), 33.43 (CH₂CO₂Me), 29.01 (OCH₂CH₂), 28.36

(CH₂CH₂CO₂Me), 22.41 (CH₂CH₃), 18.27 (CϵCCH₂), 14.07 (CH₂CH₂CH₃), 26.66 (CHCH₂), 24.72 (CH₂CH₂CO₂Me), 22.41

(CH₃) ppm. C₂₀H₂₈O₄(332.43): calcd. C 72.26, H 8.49; found C

(CH₂CH₃), 14.03 (CH₃) ppm. HRMS: calcd. for C₂₀H₃₀O₄

72.30, H 8.56.

303.19602; found 303.1966 (δ = 1 ppm).

(8R)-Methyl 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-ynoate [(+)-12]

and (8S)-Methyl 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-ynoate

[(–)-12]: The procedures for the preparation of (+)-12 (yield 94%,

Methyl 8-Hydroxy-8-(2-pentyloxyphenyl)-octanoate (15): To a sus-

pension of palladium on charcoal (36 mg, 10 wt.-%) in methanol

(4.4 mL) was added 12 (364 mg, 1.1 mmol) under hydrogen. The

163 mg; 0.49 mmol) and (–)-12 (yield 58%, 66 mg; 0.20 mmol) were reaction mixture was stirred at room temperature overnight. Then

the same as those described for the synthesis of racemic 12. Their

NMR spectroscopic data were similar to those of 12. (+)-12: [α]²_D⁰:

+20.2 (c = 3, CHCl₃); (–)-12: [α]²_D⁰: –20.2 (c = 1, CHCl₃).

it was filtered through silica gel with hexane/EtOAc (80:20) as elu-

ent. After concentration under reduced pressure, the ester 15 was

obtained as a yellow oil in 94% yield (348 mg, 1.03 mmol). ¹H

NMR (400 MHz, CDCl₃): δ = 7.41 (dd, J = 7.5, 1.8 Hz, 1 H, 6-

H), 7.17 (ddd, J = 7.8, 7.6, 1.8 Hz, 1 H, 4-H), 6.92 (dd, J = 7.6,

7.5 Hz, 1 H, 5-H), 6.91 (d, J = 7.8 Hz, 1 H, 3-H), 4.88 (dd, J =

8.0, 4.3 Hz, 1 H, CHOH), 4.00–3.92 (m, 2 H, OCH₂), 3.59 (s, 3 H,

CO₂Me), 2.29 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me), 1.78–1.70

(m, 2 H, OCH₂CH₂), 1.64–1.23 (m, 15 H, CH₂CH₂CH₂CH₂-

CH₂CH₂CO₂Me and CH₂CH₂CH₃and OH), 0.94 (t, J = 7.2 Hz, 3

H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 174.90 (CO₂Me),

156.26 (C-2), 136.40 (C-1), 128.80 (C-4), 127.42 (C-6), 121.53 (C-

5), 112.48 (C-3), 68.71 (CHOH), 67.43 (OCH₂), 52.73 (CO₂Me),

34.80, 30.14, 30.12, 30.08, 29.54, 26.93, 26.24, 25.99, 23.46 (9 C,

CH₂CH₂CH₂CH₂CH₂CH₂CO₂Me and CH₂CH₂CH₂CH₃), 15.53

(CH₃) ppm. C₂₀H₃₂O₄(336.47): calcd. C 75.36, H 7.91; found C

75.47, H 8.42.

Sodium 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-ynoate (13): The es-

ter 12 (332 mg, 1 mmol) was added to a solution of MeOH/H₂O

(9:1) (22.5 mL) and LiOH monohydrate (147 mg, 3.5 mmol). The

reaction mixture was stirred for 36 h at room temperature, and then

oxalic acid (463 mg, 5.14 mmol) was added. Water and methanol

were removed under reduced pressure, and the residue was dis-

solved in EtOAc (10 mL), washed with water (1 mL), dried

(Na₂SO₄), and concentrated under reduced pressure. After purifica-

tion by column chromatography on SiO₂with hexane/EtOAc

(80:20) as the eluent, the acid was obtained in 83% yield (263 mg,

1

0.83 mmol). H NMR (400 MHz, DMSO): δ = 7.44 (dd, J = 7.6,

1.5 Hz, 1 H, 6-H), 7.20 (ddd, J = 8.1, 7.6, 1.2 Hz, 1 H, 4-H), 6.95–

6.90 (m, 2 H, 5-H and 3-H), 5.00 (dd, J = 7.1, 4.6 Hz, 1 H, CHOH),

3.98 (t, J = 6.6 Hz, 2 H, OCH₂), 2.55–2.47 (m, 3 H, CHCH₂and

CH₂CO₂H), 2.22 (ddt, J = 16.3, 7.1, 2.0 Hz, 1 H, CHCH₂), 2.18

Sodium 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-enoate (16): The

(t, J = 7.6 Hz, 2 H, CϵCCH₂), 1.79–1.70 (m, 2 H, OCH₂CH₂), procedure for the preparation of 16 was the same as that described

1

1.63–1.53 (m,

2 H, CH₂CH₂CO₂H), 1.50–1.33 (m, 4 H, for the synthesis of 13 (yield 76%, 176 mg, 0.46 mmol). Acid: H

CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR NMR (400 MHz, DMSO): δ = 7.43 (dd, J = 7.6, 1.5 Hz, 1 H, 6-

(100 MHz, DMSO): δ = 176.36 (CO₂H), 156.33 (C-2), 134.42 (C- H), 7.18 (ddd, J = 7.6, 7.6, 1.5 Hz, 1 H, 4-H), 6.95–6.90 (m, 2 H,

1), 129.32 (C-4), 127.89 (C-6), 121.43 (C-5), 112.55 (C-3), 82.00

and 79.96 (CϵC), 68.84 (CHOH), 67.09 (OCH₂), 30.03

5-H and 3-H), 5.54–5.30 (m, 2 H, HC=CH), 4.91 (dd, J = 7.6,

4 Hz, 1 H, CHOH), 4.09–3.91 (m, 2 H, OCH₂), 2.81 (s, 1 H, OH),

(CH₂CO₂H), 29.56 (OCH₂CH₂), 29.43 (CH₂CH₂CH₃), 26.14 2.53 (t, J = 1.5 Hz, 2 H, CHCH₂), 2.45–2.15 (m, 2 H, CH₂CO₂H),

(CHCH₂), 23.46 (CH₂CH₂CO₂H), 22.35 (CH₂CH₃), 19.41

(CϵCCH₂), 15.54 (CH₃) ppm. To this acid in methanol (1 mL) was

added NaOH (32 mg, 1 equiv.), and the suspension was homoge-

nized in an ultrasonic bath. After evaporation under reduced pres-

sure, the (hygroscopic) salt 13 was obtained in 79% yield (278 mg),

after drying for two days under vacuum (10^–2Torr). HRMS: calcd.

for C₁₉H₂₅NaO₄341.17288; found 341.1730 (δ = 0 ppm).

2.10 (t, J = 7.1 Hz, 2 H, HC=CCH₂), 1.98–1.90 (m, 2 H,

OCH₂CH₂), 1.79–1.70 (m, 2 H, CH₂CH₂CO₂H), 1.53–1.31 (m, 4

H, CH₂CH₂CH₃), 0.91 (t, J = 7.6 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, DMSO): δ = 175.16 (CO₂H), 155.04 (C-2), 134.35 and

130.26 (HC=CH), 127.73 (C-1), 127.63 (C-4), 126.48 (C-6), 120.25

(C-5), 111.24 (C-3), 67.55 (CHOH), 66.74 (OCH₂), 36.00

(HC=CCH₂), 34.25 (CH₂CO₂H), 28.85 (OCH₂CH₂), 28.22

(CH₂CH₂CH₃), 26.73 (CHCH₂), 25.13 (CH₂CH₂CO₂H), 22.21

(CH₂CH₃), 14.30 (CH₃) ppm. Salt 16: HRMS: calcd. for

C₁₉H₂₇NaO₄343.18853; found 343.1893 (δ = 2 ppm).

Methyl 8-Hydroxy-8-(2-pentyloxyphenyl)-oct-5-enoate (14): To a

solution of nickel acetate tetrahydrate (100 mg, 0.4 mmol) in EtOH

(5 mL) was added a solution of sodium borohydride (15 mg,

0.4 equiv., 0.4 mmol) in EtOH (0.5 mL) under hydrogen. The reac-

tion mixture was stirred for 15 min at room temperature, and then

ethylenediamine (68 µL, 1 mmol) and 12 (332 mg, 1 mmol) were

added. The reaction mixture was stirred for 5 h at room tempera-

ture. After addition of diethyl ether (2 mL), the suspension was

filtered through silica gel and washed with diethyl ether. After con-

Sodium 8-Hydroxy-8-(2-pentyloxyphenyl)-octanoate (17): The pro-

cedure for the preparation of 17 was the same as that described for

the synthesis of 13 (yield 97%, 247 mg, 0.60 mmol). Acid: ¹H NMR

(400 MHz, DMSO): δ = 7.41 (dd, J = 7.1, 1.5 Hz, 1 H, H-6), 7.16

(ddd, J = 8.1, 7.6, 2.0 Hz, 1 H, 4-H), 6.93–6.89 (m, 2 H, 5-H and

3-H), 4.88 (dd, J = 7.6, 3.6 Hz, 1 H, CHOH), 4.00–3.90 (m, 2 H,

OCH₂), 2.53 (t, J = 1.5 Hz, 2 H, CH₂CO₂H), 2.04 (t, J = 7.6 Hz,

centration in vacuo, 14 was obtained as a viscous oil in 96% yield

1

(322 mg, 0.96 mmol). H NMR (400 MHz, CDCl₃): δ = 7.31 (dd, 2 H, OCH₂CH₂), 1.79–1.69 (m, 2 H, CH₂CH₂CO₂H), 1.64–1.18

J = 7.5, 1.7 Hz, 1 H, 6-H), 7.21 (ddd, J = 8.2, 7.8, 1.7 Hz, 1 H, 4- (m, 12 H, CH₂CH₂CH₂CH₂CH₂CH₂CO₂H and CH₂CH₂CH₃),

H), 6.94 (ddd, J = 7.8, 7.5, 0.9 Hz, 1 H, 5-H), 6.85 (d, J = 8.2 Hz,1

H, 3-H), 5.48–5.43 (m, 2 H, HC=CH), 4.90 (dd, J = 7.2, 5.9 Hz, 1

H, CHOH), 4.05–3.96 (m, 2 H, OCH₂), 3.65 (s, 3 H, CO₂Me), 2.81

0.92 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO):

δ = 177.38 (CO₂H), 156.28 (C-2), 136.49 (C-1), 128.76 (C-4), 127.44

(C-6), 121.52 (C-5), 112.45 (C-3), 68.70 (CHOH), 67.48 (OCH₂),

(s, 1 H, OH), 2.62–2.48 (m, 2 H, CHCH₂), 2.27 (t, J = 7.6 Hz, 2 39.78, 37.48, 30.70, 30.48, 30.12, 29.54, 27.12, 27.07, 23.47 (9 C,

H, CH₂CO₂Me), 2.11–2.00 (m, 2 H, HC=CCH₂), 1.85–1.74 (m, 2 CH₂CH₂CH₂CH₂CH₂CH₂CO₂H and CH₂CH₂CH₂CH₃), 15.55

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Synthesis of Aromatic Analogs of 8(S)-HETE

FULL PAPER

(CH₃) ppm. Salt 17 was obtained as a white solid (m.p. = 54–

59 °C). Salt: HRMS: calcd. for C₁₈H₂₇NaO₄345.20418; found

345.2040 (δ = 0 ppm).

oxy derivative 19 was obtained as a colorless oil in 85% yield

(180 mg, 0.73 mmol). H NMR (400 MHz, CDCl₃): δ = 7.41 (dd,

1

J = 7.6, 1.8 Hz, 1 H, 6-H), 7.24 (ddd, J = 8.2, 7.5, 1.8 Hz, 1 H, 4-

H), 6.97 (ddd, J = 7.6, 7.5, 1.0 Hz, 1 H, 5-H), 6.86 (d, J = 8.2 Hz,1

H, 3-H), 4.81 (dd, J = 7.3, 4.3 Hz, 1 H, CHOMe), 3.97 (t, J =

6.4 Hz, 2 H, OCH₂), 3.34 (s, 3 H, OMe), 2.68 (ddd, J = 16.9, 4.3,

2.6 Hz, 1 H, CHCH₂), 2.54 (ddd, J = 16.9, 7.3, 2.6 Hz, 1 H,

CHCH₂), 1.98 (t, J = 2.6 Hz, 1 H, CϵCH), 1.86–1.76 (m, 2 H,

OCH₂CH₂), 1.51–1.34 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.2 Hz,

3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.29 (C-2),

128.57 (C-4), 128.53 (C-6), 126.51 (C-1), 120.34 (C-5), 111.01 (C-

3), 81.52 (CϵCH), 75.53 (CϵCH), 69.24 (OCH₂), 67.83 (CHOH),

57.37 (OMe), 28.95 (CHCH₂), 28.34 (OCH₂CH₂), 26.26

(CH₂CH₂CH₃), 22.42 (CH₂CH₃), 14.06 (CH₃) ppm.

1-(2-Pentyloxyphenyl)-but-3-ynyl Methoxyphenylacetate (18a and

18b): To a solution of DCC, (1.39 g, 2.8 equiv., 6.75 mmol), (S)-O-

methyl-L-mandelic acid (800 mg, 2 equiv., 4.82 mmol) and DMAP

(147 mg, 0.5 equiv., 1.2 mmol) in CH₂Cl₂(5 mL) was added a solu-

tion of 9 (560 mg, 2.41 mmol) in CH₂Cl₂(6 mL). The reaction mix-

ture was stirred at room temperature for 30 min. The crude mixture

was filtered first on Celite, which was washed further with EtOAc.

After evaporation of the solvents under vacuum, the residue was

filtered through silica gel with PE as eluent to afford a mixture of

the two diastereoisomers 18a and 18b in 93% yield (852 mg). These

derivatives were separated by several successive column chromatog-

raphy steps on silica gel, using as eluents PE and then PE/tert-

butylmethyl ether (TBME) mixtures 99:1, 98:2, 97:3, 96:4, and 95:5.

The separation was monitored by TLC with PE/TBME (95:5 with

2 elutions) as eluent. The ester 18a (the less polar product) was

isolated in 39% yield (329 mg, 0.86 mmol), while the isomer 18b

(the more polar product) was obtained in 25% yield (210 mg,

0.60 mmol).

Methyl 8-Methoxy-8-(2-pentyloxyphenyl)-oct-5-ynoate (20): The

procedure for the preparation of 20 was the same as that described

for the synthesis of 11 in 92% yield (210 mg, 0.61 mmol). ¹H NMR

(400 MHz, CDCl₃): δ = 7.39 (dd, J = 7.6, 1.8 Hz, 1 H, 6-H), 7.23

(ddd, J = 8.2, 7.5, 1.8 Hz 1 H, 4-H), 6.94 (ddd, J = 7.6, 7.5, 1.0 Hz,

1 H, 5-H), 6.85 (dd, J = 8.2, 1.0 Hz,1 H, 3-H), 4.76 (dd, J = 7.0,

4.6 Hz, 1 H, CHOMe), 3.97 (t, J = 6.5 Hz, 2 H, OCH₂), 3.67 (s, 3

H, CO₂Me), 3.32 (s, 3 H, OMe), 2.63 (ddt, J = 16.7, 4.6, 2.3 Hz, 1

H, CHCH₂), 2.50 (ddt, J = 16.7, 7, 2.4 Hz, 1 H, CHCH₂), 2.37 (t,

J = 7.6 Hz, 2 H, CH₂CO₂Me), 2.21 (tdd, J = 6.9, 2.4, 2.3 Hz, 2 H,

First Diastereoisomer (Less Polar) 18a: ¹H NMR (400 MHz,

CDCl₃): δ = 7.53–7.49 (m, 2 H, H-arom.), 7.38–7.31 (m, 3 H, 2 H-

arom. and 6-H), 7.29–7.21 (m, 2 H, H-arom. and 4-H), 6.89 (ddd,

J = 7.5, 7.5, 1.0 Hz, 1 H, 5-H), 6.83 (dd, J = 8.2, 1.0 Hz, 1 H, 3-

H), 6.31 (dd, J = 7.0, 4.7 Hz, 1 H, CHOCO), 4.87 (s, 1 H,

CHOMe), 3.95 (t, J = 6.5 Hz, 2 H, OCH₂), 3.46 (s, 3 H, OMe),

2.72 (ddd, J = 17.0, 4.7, 2.7 Hz, 1 H, CHCH₂), 2.59 (ddd, J = 17.0,

7.0, 2.7 Hz, 1 H, CHCH₂), 1.81–1.73 (m, 2 H, OCH₂CH₂), 1.70 (t,

J = 2.7 Hz, 1 H, CϵCH), 1.48–1.32 (m, 4 H, CH₂CH₂CH₃), 0.92

(t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

169.73 (CO), 155.50 (C-2), 136.29, 129.15, 128.56, 128.48, 127.24,

126.85, 126.44 (5 C-arom., C-4, C-6 and C-1), 120.13 (C-5), 111.16

(C-3), 82.69 (CϵCH), 79.45 (CHOMe), 76.72 (CϵCH), 69.37

(CHOCO), 68.05 (OCH₂), 57.57 (OMe), 28.85 (CHCH₂), 28.23

(OCH₂CH₂), 24.63 (CH₂CH₂CH₃), 22.39 (CH₂CH₃), 14.02 (CH₃).

[α]²_D⁰: +27.2 (c = 3, CHCl₃) ppm.

CϵCCH₂), 1.85–1.74 (m,

4 H, OCH₂CH₂and CH₂CH₂-

CO₂Me), 1.50–1.33 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.2 Hz, 3

H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.88 (CO₂Me),

156.34 (C-2), 128.96 (C-1), 128.34 (C-4), 126.62 (C-6), 120.28 (C-

5), 111.98 (C-3), 80.03 and 75.94 (CϵC), 67.83 (OCH₂), 57.27

(CHOH), 51.49 (CO₂Me), 32.76 (CH₂CO₂Me), 28.96 (CHCH₂),

28.34 (OCH₂CH₂), 26.49 (CH₂CH₂CH₃), 24.08 (CH₂CH₂CO₂Me),

22.42 (CH₂CH₃), 18.33 (CHCH₂), 14.07 (CH₃) ppm. C₂₁H₃₀O₄

(346.46): calcd. C 72.8, H 8.73; found C 73.14, H 8.70.

2-Pentyloxyphenyl-methanol (21): To a solution of 8 (1.748 g,

9.1 mmol) in EtOH/THF (7:3, 11 mL) was added NaBH₄(344 mg,

1 equiv., 9.1 mmol). The reaction mixture was stirred at room tem-

perature for 1 h. After addition of brine, the product was extracted

with EtOAc to afford 21 as a colorless oil in 68% yield (1.016 g,

Second Diastereoisomer (More Polar) 18b: ¹H NMR (400 MHz,

CDCl₃): δ = 7.48–7.43 (m, 2 H, H-arom.), 7.38–7.31 (m, 3 H, 2 H-

arom. and 6-H), 7.15 (ddd, J = 7.5, 7.5, 1.6 Hz, 1 H, 4-H), 6.80–

6.74 (m, 2 H, H-arom. and 5-H), 6.67 (dd, J = 8.2, 1.0 Hz,1 H, 3-

H), 6.31 (dd, J = 7.4, 4.2 Hz, 1 H, CHOCO), 4.90 (s, 1 H,

CHOMe), 3.94–3.85 (m, 2 H, OCH₂), 3.46 (s, 3 H, OMe), 2.81

(ddd, J = 17.0, 4.2, 2.7 Hz, 1 H, CHCH₂), 2.64 (ddd, J = 17.0, 7.4,

2.7 Hz, 1 H, CHCH₂), 1.92 (t, J = 2.7 Hz, 1 H, CϵCH), 1.81–1.69

(m, 2 H, OCH₂CH₂), 1.48–1.32 (m, 4 H, CH₂CH₂CH₃), 0.93 (t, J

= 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

169.42 (CO), 155.29 (C-2), 136.17, 128.89, 128.70, 128.55, 127.54,

126.79, 125.92 (5 C-arom., C-4, C-6 and C-1), 119.99 (C-5), 110.95

(C-3), 82.53 (CϵCH), 79.95 (CHOMe), 76.72 (CϵCH), 69.36

(CHOCO), 67.98 (OCH₂), 57.41 (OMe), 28.82 (CHCH₂), 28.23

(OCH₂CH₂), 24.90 (CH₂CH₂CH₃), 22.40 (CH₂CH₃), 14.03 (CH₃)

ppm. [α]²_D⁰: +23.7 (c = 3, CHCl₃).

1

6.18 mmol). H NMR (400 MHz, CDCl₃): δ = 7.26–7.23 (m, 2 H,

6-H and 4-H), 6.92 (ddd, J = 7.4, 7.4, 1.0 Hz, 1 H, 5-H), 6.87 (d,

J = 8.6 Hz,1 H, 3-H), 4.69 (d, J = 6.5 Hz, 2 H, CH₂OH), 4.01 (t,

J = 6.5 Hz, 2 H, OCH₂), 2.47 (t, J = 6.5 Hz, 1 H, OH), 1.86–1.78

(m, 2 H, OCH₂CH₂), 1.50–1.34 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J

= 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

156.98 (C-2), 129.12 (C-4), 128.88 (C-6), 128.65 (C-1), 120.48 (C-

5), 111.01 (C-3), 67.93 (OCH₂), 62.44 (CH₂OH), 28.98

(OCH₂CH₂), 28.33 (CH₂CH₂CH₃), 22.44 (CH₂CH₃), 14.03 (CH₃)

ppm.

1-Bromomethyl-2-pentyloxybenzene (22): To a solution of pyridine

(600 µL, 2 equiv., 7.38 mmol) in Et₂O (15 mL) was added 21

(717 mg, 3.69 mmol) under nitrogen. Then, PBr₃(210 µL,

0.6 equiv., 2.21 mmol) was added slowly at 0 °C. The reaction mix-

ture was stirred for 1 h at 0 °C before addition of HCl (0.5  solu-

tion). The product was extracted with EtOAc. It was purified by

1-(1-Methoxybut-3-ynyl)-2-pentyloxybenzene (19): To a suspension

of NaH (55 mg, 1.6 equiv., 1.38 mmol) in THF/DMF (5:1, 3.8 mL) filtration through silica gel using PE as eluent to afford 22 as a

was added a solution of 9 (200 mg, 0.86 mmol) in THF (1.7 mL). colorless oil in 35% yield (334 mg, 1.3 mmol). ¹H NMR (400 MHz,

The reaction mixture was stirred for 20 min at room temperature,

cooled to 0 °C before adding Me₂SO₄(115 µL, 1.4 equiv.,

1.2 mmol), and then stirred at room temperature overnight. After

addition of water, the product was extracted with EtOAc, and the

organic phase was dried (Na₂SO₄) and concentrated under reduced

pressure. After flash chromatography with PE as eluent, the meth-

CDCl₃): δ = 7.33 (dd, J = 7.5, 1.8 Hz, 1 H, 6-H), 7.27 (ddd, J =

8.3, 7.5, 1.8 Hz, 1 H, 4-H), 6.90 (ddd, J = 7.5, 7.4, 1.1 Hz, 1 H, 5-

H), 6.87 (d, J = 8.3 Hz, 1 H, 3-H), 4.56 (s, 2 H, CH₂Br), 4.03 (t, J

= 6.4 Hz, 2 H, OCH₂), 1.89–1.81 (m, 2 H, OCH₂CH₂), 1.55–1.46

(m, 2 H, CH₂CH₂CH₃), 1.46–1.35 (m, 2 H, CH₂CH₃), 0.94 (t, J =

7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 156.90

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2191

P. Mosset, R. Grée et al.

FULL PAPER

(C-2), 130.8 (C-4), 130.13 (C-6), 126.15 (C-1), 120.38 (C-5), 111.68

H), 7.11 (ddd, J = 8.2, 7.8, 1.7 Hz, 1 H, 4-H), 6.85 (ddd, J = 7.6,

(C-3), 68.14 (OCH₂), 29.22 (CH₂Br), 28.92 (OCH₂CH₂), 28.26 7.5, 0.9 Hz, 1 H, 5-H), 6.79 (dd, J = 8.2, 0.9 Hz, 1 H, 3-H), 5.14

(CH₂CH₂CH₃), 22.42 (CH₂CH₃), 14.06 (CH₃) ppm.

(dd, J = 8.2, 3.5 Hz, 1 H, CHOSi), 3.92–3.84 (m, 2 H, OCH₂), 3.59

(s, 3 H, CO₂Me), 2.43 (ddt, J = 16.5, 3.5, 2.4 Hz, 1 H, CHCH₂),

2.29 (ddt, J = 16.5, 8.2, 2.2 Hz, 1 H, CHCH₂), 2.01 (tdd, J = 8.2,

2.4, 2.2 Hz, 2 H, CϵCCH₂), 1.77–1.66 (m, 4 H, OCH₂CH₂and

CH₂CMe₂), 1.45–1.27 (m, 4 H, CH₂CH₂CH₃), 1.10 (s, 6 H, CMe₂),

0.88 (t, J = 7.2 Hz, 3 H, CH₃), 0.84 (s, 9 H, tBuSi), 0.07 (s, 3 H,

CH₃Si), –0.04 (s, 3 H, CH₃Si) ppm. ¹³C NMR (100 M Hz, CDCl₃):

δ = 177.86 (CO₂Me), 154.76 (C-2), 132.94 (C-1), 127.80 (C-4),

126.70 (C-6), 120.14 (C-5), 110.57 (C-3), 80.36 and 78.42 (CϵC),

67.94 (OCH₂), 67.71 (CHOSi), 51.75 (CO₂Me), 41.95 (CMe₂),

39.92 (CH₂CMe₂), 29.48 (CHCH₂), 28.97 (CϵCCH₂), 28.4

(OCH₂CH₂), 25.85 [3C, (CH₃)₃CSi], 24.93 (CH₂CH₂CH₃), 22.45

(CH₂CH₃), 18.40 [(CH₃)₃CSi], 14.89 (2C, CMe₂), 14.09 (CH₃),

–4.78 and –4.99 [(CH₃)₂Si] ppm.

1-But-3-ynyl-2-pentyloxybenzene (23): In a double-necked round-

bottom flask, magnesium metal turnings (67 mg, 1.3 equiv.,

2.74 mmol) were flame-dried under nitrogen. After cooling to room

temperature, anhydrous ether (2.1 mL) and mercury() chloride

(8 mg, 0.013 equiv., 0.027 mmol) were added. Propargyl bromide

(340 µL, 1.5 equiv., 3.16 mmol) was added slowly, and the forma-

tion of the Grignard reagent induced a slight boiling of ether; if

not, the reaction mixture was warmed with a heat gun. When the

magnesium turnings were consumed (20 to 30 min), the reaction

mixture was cooled to –80 °C and, at this temperature, CuI (27 mg,

5 wt.-%) and 22 (542 mg, 2.11 mmol) were added. The reaction

mixture was stirred for 24 h at room temperature. After addition

of water, the product was extracted with PE. The product was puri-

fied by filtration through silica gel using PE as eluent to afford 23

Methyl 8-Hydroxy-2,2-dimethyl-8-(2-pentyloxyphenyl)-oct-5-ynoate

(26): The procedure for the preparation of 26 was the same as that

described for the synthesis of 12 (yield 69%, 166 mg, 0.46 mmol).

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (dd, J = 7.5, 1.7 Hz, 1 H,

6-H), 7.23 (ddd, J = 7.8, 7.8, 1.7 Hz, 1 H, 4-H), 6.95 (ddd, J = 7.8,

7.5, 1.0 Hz, 1 H, 5-H), 6.85 (dd, J = 7.8, 1.0 Hz, 1 H, 3-H), 5.02

1

as an oil in 27% yield. (123 mg, 0.57 mmol). H NMR (400 MHz,

CDCl₃): δ = 7.21–7.15 (m, 2 H, 6-H and 4-H), 6.87 (ddd J = 7.4,

7.4, 1.1 Hz, 1 H, 5-H), 6.82 (d, J = 8.5 Hz, 1 H, 3-H), 3.96 (t, J =

6.4 Hz, 2 H, OCH₂), 2.86 (t, J = 7.6 Hz, 2 H, ArCH₂), 2.48 (td, J

= 7.6, 2.6 Hz, 2 H, CH₂CϵC), 1.95 (t, J = 2.6 Hz, 1 H, CϵCH),

1.84–1.77 (m, 2 H, OCH₂CH₂), 1.50–1.34 (m, 4 H, CH₂CH₂CH₃), (ddd, J = 7.7, 5.9, 4.8 Hz, 1 H, CHOH), 4.03–3.94 (m, 2 H, OCH₂),

0.94 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 156.90 (C-2), 130.11 (C-4), 128.78 (C-6), 127.61 (C-1), 120.04

3.67 (s, 3 H, CO₂Me), 3.02 (d, J = 5.9 Hz, 1 H, OH), 2.71 (ddt, J

= 16.5, 4.8, 2.4 Hz, 1 H, CHCH₂), 2.54 (ddt, J = 16.5, 7.7, 2.4 Hz,

(C-5), 110.94 (C-3), 84.56 (CϵCH), 68.36 (CϵCH), 67.70 (OCH₂), 1 H, CHCH₂), 2.13 (tt, J = 8.0, 2.4 Hz, 2 H, CϵCCH₂), 1.85–1.75

30.00 (CHOH), 29.02 (OCH₂CH₂), 28.36 (CH₂CH₂CH₃), 22.44 (m, H, OCH₂CH₂and CH₂CMe₂), 1.50–1.33 (m, H,

(CH CH ), 18.76 (CH CϵC), 14.06 (CH ) ppm. IR (KBr): ν = CH₂CH₂CH₃), 1.20 (s, 6 H, CMe₂), 0.94 (t, J = 7.1 Hz, 3 H, CH₃)

4

˜

2

3

2

3

3306, 3026, 2954, 2932, 2868, 2858, 2119, 1600, 1586, 1493, 1453,

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.05 (CO₂Me), 155.72

(C-2), 130.80 (C-1), 128.48 (C-4), 126.84 (C-6), 120.46 (C-5), 111.05

(C-3), 82.11 and 80.21 (CϵC), 69.22 (CHOH), 67.93 (OCH₂), 51.57

(CO₂Me), 41.95 (CMe₂), 39.68 (CH₂CMe₂), 29.02 (CHCH₂), 28.40

(CϵCCH₂), 28.09 (OCH₂CH₂), 25.03 (CH₂CH₂CH₃), 22.49

(CH₂CH₃), 14.95 (2C, CMe₂), 14.10 (CH₃) ppm. C₂₂H₃₂O₄

(360.49): calcd. C 73.30, H 8.95; found C 73.44, H 9.10.

1242, 1110, 1050, 748, 628 cm^–1.

Methyl 8-(2-Pentyloxyphenyl)-oct-5-ynoate (24): The procedure for

the preparation of 24 was the same as that described for the synthe-

sis of 11 (yield 80%, 195 mg, 0.62 mmol). ¹H NMR (400 MHz,

CDCl₃): δ = 7.19–7.14 (m, 2 H, 6-H and 4-H), 6.86 (ddd, J = 7.4,

7.4, 1.1 Hz, 1 H, 5-H), 6.81 (dd, J = 8.7, 1.1 Hz, 1 H, 3-H), 3.95

(t, J = 6.5 Hz, 2 H, OCH₂), 3.68 (s, 3 H, CO₂Me), 2.80 (t, J = 2-Pentyloxy-naphthalene (28): The procedure for the preparation of

7.6 Hz, 2 H, ArCH₂), 2.42 (tt, J = 7.6, 2.4 Hz, 2 H, CH₂CϵC),

2.40 (t, J = 7.6 Hz, 2 H, CH₂CO₂Me), 2.21 (tt, J = 6.9, 2.4 Hz, 2

28 was the same as that described for the synthesis of 8. After

purification by flash column chromatography (5% EtOAc in PE,

H, CϵCCH₂), 1.84–1.73 (m, 4 H, OCH₂CH₂and CH₂CH₂- R_f: 0.55), 28 was obtained in 97% yield (5.2 g, 24.27 mmol). ¹H

CO₂Me), 1.50–1.34 (m, 4 H, CH₂CH₂CH₃), 0.94 (t, J = 7.2 Hz, 3 NMR (400 MHz, CDCl₃): δ = 7.77–7.69 (m, 3 H, 8-H, 5-H and 4-

H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.86 (CO₂Me),

H), 7.41 (ddd, J = 6.9, 6.9, 1.2 Hz, 1 H, 6-H) 7.31 (ddd, J = 6.9,

156.9 (C-2), 130.15 (C-4), 129.25 (C-6), 127.39 (C-1), 119.99 (C- 6.9, 1.2 Hz, 1 H, 7-H), 7.17–7.10 (m, 2 H, 4-H, 1-H), 4.05 (t, J =

5), 110.92 (C-3), 81.11 and 79.11 (CϵCCH₂), 67.70 (C-7), 51.52 6.6 Hz, OCH₂), 1.89–1.79 (m, CH₂CH₃), 1.52–1.38 (m, 4 H,

(CO₂Me), 32.83 (CH₂CO₂Me), 30.48 (ArCH₂), 29.02 (OCH₂CH₂), OCH₂CH₂and CH₂CH₂CH₃), 0.95 (t, J = 7.1 Hz, 3 H, CH₃) ppm.

28.35 (CH₂CH₂CH₃), 24.37 (CH₂CH₂CO₂Me), 22.45 (CH₂CH₃), ¹³C NMR (100 MHz, CDCl₃): δ = 157.09 (C-2), 134.60 (C-8_a),

19.10 (CH₂CϵC), 18.25 (CϵCCH₂), 14.06 (CH₃) ppm. IR (KBr): 129.28 (C-4), 128.84 (C-4_a), 127.62 (C-5), 126.67 (C-8), 126.26 (C-

ν = 3023, 2953, 2934, 2871, 2860, 1739, 1601, 1494, 1455, 1436,

7), 123.43 (C-6), 119.03 (C-3), 106.47 (C-1), 67.96 (OCH₂), 28.95

(OCH₂CH₂), 28.27 (CH₂CH₂CH₃), 22.50 (CH₂CH₃), 14.06 (CH₃)

˜

1243, 1192, 1162, 1110, 1050, 752 cm^–1. HRMS: calcd. for

C₂₀H₂₈O₃316.20385; found 316.2031 (δ = 2 ppm).

ppm. IR (KBr): ν = 3058, 2955, 2931, 2871, 2860, 1629, 1601, 1512,

˜

1465, 1390, 1268, 1258, 1217, 1182, 1119, 835, 809, 745, 624,

Methyl 8-(tert-Butyldimethylsilanyloxy)-2,2-dimethyl-8-(2-pentyl-

472 cm^–1.

oxyphenyl)-oct-5-ynoate (25): To

a solution of 11 (356 mg,

0.8 mmol) in THF (1.6 mL) was added LDA (2  in THF, 1.4 mL,

3.5 equiv., 2.8 mmol) at –90 °C under nitrogen. The reaction mix-

ture was stirred for 30 min at this temperature, and then raised to

–80 °C before addition of iodomethane (400 µL, 8 equiv.,

6.4 mmol). The solution was stirred for 30 min at this temperature,

before being slowly warmed to room temperature in 3 h. After ad-

dition of water, the product was extracted with EtOAc. The organic

phase was dried (Na₂SO₄) and concentrated under vacuum. The

residue was purified by flash chromatography with PE as eluent to

3-Pentyloxy-2-carbaldehydenaphthalene (29): To tBuLi (1.7  in

pentane, 7.7 mL, 1.12 equiv., 13.08 mmol) was added a solution of

28 (2.5 g, 11.67 mmol) in tetrahydropyran (THP, 7 mL) at 0 °C un-

der argon, and the reaction mixture was stirred at this temperature

for 10 min. Then, the ice bath was removed, and the solution was

stirred for 4 h at room temperature. After cooling down to 0 °C, a

solution of DMF (2.7 mL, 3 equiv., 35 mmol) in THP (6 mL) was

added. The solution became clear, and the reaction mixture was

stirred overnight. The product was extracted with EtOAc, washed

with water, and dried (Na₂SO₄). After evaporation of the solvent,

1

afford 25 as a colorless oil in 84% yield (317 mg, 0.67 mmol). H

NMR (400 MHz, CDCl₃): δ = 7.41 (dd, J = 7.6, 1.7 Hz, 1 H, 6- the crystalline product was washed with PE. The naphthalene 29

2192

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Eur. J. Org. Chem. 2006, 2181–2196

Synthesis of Aromatic Analogs of 8(S)-HETE

FULL PAPER

was obtained as a yellow powder (m.p. = 63–68 °C) in 66% yield

1 H, CHOH), 4.08 (t, J = 6.4 Hz, OCH₂), 3.66 (s, 3 H, CO₂Me),

(1.862 g, 7.68 mmol). ¹H NMR (400 MHz, CDCl₃): δ = 10.62 (s, 1 2.65 (ddt, J = 16.5, 3.4, 2.5 Hz, 1 H, CHCH₂), 2.47 (ddt, J = 16.5,

H, CHO), 8.35 (s, 1 H, 4-H), 7.85 (d, J = 8.1 Hz, 1 H, 5-H), 7.7

(d, J = 8.2 Hz, 1 H, 8-H), 7.51 (ddd, J = 8.2, 6.9, 1.0 Hz, 1 H, 7- 2.24–2.18 (m, 2 H, CϵCCH₂), 1.93–1.85 (m, 2 H, OCH₂CH₂),

H), 7.36 (ddd, J = 8.1, 6.9, 0.9 Hz, 1 H, 6-H), 7.16 (s, 1 H, 1-H), 1.82–1.73 (m, H, CH₂CH₂CO₂Me), 1.55–1.38 (m, H,

7.3, 2.3 Hz, 1 H, CHCH₂), 2.40 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me),

2

4

4.14 (t, J = 6.5 Hz, 2 H, OCH₂), 1.95–1.87 (m, 2 H, OCH₂CH₂), CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz, 3 H, CH₃), 0.95 (s, 9 H, SitBu),

1.56–1.38 (m, 4 H, CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz, 3 H, CH₃) 0.12 (s, 3 H, MeSi), –0.08 (s, 3 H, MeSi) ppm. ¹³C NMR (100 MHz,

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 190.44 (CHO), 157.21 (C- CDCl₃): δ = 173.84 (CO₂Me), 153.86 (C-2), 134.4 (C-8_a), 133.71

2), 137.62 (C-8_a), 130.30 (C-4), 129.95 (C-4_a), 129.10 (C-5), 127.60

(C-8), 126.56 (C-7), 125.60 (C-6), 124.50 (C-3), 106.97 (C-1), 68.43

(C-4_a), 128.48 (C-3), 127.81 (C-5), 126.20 (C-8), 126.09 (C-4),

125.84 (C-7), 123.41 (C-6), 105.22 (C-1), 79.88 and 78.93 (CϵCH),

(OCH₂), 28.75 (OCH₂CH₂), 28.31 (CH₂CH₂CH₃), 22.45 68.34 (CHOH), 67.73 (OCH₂), 51.48 (CO₂Me), 32.81

(CH CH ), 14.05 (CH ) ppm. IR (KBr): ν = 3447, 3047, 2948,

(CH₂CO₂Me), 29.47 (CHCH₂), 28.80 (OCH₂CH₂), 28.44

(CH₂CH₂CH₃), 25.86 [3C, (CH₃)₃CSi], 24.08 (CH₂CH₂CO₂Me),

22.42 (CH₂CH₃), 18.33 [2C, CϵCCH₂and (CH₃)₃CSi], 14.10

˜

2

3

2867, 1734, 1683, 1623, 1596, 1503, 1454, 1391, 1340, 1255, 1183,

1149, 1104, 1017, 836, 750, 700, 478 cm^–1.

(CH ), –4.78 and –4.95 (Me Si) ppm. IR (KBr): ν = 3055, 2953,

˜

3

2

1-(3-Pentyloxy-naphthalen-2-yl)-but-3-yn-1-ol (30): The procedure

for the preparation of 30 was the same as that described for the

synthesis of

2929, 2856, 2357, 1738, 1634, 1504, 1463, 1330, 1248, 1209, 1179,

1109, 1084, 938, 834, 777, 745 cm^–1.

9

(yield 61%, 1.497 g, 5.34 mmol). ¹H NMR

(400 MHz, CDCl₃): δ = 7.85 (s, 1 H, 4-H), 7.78 (d, J = 8.0 Hz, 1

H, 5-H), 7.70 (d, J = 8.2 Hz, 1 H, 8-H), 7.43 (ddd, J = 8.2, 6.8,

Methyl

8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-oct-5-ynoate

(33): The procedure for the preparation of 33 was the same as that

1.3 Hz, 1 H, 7-H), 7.35 (ddd, J = 8.0, 6.8, 1.3 Hz, 1 H, 6-H), 7.11 described for the synthesis of 12 (yield 68%, 892 mg, 2.33 mmol).

(s, 1 H, 1-H), 5.2 (ddd, J = 7.4, 6.2, 5.0 Hz, 1 H, CHOH), 4.11 (m,

2 H, OCH₂), 3.03 (d, J = 6.2 Hz, 1 H, OH), 2.89 (ddd, J = 16.8,

5.0, 2.6 Hz, 1 H, CHCH₂), 2.72 (ddd, J = 16.8, 7.4, 2.6 Hz, 1 H,

CHCH₂), 2.06 (t, J = 2.6 Hz, 1 H, CϵCH), 1.93–1.86 (m, 2 H,

OCH₂CH₂), 1.55–1.38 (m, 4 H, CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz,

3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 154.70 (C-2),

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (s, 1 H, 4-H), 7.78 (d, J =

8.0 Hz, 1 H, 5-H), 7.70 (d, J = 8.1 Hz, 1 H, 8-H), 7.42 (ddd, J =

8.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.35 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H, 6-

H), 7.26 (s, 1 H, 1-H), 5.15 (s, 1 H, CHOH), 4.11–4.05 (m, 2 H,

OCH₂), 3.65 (s, 3 H, CO₂Me), 3.06 (s, 1 H, OH), 2.85 (ddt, J =

16.5, 5.0, 2.4 Hz, 1 H, CHCH₂), 2.47 (ddt, J = 16.5, 7.1, 2.4 Hz, 1

134.29 (C-8_a), 132 (C-4), 128.81 (C-4_a), 128.28 (C-5), 126.76 (C-8), H, CHCH₂), 2.36 (t, J = 7.4 Hz, 2 H, CH₂CO₂Me), 2.22 (tt, J =

126.71 (C-7), 126.56 (C-6), 124.29 (C-3), 106.41 (C-1), 81.56

(CϵCH), 71.04 (CϵCH), 69.92 (CHOH), 68.41 (OCH₂), 29.25

(OCH₂CH₂), 28.80 (CH₂CH₂CH₃), 27.97 (CHCH₂), 22.83

6.8, 2.4 Hz, 2 H, CϵCCH₂), 1.92–1.84 (m, 2 H, OCH₂CH₂), 1.77

(tt, J = 7.4, 6.8 Hz, 2 H, CH₂CH₂CO₂Me), 1.55–1.38 (m, 4 H,

CH₂CH₂CH₃), 0.96 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR

(CH CH ), 14.44 (CH ) ppm. IR (KBr): ν = 3329, 3305, 3297, (100 MHz, CDCl₃): δ = 173.76 (CO₂Me), 154.35 (C-2), 133.81 (C-

˜

2

3

3056, 2951, 2932, 2861, 2121, 1632, 1601, 1503, 1465, 1394, 1322,

1251, 1219, 1183, 1149, 1103, 1071, 1015, 872, 840, 747, 643, 621,

480 cm^–1.

8_a), 132.05 (C-4_a), 128.44 (C-3), 127.82 (C-5), 126.26 (C-8), 126.19

(C-4), 126.05 (C-7), 123.77 (C-6), 105.87 (C-1), 81.67 and 77.56

(CϵC), 69.54 (CHOH), 67.94 (OCH₂), 51.56 (CO₂Me), 32.78

(CH₂CO₂Me), 28.85 (CHCH₂), 28.40 (OCH₂CH₂), 28.01

(CH₂CH₂CH₃), 23.98 (CH₂CH₂CO₂Me), 22.43 (CH₂CH₃), 18.26

(CϵCCH₂), 14.05 (CH₃) ppm. C₂₄H₃₀O₄(382.49): calcd. C 75.36,

H 7.91; found C 75.47, H 8.42.

tert-Butyldimethyl[1-(3-pentyloxy-naphthalen-2-yl)-but-3-ynyloxy]-

silane (31): The procedure for the preparation of 31 was the same

as that described for the synthesis of 10 (yield 87%, 1.819 g,

4.6 mmol). ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (s, 1 H, 4-H),

7.78 (d, J = 8.0 Hz, 1 H, 5-H), 7.70 (d, J = 8.2 Hz, 1 H, 8-H), 7.43

Sodium

8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-oct-5-ynoate

(ddd, J = 8.2, 6.8, 1.3 Hz, 1 H, 7-H), 7.35 (ddd, J = 8.0, 6.8, 1.3 Hz, (34): The procedure for the preparation of 34 was the same as that

1 H, 6-H), 7.11 (s, 1 H, 1-H), 5.20 (ddd, J = 7.4, 6.2, 5.0 Hz, 1 H,

CHOSi), 4.11–4.06 (m, 2 H, OCH₂), 2.89 (ddd, J = 16.8, 5.0, 2.6 Hz

described for the synthesis of 13 (yield 99%, 164 mg, 0.42 mmol).

Acid: ¹H NMR (400 MHz, DMSO): δ = 7.84 (s, 1 H, 4-H), 7.77

1 H, CHCH₂), 2.72 (ddd, J = 16.8, 7.4, 2.6 Hz, 1 H, CHCH₂), 2.06 (d, J = 8.0 Hz, 1 H, 5-H), 7.69 (d, J = 8.1 Hz, 1 H, 8-H), 7.41 (ddd,

(t, J = 2.6 Hz, 1 H, CϵCH), 1.93–1.86 (m, 2 H, OCH₂CH₂), 1.55– J = 8.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.35 (ddd, J = 8.0, 6.9, 1.2 Hz, 1

1.38 (m, 4 H, CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz, 3 H, CH₃), 0.91

H, 6-H), 7.26 (s, 1 H, 1-H), 5.15 (dd, J = 6.6, 5.3 Hz, 1 H, CHOH),

(s, 9 H, tBuSi), 0.10 (s, 3 H, CH₃Si), –0.05 (s, 3 H, CH₃Si) ppm.

4.14–4.04 (m, 2 H, OCH₂), 2.85 (ddt, J = 16.5, 4.8, 2.3 Hz, 1 H,

¹³C NMR (100 MHz, CDCl₃): δ = 154.70 (C-2), 134.29 (C-8_a), CHCH₂), 2.66 (ddt, J = 16.5, 7.0, 2.3 Hz, 1 H, CHCH₂), 2.36 (t, J

132.00 (C-4), 128.81 (C-4_a), 128.28 (C-5), 126.76 (C-8), 126.71 (C- = 7.4 Hz, 2 H, CH₂CO₂H), 2.23 (tt, J = 6.7, 2.3 Hz, 2 H,

7), 126.56 (C-6), 124.29 (C-3), 106.41 (C-1), 81.56 (CϵCH), 71.04 CϵCCH₂), 1.92–1.82 (m, 2 H, OCH₂CH₂), 1.77 (tt, J = 7.4, 6.7 Hz,

(CϵCH), 69.92 (CHOH), 68.41 (OCH₂), 29.25 (OCH₂CH₂), 28.80

(CH₂CH₂CH₃), 27.97 (CHCH₂), 25.86 [3C, (CH₃)₃CSi], 22.83

2 H, CH₂CH₂CO₂H), 1.54–1.34 (m, 4 H, CH₂CH₂CH₃), 0.96 (t, J

= 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO): δ =

(CH₂CH₃), 18.35 [(CH₃)₃CSi], 14.44 (CH₃), 4.81 and –4.93 (CH₃Si) 179.01 (CO₂H), 154.31 (C-2), 133.81 (C-8_a), 131.90 (C-4_a), 128.41

ppm. IR: ν = 3302, 3056, 2953, 2929, 2857, 2359, 1633, 1601, 1502,

(C-3), 128.41 (C-5), 126.25 (C-8), 126.22 (C-4), 126.10 (C-7), 123.81

(C-6), 105.89 (C-1), 81.49 and 77.72 (CϵC), 69.69 (CHOH), 67.95

(OCH₂), 32.66 (CH₂CO₂H), 28.83 (CHCH₂), 28.38 (OCH₂CH₂),

27.93 (CH₂CH₂CH₃), 23.68 (CH₂CH₂CO₂Me), 22.42 (CH₂CH₃),

18.17 (CϵCCH₂), 14.04 (CH₃) ppm. Salt: C₂₃H₂₇NaO₄(390.45)

calcd. C 70.75, H 7.97; found C 70.89, H 8.02.

˜

1465, 1398, 1329, 1250, 1215, 1184, 1117, 1095, 1014, 934, 836,

776, 746, 645, 482 cm^–1.

Methyl 8-(tert-Butyldimethylsilanyloxy)-8-(3-pentyloxy-naphthalen-

2-yl)-oct-5-ynoate (32): The procedure for the preparation of 32 was

the same as that described for the synthesis of 11 (yield 77%,

1.759 g, 3.54 mmol). ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (s, 1

H, 4-H), 7.77 (d, J = 7.9 Hz, 1 H, 5-H), 7.70 (d, J = 8.1 Hz, 1 H,

8-H), 7.39 (ddd, J = 8.1, 6.7, 1.2 Hz, 1 H, 7-H), 7.35 (ddd, J = 7.9,

Methyl

8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-oct-5-enoate

(35): The procedure for the preparation of 35 was the same as that

described for the synthesis of 14 (yield 84%, 251 mg, 0.65 mmol).

6.7, 1.2 Hz, 1 H, 6-H), 7.05 (s, 1 H, 1-H), 5.30 (dd, J = 7.3, 3.4 Hz, ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (s, 1 H, 4-H), 7.76 (d, J =

Eur. J. Org. Chem. 2006, 2181–2196

www.eurjoc.org

2193

P. Mosset, R. Grée et al.

FULL PAPER

8.0 Hz, 1 H, 5-H), 7.69 (d, J = 8.0 Hz, 1 H, 8-H), 7.40 (ddd, J =

8.0, 7.0, 1.2 Hz, 1 H, 7-H), 7.32 (ddd, J = 8.0, 7.0, 1.2 Hz, 1 H, 6-

H), 7.10 (s, 1 H, 1-H), 5.60–5.40 (m, 2 H, HC=CH), 5.04 (dd, J =

H), 7.27 (s, 1 H, 1-H), 4.98 (dd, J = 8.1, 3.6 Hz, 1 H, CHOH),

4.14–4.06 (m, 2 H, OCH₂), 2.20 (t, J = 7.3 Hz, 2 H, CH₂CO₂H),

1.87–1.77 (m, 2 H, CH₂CH₂CH₂CO₂H), 1.77–1.68 (m, 2 H,

7.5, 5.3 Hz, 1 H, CHOH), 4.15–4.06 (m, 2 H, OCH₂), 3.63 (s, 3 H, OCH₂CH₂), 1.55–1.21 (m, 2 H, CH₂CH₂CO₂H), 1.55–1.27 (m, 10

CO₂Me), 2.72–2.64 (m, 1 H, CHCH₂), 2.63–2.54 (m, 1 H, CHCH₂), H, CHCH₂CH₂CH₂and CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz, 3 H,

2.25 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me), 2.11–2.02 (m, 2 H,

C=CCH₂), 1.92–1.83 (m, 2 H, OCH₂CH₂), 1.68–1.59 (m, 2 H, 155.51 (C-2), 138.37 (C-8_a), 134.71 (C-4_a), 129.69 (C-3), 128.91 (C-

CH₃) ppm. ¹³C NMR (100 MHz, DMSO): δ = 176.05 (CO₂H),

CH₂CH₂CO₂Me), 1.55–1.37 (m, 4 H, CH₂CH₂CH₃), 0.96 (t, J =

5), 127.80 (C-8), 127.10 (C-4), 126.13 (C-7), 124.93 (C-6), 106.89

7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 174.19 (C-1), 68.82 (CHOH), 68.09 (OCH₂), 39.66, 35.22, 30.25, 30.20,

(CO₂Me), 154.60 (C-2), 133.70 (C-8_a), 133.29 (C-4_a), 131.29 and 30.03, 29.61, 27.11, 26.09, 23.49 (9 C, CH₂CH₂CH₂CH₂-

126.73 (CH=CH), 128.50 (C-3), 127.71 (C-5), 126.27 (C-8), 126.08

(C-4), 125.95 (C-7), 123.76 (C-6), 105.90 (C-1), 70.94 (CHOH),

CH₂CH₂CO₂H and CH₂CH₂CH₂CH₃), 15.57 (CH₃) ppm. Salt:

HRMS: calcd. for C₂₃H₃₁NaO₄395.21983; found 395.2192 (δ =

67.92 (OCH₂), 51.52 (CO₂Me), 35.35 (C=CCH₂), 33.40 2 ppm).

(CH₂CO₂Me), 28.91 (CHCH₂), 28.42 (OCH₂CH₂), 26.69

2-Chloro-3-carbaldehydepyridine (40): To a solution of phenyllith-

(CH₂CH₂CH₃), 24.71 (CH₂CH₂CO₂Me), 22.43 (CH₂CH₃), 14.05

(CH₃) ppm. C₂₄H₃₂O₄(384.51): calcd. C 74.97, H 8.39; found C

75.38, H 8.58.

ium (9.35 mL, 2  in pentane/THF, 1.1 equiv., 18.7 mmol) in THF

(34 mL) were added, at –60 °C under argon, 2-chloropyridine

(1.61 mL, 17 mmol) and diisopropylamine (50 µL, 0.02 equiv.,

0.34 mmol). The temperature was raised to –40 °C and the reaction

mixture was stirred for 1 h at this temperature. Then, after cooling

the reaction mixture to –60 °C, N-formylpiperidine (4.80 mg,

2.5 equiv., 42.5 mmol) was added. The temperature was warmed

to –40 °C, and the reaction mixture was stirred for 1 h at this tem-

perature. The hydrolysis was performed by addition of HCl (0.5 ).

The aqueous phase was neutralized by a saturated NaHCO₃solu-

tion, and the product was extracted with Et₂O. The organic phase

was dried (Na₂SO₄) and concentrated under vacuum. The pyridine

Methyl 8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-octanoate (36):

The procedure for the preparation of 36 was the same as that de-

1

scribed for the synthesis of 15 (yield 88%, 165 mg, 0.43 mmol). H

NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.0 Hz, 1 H, 5-H), 7.72

(s, 1 H, 4-H), 7.70 (d, J = 8.1 Hz, 1 H, 8-H), 7.40 (ddd, J = 8.1,

6.9, 1.3 Hz, 1 H, 7-H), 7.32 (ddd, J = 8.0, 6.9, 1.2 Hz, 1 H, 6-H),

7.11 (s, 1 H, 1-H), 4.97 (dd, J = 12.5, 6.2 Hz, 1 H, CHOH), 4.11

(t, J = 6.4 Hz, 2 H, OCH₂), 3.65 (s, 3 H, CO₂Me), 2.72 (d, J =

6.2 Hz, 1 H, OH), 2.25 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me), 1.92–1.83

(m, 4 H, CH₂CH₂CH₂CO₂Me and OCH₂CH₂), 1.66–1.56 (m, 2 was purified by column chromatography, with PE as eluent, R_f:

H, CH₂CH₂CO₂Me), 1.55–1.27 (m, 10 H, CHCH₂CH₂CH₂and 0.07 eluent PE/EtOAc (95:5), to afford 40 as a colorless powder

CH₂CH₂CH₃), 0.96 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (m.p.: 33–37 °C) in 39% yield (942 mg, 6.65 mmol). ¹H NMR

(100 MHz, CDCl₃): δ = 174.29 (CO₂Me), 154.79 (C-2), 134.00 (C-

8_a), 133.65 (C-4_a), 128.54 (C-3), 127.66 (C-5), 126.27 (C-8), 126.08

(C-4), 125.89 (C-7), 123.78 (C-6), 105.99 (C-1), 71.70 (CHOH),

67.88 (OCH₂), 51.46 (CO₂Me), 37.35, 34.07, 29.19, 29.11, 28.90,

(400 MHz, CDCl₃): δ = 10.46 (d, J = 0.8 Hz, 1 H, CHO), 8.62 (dd,

J = 4.8, 2.1 Hz, 1 H, 6-H), 8.25 (dd, J = 7.7, 2.1 Hz, 1 H, 4-H),

7.44 (ddd, J = 7.7, 4.8, 0.8 Hz, 1 H, 5-H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 189.22 (CHO), 154.20 (C-6), 153.64 (C-2),

28.44, 26.02, 24.90, 22.42 (9 C, CH₂CH₂CH₂CH₂CH₂CH₂CO₂Me 138.07 (C-4), 128.88 (C-3), 123.25 (C-5) ppm. IR (KBr): ν = 3353,

˜

and CH₂CH₂CH₂CH₃), 14.06 (CH₃) ppm. C₂₄H₃₄O₄(386.52):

calcd. C 74.58, H 8.87; found C 74.83, H 8.97.

3040, 2887, 1698, 1579, 1416, 1378, 1263, 1068, 834, 808, 730,

417 cm^–1.

Sodium

8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-oct-5-enoate 2-Chloro-3-dimethoxy-methylpyridine (41): To a solution of 40

(37): The procedure for the preparation of 37 was the same as that

described for the synthesis of 13 (yield 95%, 165 mg, 0.42 mmol).

Acid: ¹H NMR (400 MHz, DMSO): δ = 7.93 (s, 1 H, 4-H), 7.74

(d, J = 7.9 Hz, 1 H, 5-H), 7.79 (d, J = 8.1 Hz, 1 H, 8-H), 7.42 (ddd,

J = 8.1, 6.9, 1.2 Hz, 1 H, 7-H), 7.33 (ddd, J = 7.9, 6.9, 1.1 Hz, 1

(1.838 g, 13 mmol) and ammonium nitrate (52 mg, 0.05 equiv.,

0.65 mmol) in methanol (13 mL) was added trimethyl orthoformate

(1.7 mL, 1.2 equiv., 15.6 mmol, 1.653 g). The reaction mixture was

heated to reflux for 2.5 h. After addition of a saturated Na₂CO₃

solution, the product was extracted with Et₂O (2×). The organic

H, 6-H), 7.28 (s, 1 H, 1-H), 5.62–5.33 (m, 2 H, HC=CH), 5.03 (m, phase was dried (Na₂SO₄) and concentrated under vacuum. The

1 H, CHOH), 4.18–4.07 (m, 2 H, OCH₂), 2.59–2.50 (m, 1 H, residue was purified by filtration through silica gel with PE as elu-

CHCH₂), 2.32–2.21 (m, 1 H, CHCH₂), 2.15 (t, J = 7.5 Hz, 2 H,

CH₂CO₂H), 2.01–1.94 (m, 2 H, C=CCH₂), 1.87–1.79 (m, 2 H, 12.47 mmol). H NMR (400 MHz, CDCl₃): δ = 8.37 (dd, J = 4.8,

OCH₂CH₂), 1.54–1.35 (m, 6 H, CH₂CH₂CO₂H and CH₂CH₂CH₃), 2.0 Hz, 1 H, 6-H), 7.97 (dd, J = 7.6, 2.0 Hz, 1 H, 4-H), 7.29 (dd,

ent to afford 41 as a colorless oil in 96% yield (2.189 g,

1

0.94 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO):

δ = 175.91 (CO₂H), 155.45 (C-2), 137.40 (C-8_a), 134.81 (C-4_a),

131.37 and 126.54 (CH=CH), 129.98 (C-3), 129.64 (C-5), 129.01

(C-8), 127.82 (C-4), 127.19 (C-7), 124.97 (C-6), 106.96 (C-1), 68.93

(CHOH), 68.54 (OCH₂), 37.13 (C=CCH₂), 34.67 (CH₂CO₂H),

29.98 (CHCH₂), 29.51 (OCH₂CH₂), 27.87 (CH₂CH₂CH₃), 23.47

(CH₂CH₂CO₂H), 22.35 (CH₂CH₃), 15.57 (CH₃) ppm. Salt:

HRMS: calcd. for C₂₃H₂₉NaO₄393.20418; found 393.2060 (δ =

5 ppm).

J = 7.6, 4.8 Hz, 1 H, 5-H), 5.59 [s, 1 H, CH(OMe)₂], 3.40 [s, 6 H,

(OMe)₂] ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 150.16 (C-6),

149.58 (C-2), 137.23 (C-4), 132.18 (C-3), 122.38 (C-5), 100.44 (CH),

54.05 [2C, (OMe)₂] ppm.

2-Pentyloxy-3-dimethoxy-methylpyridine (42): To a suspension of

NaH (1.995 g, 60% dispersion in oil which was washed three times

with petroleum ether, 4 equiv., 49.88 mmol) in NMP (10 mL) was

added n-pentyl alcohol (5.42 mL, 4 equiv., 49.88 mmol) very slowly

at 0 °C. The reaction mixture was stirred for 10 min at this tem-

perature, and a solution of 41 (2.189 g, 12.47 mmol) in NMP

(2.5 mL) was added. After stirring overnight at room temperature,

the reaction mixture was poured on ice and the product was ex-

tracted with PE. After filtration through silica gel, using PE as

Sodium 8-Hydroxy-8-(3-pentyloxy-naphthalen-2-yl)-octanoate (38):

The procedure for the preparation of 38 was the same as that de-

scribed for the synthesis of 13 (yield 86%, 146 mg, 0.41 mmol).

1

Acid: H NMR (400 MHz, DMSO): δ = 7.82 (d, J = 7.9 Hz, 1 H,

5-H), 7.90 (s, 1 H, 4-H), 7.78 (d, J = 8.0 Hz, 1 H, 8-H), 7.41 (dd, eluent, the pyridine 42 was isolated as a colorless oil in 42% yield

1

J = 8.0, 7.0 Hz, 1 H, 7-H), 7.33 (ddd, J = 7.9, 7.0, 1.2 Hz, 1 H, 6- (1.247 g, 5.2 mmol). H NMR (400 MHz, CDCl₃): δ = 8.12 (dd, J

2194

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Eur. J. Org. Chem. 2006, 2181–2196

Synthesis of Aromatic Analogs of 8(S)-HETE

FULL PAPER

= 5.0, 2.0 Hz, 1 H, 6-H), 7.79 (dd, J = 7.3, 2.0 Hz, 1 H, 4-H), 6.88

CHOSi), 4.31 (t, J = 6.1 Hz, 2 H, OCH₂), 3.68 (s, 3 H, CO₂Me),

(dd, J = 7.3, 5.0 Hz, 1 H, 5-H), 5.55 [s, 1 H, CH(OMe)₂], 4.34 (t, 2.57 (ddt, J = 16.6, 4.0, 2.2 Hz, 1 H, CHCH₂), 2.43 (ddt, J = 16.6,

J = 6.7 Hz, 2 H, OCH₂), 3.39 [s, 6 H, (OMe)₂], 1.84–1.75 (m, 2 H,

OCH₂CH₂), 1.48–1.33 (m, 4 H, CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz,

3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 161.22 (C-

6.8, 2.2 Hz, 1 H, CHCH₂), 2.39 (t, J = 7.4 Hz, 2 H, CH₂CO₂Me),

1.83–1.72 (m, 4 H, OCH₂CH₂and CH₂CH₂CO₂Me), 1.48–1.24 (m,

6 H, CH₂CH₂CH₃and CϵCCH₂), 0.93 (t, J = 6.8 Hz, 3 H, CH₃),

2), 146.89 (C-6), 135.99 (C-4), 120.54 (C-3), 116.24 (C-5), 99.13 0.91 (s, 9 H, tBuSi), 0.09 (s, 3 H, CH₃Si), –0.04 (s, 3 H, CH₃Si)

[CH(OMe)₂], 66.09 (OCH₂), 53.99 [2C, (OMe)₂], 28.71

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.80 (CO₂Me), 159.76

(OCH₂CH₂), 28.24 (CH₂CH₂CH₃), 22.45 (CH₂CH₃), 14.07 (CH₃) (C-2), 145.22 (C-6), 135.50 (C-4), 126.72 (C-3), 116.52 (C-5), 80.29

ppm.

and 78.19 (CϵC), 67.48 (OCH₂), 65.77 (CHOSi), 51.51 (CO₂Me),

32.81 (CH₂CO₂Me), 28.73 (CϵCCH₂), 28.64 (CHCH₂), 28.37

(OCH₂CH₂), 24.07 (CH₂CH₂CH₃), 25.78 [3C, (CH₃)₃CSi], 22.45

(CH₂CH₃), 18.27 [2C, CH₂CH₂CO₂Me and (CH₃)₃CSi], 14.07

(CH₃), –4.86 and –4.96 [(CH₃)₂Si] ppm.

2-Pentyloxy-3-carbaldehydepyridine (43): To

a solution of 42

(1.247 g, 5.2 mmol) in THF/H₂O (9:1, 52 mL) was added p-tolu-

enesulfonic acid (149 mg, 0.15 equiv., 0.78 mmol). The reaction

mixture was heated to reflux for 3 h. The product was extracted

with PE (3×). After filtration through silica gel, 43 was obtained

as a yellow oil in 91% yield (910 mg, 4.71 mmol). ¹H NMR

(400 MHz, CDCl₃): δ = 10.45 (d, J = 0.9 Hz, 1 H, CHO), 8.36 (dd,

J = 4.9, 2.1 Hz, 1 H, 6-H), 8.11 (dd, J = 7.5, 2.1 Hz, 1 H, 4-H),

6.99 (ddd, J = 7.5, 4.9, 0.9 Hz, 1 H, 5-H), 4.44 (t, J = 6.7 Hz, 2 H,

OCH₂), 1.88–1.80 (m, 2 H, OCH₂CH₂), 1.5–1.37 (m, 4 H,

CH₂CH₂CH₃), 0.94 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 189.38 (CHO), 164.59 (C-2), 152.95 (C-

6), 137.40 (C-4), 118.76 (C-3), 117.03 (C-5), 66.77 (OCH₂), 28.58

(OCH₂CH₂), 28.24 (CH₂CH₂CH₃), 22.44 (CH₂CH₃), 14.03 (CH₃)

ppm.

Methyl 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-oct-5-ynoate (47):

The procedure for the preparation of 47 was the same as that de-

scribed for the synthesis of 12 (yield 71%, 566 mg, 1.69 mmol). ¹H

NMR (400 MHz, CDCl₃): δ = 8.06 (dd, J = 5.0, 1.9 Hz, 1 H, 6-

H), 7.69 (dd, J = 7.3, 1.9 Hz, 1 H, 4-H), 6.89 (dd, J = 7.3, 5.0 Hz,

1 H, 5-H), 4.94 (ddd, J = 7.0, 5.9, 5.0 Hz, 1 H, CHOH), 4.34 (t, J

= 6.7 Hz, 2 H, OCH₂), 3.69 (s, 3 H, CO₂Me), 2.96 (d, J = 5.9 Hz,

1 H, OH), 2.77 (ddt, J = 16.5, 5.0, 2.5 Hz, 1 H, CHCH₂), 2.56 (ddt,

J = 16.5, 7.0, 2.4 Hz, 1 H, CHCH₂), 2.38 (t, J = 7.4 Hz, 2 H,

CH₂CO₂Me), 2.23 (tdd, J = 6.9, 2.5, 2.4 Hz, 2 H, CϵCCH₂), 1.83–

1.75 (m, 4 H, OCH₂CH₂and CH₂CH₂CO₂Me), 1.48–1.34 (m, 4 H,

CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 173.76 (CO₂Me), 160.33 (C-2), 145.59 (C-

6), 135.36 (C-4), 124.89 (C-3), 116.62 (C-5), 82.02 and 76.71

(CϵC), 68.28 (OCH₂), 66.03 (CHOH), 51.62 (CO₂Me), 32.84

(CH₂CO₂Me), 28.72 (CϵCCH₂), 28.34 (CHCH₂), 27.39

(OCH₂CH₂), 23.95 (CH₂CH₂CH₃), 22.44 (CH₂CH₃), 18.22

(CH₂CH₂CO₂Me), 14.05 (CH₃) ppm.

1-(2-Pentyloxypyridin-3-yl)-but-3-yn-1-ol (44): The procedure for

the preparation of 44 was the same as that described for the synthe-

sis of 9 (yield 79%, 856 mg, 3.66 mmol). ¹H NMR (400 MHz,

CDCl₃): δ = 8.07 (dd, J = 5.0, 1.9 Hz, 1 H, 6-H), 8.11 (dd, J = 7.3,

1.9 Hz, 1 H, 4-H), 6.99 (dd, J = 7.3, 5.0 Hz, 1 H, 5-H), 4.99 (ddd,

J = 7.1, 6.0, 5.2 Hz, 1 H, CHOH), 4.39–4.30 (m, 2 H, OCH₂), 3.00

(d, J = 6.0 Hz, 1 H, OH), 2.81 (ddd, J = 16.7, 5.2, 2.6 Hz, 1 H,

CHCH₂), 2.62 (ddd, J = 16.7, 7.1, 2.6 Hz, 1 H, CHCH₂), 2.05 (t,

J = 2.6 Hz, 1 H, CϵCH), 1.84–1.73 (m, 2 H, OCH₂CH₂), 1.47–

1.39 (m, 4 H, CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 160.30 (C-2), 145.82 (C-6),

135.44 (C-4), 124.50 (C-3), 116.69 (C-5), 80.60 (CϵCH), 70.98

(CϵCH) 68.12 (CHOH), 66.09 (OCH₂), 29.44 (OCH₂CH₂), 28.71

(CH₂CH₂CH₃), 26.97 (CHCH₂), 22.51 (CH₂CH₃), 14.05 (CH₃)

ppm.

Sodium 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-oct-5-ynoate (48):

The procedure for the preparation of 48 was the same as that de-

scribed for the synthesis of 13 (yield 96%, 92 mg, 0.27 mmol). Acid:

¹H NMR (400 MHz, DMSO): δ = 8.07 (dd, J = 5.1, 2.0 Hz, 1 H,

6-H), 7.69 (dd, J = 7.6, 1.5 Hz, 1 H, 4-H), 6.89 (dd, J = 7.1, 5.1 Hz,

1 H, 5-H), 4.95 (dd, J = 5.6, 5.0 Hz, 1 H, CHOH), 4.34 (t, J =

6.6 Hz, 2 H, OCH₂), 2.77 (ddt, J = 16.3, 5.0, 2.0 Hz, 1 H, CHCH₂),

2.58 (ddt, J = 16.3, 5.6, 2.5 Hz, 1 H, CHCH₂), 2.43 (t, J = 7.1 Hz,

2 H, CH₂CO₂H), 2.25 (tdd, J = 6.6, 2.0, 2.4 Hz, 2 H, CϵCCH₂),

1.84–1.74 (m, 4 H, OCH₂CH₂and CH₂CH₂CO₂H), 1.48–1.34 (m,

4 H, CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, DMSO): δ = 178.33 (CO₂H), 160.30 (C-2), 145.59 (C-

6), 135.43 (C-4), 124.89 (C-3), 116.66 (C-5), 81.87 and 77.18

(CϵC), 68.33 (OCH₂), 66.12 (CHOH), 32.69 (CH₂CO₂H), 28.70

(CϵCCH₂), 28.34 (CHCH₂), 27.33 (OCH₂CH₂), 23.67

(CH₂CH₂CH₃), 22.44 (CH₂CH₃), 18.16 (CH₂CH₂CO₂H), 14.04

(CH₃) ppm.

3-[1-(tert-Butyldimethylsilanyloxy)-but-3-ynyl]-2-pentyloxypyridine

(45): The procedure for the preparation of 45 was the same as that

described for the synthesis of 10 (yield 76%, 963 mg, 2.77 mmol).

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (dd, J = 5.0, 1.9 Hz, 1 H,

6-H), 8.11 (dd, J = 7.3, 1.9 Hz, 1 H, 4-H), 6.99 (dd, J = 7.3, 5.0 Hz,

1 H, 5-H), 5.12 (dd, J = 6.9, 3.8 Hz, 1 H, CHOSi), 4.32 (t, J =

6.6 Hz, 2 H, OCH₂), 2.62 (ddd, J = 16.7, 3.9, 2.7 Hz, 1 H, CHCH₂),

2.47 (ddd, J = 16.7, 6.9, 2.6 Hz, 1 H, CHCH₂), 1.93 (dd, J = 2.7,

2.6 Hz, 1 H, CϵCH), 1.83–1.74 (m, 2 H, OCH₂CH₂), 1.49–1.33

(m, 4 H, CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃), 0.91 (s, 9

H, tBuSi), 0.12 (s, 3 H, CH₃Si), –0.03 (s, 3 H, CH₃Si) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 159.75 (C-2), 145.42 (C-6), 135.53

(C-4), 126.34 (C-3), 116.57 (C-5), 81.64 (CϵCH), 69.70 (CϵCH),

67.10 (CHOSi), 65.84 (OCH₂), 28.74 (OCH₂CH₂), 28.39

(CH₂CH₂CH₃), 25.84 (CHCH₂), 25.71 [3C, (CH₃)₃CSi], 22.46

(CH₂CH₃), 18.29 [(CH₃)₃CSi], 14.09 (CH₃), –4.82 and –4.90

[(CH₃)₂Si] ppm.

Methyl 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-oct-5-enoate (49): To

a suspension of Lindlar catalyst (26 mg, 10 wt.-% Pd) in toluene

(3.12 mL) was added 47 (261 mg, 0.78 mmol). The reaction mixture

was stirred under hydrogen for 36 h at room temperature. After

filtration through Celite, the alkene 49 was obtained as a yellow oil

in 74% yield (193 mg, 0.58 mmol). ¹H NMR (400 MHz, CDCl₃):

δ = 8.05 (dd, J = 5.0, 1.9 Hz, 1 H, 6-H), 7.61 (dd, J = 7.3, 1.9 Hz,

1 H, 4-H), 6.87 (dd, J = 7.3, 5.0 Hz, 1 H, 5-H), 5.54–5.43 (m, 2 H,

Methyl

8-(tert-Butyldimethylsilanyloxy)-8-(2-pentyloxypyridin-3- HC=CH), 4.84 (dd, J = 7.3, 5.5 Hz, 1 H, CHCH₂), 4.38–4.30 (m,

yl)-oct-5-ynoate (46): The procedure for the preparation of 46 was

2 H, OCH₂), 3.66 (s, 3 H, CO₂Me), 2.72 (broad s, 1 H, OH), 2.64–

2.44 (m, 2 H, CHCH₂), 2.28 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me),

the same as that described for the synthesis of 11 (yield 45%,

1

558 mg, 1.25 mmol). H NMR (400 MHz, CDCl₃): δ = 8.03 (dd, J 2.09–1.99 (m, 2 H, C=CCH₂), 1.84–1.75 (m, 2 H, OCH₂CH₂),

= 5.0, 1.9 Hz, 1 H, 6-H), 7.75 (dd, J = 7.3, 1.9 Hz, 1 H, 4-H), 6.87

(dd, J = 7.3, 5.0 Hz, 1 H, 5-H), 5.07 (dd, J = 6.8, 4.0 Hz, 1 H,

1.70–1.61 (m,

2 H, CH₂CH₂CO₂Me), 1.48–1.34 (m, 4 H,

CH₂CH₂CH₃), 0.93 (t, J = 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR

Eur. J. Org. Chem. 2006, 2181–2196

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2195

P. Mosset, R. Grée et al.

FULL PAPER

(100 MHz, CDCl₃): δ = 174.10 (CO₂Me), 160.48 (C-2), 145.32 (C-

(CHOH), 36.74, 33.96, 29.07, 28.73, 28.38, 25.65, 24.61, 22.42,

6), 135.27 (C-4), 131.80 and 126.14 (HC=CH), 125.29 (C-3), 116.68 21.07 (9 CH₂, CH₂CH₂CH₂CH₂CH₂CH₂CO₂H and CH₂CH₂CH₂-

(C-5), 69.71 (C-7), 65.97 (CHCH₂), 51.52 (CO₂Me), 33.38

(CH₂CO₂Me), 28.77 (C=CCH₂), 28.38 (CH₂CH₂CO₂Me), 26.63

(OCH₂CH₂), 24.68 (CH₂CH₂CH₃), 22.45 (CH₂CH₃), 14.05 (CH₃)

ppm. C₁₉H₂₉NO₄(335.44): calcd. C 68.03, H 8.71, N 4.18; found

C 68.08, H 8.85, N 4.21.

CH₃), 14.05 (CH₃) ppm.

Acknowledgments

F. C. thanks the Société de Chimie Thérapeutique and the Labora-

toires Servier for a Ph.D. Thesis fellowship. We thank Mrs. M.

Liutkus for very fruitful discussions.

Methyl 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-octanoate (50): The

procedure for the preparation of 50 was the same as that described

1

for the synthesis of 15 (yield 88%, 169 mg, 0.50 mmol). H NMR

[1] I. Issemann, S. Green, Nature 1990, 347, 645–650.

[2] C. Dreyer, G. Krey, H. Keller, F. Givel, G. Helftenbein, W.

Wahli, Cell 1992, 68, 879–887.

[3] C. J. Lyon, R. E. Law, W. A. Hsueh, Endocrinology 2003, 144,

2195–2200.

[4] a) Y. Momose, K. Meguro, H. Ikeda, Chem. Pharm. Bull. 1991,

39, 1440–1445; b) B. C. Cantello, M. A. Cawthorne, D. Haigh,

R. M. Hindley, S. A. Smith, P. L. Thurlby, Bioorg. Med. Chem.

Lett. 1994, 4, 1181–1184.

(400 MHz, CDCl₃): δ = 8.06 (dd, J = 5.0, 1.9 Hz, 1 H, 6-H), 7.6

(dd, J = 7.3, 1.9 Hz, 1 H, 4-H), 6.88 (dd, J = 7.3, 5.0 Hz, 1 H, 5-

H), 4.8 (t, J = 6.5 Hz, 1 H, CHOH), 4.38–4.29 (m, 2 H, OCH₂),

3.65 (s, 3 H, CO₂Me), 2.34 (t, J = 7.5 Hz, 2 H, CH₂CO₂Me), 1.84–

1.72 (m, 4 H, OCH₂CH₂and CH₂CH₂CH₂CO₂Me), 1.67–1.57 (m,

2 H, CH₂CH₂CO₂Me), 1.50–1.30 (m, 10 H, CHCH₂CH₂CH₂and

CH₂CH₂CH₃), 0.93 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 174.10 (CO₂Me), 160.52 (C-2), 145.00 (C-

6), 135.48 (C-4), 126.96 (C-3), 116.80 (C-5), 70.16 (OCH₂), 66.21 [5] I. Issemann, R. A. Prince, J. D. Tugwood, S. Green, J. Mol.

Endocrinol. 1993, 11, 37–47.

(CHOH), 51.85 (CO₂Me), 36.74, 33.96, 29.07, 28.72, 28.38, 25.66,

24.61, 22.42, 21.07 (9 CH₂, CH₂CH₂CH₂CH₂CH₂CH₂CO₂Me and

CH₂CH₂CH₂CH₃), 14.05 (CH₃) ppm. C₁₉H₃₁NO₄(337.45): calcd.

C 67.63, H 9.26, N 4.15; found C 67.47, H 9.48, N 4.36.

[6] H. B. Rubins, S. Robins, Am. J. Cardiol. 2000, 86, 543–544.

[7] B. Staels, J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leit-

ersdorf, J.-C. Fruchart, Circulation 1998, 98, 2088–2093.

[8] T. M. Willson, P. J. Brown, D. D. Sternbach, B. R. Henke, J.

Med. Chem. 2000, 43, 527–550.

Sodium 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-oct-5-enoate (51):

The procedure for the preparation of 51 was the same as that de-

scribed for the synthesis of 13 (yield 93%, 93 mg, 0.27 mmol). Acid:

¹H NMR (400 MHz, DMSO): δ = 8.07 (dd, J = 5.2, 1.9 Hz, 1 H,

6-H), 7.66 (dd, J = 7.3, 1.9 Hz, 1 H, 4-H), 6.91 (dd, J = 7.3, 5.2 Hz,

1 H, 5-H), 5.56–5.44 (m, 2 H, HC=CH), 4.87 (dd, J = 7.3, 5.5 Hz,

1 H, CHCH₂), 4.42–4.32 (m, 2 H, OCH₂), 2.64–2.44 (m, 2 H,

CHCH₂), 2.31 (t, J = 7.4 Hz, 2 H, CH₂CO₂H), 2.10–2.00 (m, 2

H, C=CCH₂), 1.86–1.76 (m, 2 H, OCH₂CH₂), 1.70–1.60 (m, 2 H,

CH₂CH₂CO₂H), 1.49–1.34 (m, 4 H, CH₂CH₂CH₃), 0.93 (t, J =

7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO): δ = 176.92

(CO₂H), 160.16 (C-2), 144.61 (C-6), 135.97 (C-4), 135.97 and

131.83 (HC=CH), 126.02 (C-3), 116.77 (C-5), 69.57 (C-7), 66.62

(CHCH₂), 33.06 (CH₂CO₂H), 28.72 (C=CCH₂), 28.33

(CH₂CH₂CO₂H), 26.49 (OCH₂CH₂), 24.38 (CH₂CH₂CH₃), 22.41

(CH₂CH₃), 14.03 (CH₃) ppm. Salt: HRMS: calcd. for

C₁₈H₂₆NNaO₄344.18378; found 344.1835 (δ = 1 ppm).

[9] a) H. Miyachi, Expert Opin. Ther. Pat. 2004, 14, 607–618; b)

G. J. Etgen, Curr. Top. Med. Chem. 2003, 3, 1649–1661; c) T.

Leff, J. E. Reed, Curr. Med. Chem.– Imun., Endoc. & Metab.

Agents 2002, 2, 33–47.

[10] For a preliminary communication see: F. Caijo, P. Mosset, R.

Grée, V. Audinot-Bouchez, J. Boutin, P. Renard, D.-H. Caig-

nard, C. Dacquet, Bioorg. Med. Chem. Lett. 2005, 15, 4421–

4426.

[11] H. Keller, C. Dreyer, J. Medin, A. Mahfoudi, K. Ozato, W.

Wahli, Proc. Natl. Acad. Sci. USA 1993, 90, 2160–2164.

[12] a) B. M. Forman, J. Chen, R. M. Evans, Proc. Natl. Acad. Sci.

USA 1997, 94, 4312–4317; b) S. A. Kliewer, S. S. Sundseth,

S. A. Jones, P. J. Brown, G. B. Wisely, C. S. Koble, P. Devchand,

W. Wahli, T. M. Willson, J. M. Lenhard, J. M. Lehmann, Proc.

Natl. Acad. Sci. USA 1997, 94, 4318–4323; c) S. J. Muga, P.

Thuillier, A. Pavone, J. E. Rundhaug, W. E. Boeglin, M. Jisaka,

A. R. Brash, S. M. Fischer, Cell Growth & Differentiation 2000,

11, 447–454.

[13] K. Yu, W. Bayona, C. B. Kallen, H. P. Harding, C. P. Ravera,

G. McMahon, M. Brown, M. A. Lazar, J. Biol. Chem. 1995,

270, 23975–23983.

[14] a) For recent examples see: A. Hachem, Y. Le FlocЈh, R. Grée,

C. Cerletti, Y. Rolland, S. Simonet, T. Verbeuren, Tetrahedron

Lett. 2002, 43, 5217–5219; b) T. E. Jonhson, M. K. Holloway,

R. Vogel, S. J. Rutledge, J. P. Perkins, G. A. Rodan, A. Schmidt,

J. Steroid Biochem. Mol. Biol. 1997, 63, 1–8.

[15] B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M.

Balkovec, J. J. Baldwin, M. E. Christy, G. S. Ponticello, S. L.

Varga, J. P. Springer, J. Org. Chem. 1986, 51, 2370–2374.

[16] M. Mallet, J. Organomet. Chem. 1991, 406, 49–56.

Received: November 24, 2005

Sodium 8-Hydroxy-8-(2-pentyloxypyridin-3-yl)-octanoate (52): The

procedure for the preparation of 52 was the same as that described

for the synthesis of 13 (yield 96%, 83 mg, 0.24 mmol). Acid: ¹H

NMR (400 MHz, DMSO): δ = 8.06 (dd, J = 5.1, 1.2 Hz, 1 H, 6-

H), 7.60 (dd, J = 7.1, 2.0 Hz, 1 H, 4-H), 6.88 (dd, J = 7.1, 5.0 Hz,

1 H, 5-H), 4.8 (t, J = 6.6 Hz, 1 H, CHOH), 4.39–4.29 (m, 2 H,

OCH₂), 2.33 (t, J = 7.6 Hz, 2 H, CH₂CO₂H), 1.84–1.70 (m, 4 H,

OCH₂CH₂and CH₂CH₂CH₂CO₂H), 1.68–1.56 (m,

2

H,

CH₂CH₂CO₂H), 1.50–1.30 (m, 10 H, CHCH₂CH₂CH₂and

CH₂CH₂CH₃), 0.93 (t, J = 6.6 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, DMSO): δ = 179.26 (CO₂H), 160.52 (C-2), 145.00 (C-

6), 135.48 (C-4), 126.96 (C-3), 116.78 (C-5), 70.16 (OCH₂), 66.20

Published Online: March 1, 2006

2196

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2181–2196

Article Doi

Synthesis of aromatic analogs of 8(S)-HETE and their biological evaluation as activators of the PPAR nuclear receptors

DOI: 10.1002/ejoc.200500918

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Article abstract of DOI:10.1002/ejoc.200500918

Full text of DOI:10.1002/ejoc.200500918

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