Total synthesis of 12(R)-HETE, 12(S)-HETE, 2H2-12(R)-HETE and LTB4 from racemic glycidol via hydrolytic kinetic resolution

Article abstract of DOI:10.1016/S0040-4020(00)00983-2

The total synthesis of 12(R)-HETE, 12(S)-HETE (Samuelsson's HETE), [14,15-²H₂]-12(R)-HETE and Leukotriene B₄ from racemic glycidol is described. The key steps are the hydrolytic kinetic resolution of racemic TES-glycidol with salen-Co catalyst and the selective oxidation of primary silyl ethers, in the presence of secondary ones, under Swern conditions to give a short entry to both enantiomers of 12-HETE and LTB₄.

Full text of DOI:10.1016/S0040-4020(00)00983-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 25±37
2
Total synthesis of 12(R)-HETE, 12(S)-HETE, H2-12(R)-HETE
and LTB4 from racemic glycidol via hydrolytic
kinetic resolution
a a,²
A. Rodrõguez, M. Nomen, B. W. Spur,
a,b,
c
J. J. Godfroid and T. H. Lee
b
*
Â
aDepartment of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
bDepartment of Respiratory Medicine and Allergy, King's College London, Guy's Hospital, London SE1 9RT, UK
c
 Â
Laboratorie de Pharmacochimie Moleculaire, Universite Paris 7, Paris 75251, France
Received 30 June 2000; revised 16 October 2000; accepted 18 October 2000
AbstractÐThe total synthesis of 12(R)-HETE, 12(S)-HETE (Samuelsson's HETE), [14,15-2H2]-12(R)-HETE and Leukotriene B4 from
racemic glycidol is described. The key steps are the hydrolytic kinetic resolution of racemic TES-glycidol with salen-Co catalyst and the
selective oxidation of primary silyl ethers, in the presence of secondary ones, under Swern conditions to give a short entry to both
enantiomers of 12-HETE and LTB4. q 2000 Elsevier Science Ltd. All rights reserved.
The metabolism of arachidonic acid has attracted much
attention over the years.1 12(R)-HETE (1) is formed via
the cytochrome P-450 pathway and is present in high
concentration in psoriasis lesions.2 Its enantiomer, 12(S)-
HETE (2), the major 12-lipoxygenase metabolite in plate-
lets,3 has been found to play a central role in various stages
of metastatic process in tumors and is therefore a potential
target for an anticancer treatment. 12(S)-HETE (2) inhibits
tumor cell adhesion to endothelial cells.4
d(2)-arabinose were used in the synthesis of 12(S)-HETE
(2) whereas l(1)-arabinose has been the chiral source of
12(R)-HETE (1) and LTB4 (3).10 Alpina-borane reduction11
and the Sharpless kinetic resolution of racemic g-iodoallylic
alcohols (Sato's procedure)12 were used in the synthesis of
both enantiomers of 12-HETE and LTB4. A recent report by
Corey et al. described the synthesis of 12(R)-HETE and
12(S)-HETE utilizing the Sharpless asymmetric dihydroxyl-
ation.13
LTB4 (3), a metabolite of arachidonic acid via the 5-lipoxy-
genase pathway, is a potent chemotactic agent for human
eosinophils and neutrophils and a modulator of in¯amma-
tory responses.5 Newer results demonstrated that LTB4 (3)
has high antiviral activity towards DNA viruses as well as
retroviruses, including HIV-1 and HIV-2, comparable with
antiviral drugs, such as Acylovir or Ganciclovir,6 opening
new perspectives for 3 and metabolically stable LTB4
analogs.7
In this paper we report a short synthesis of the two
enantiomers of 12-HETE, [14,15-2H2]-12(R)-HETE (37)
and LTB4 (3) (Fig. 1) from easily available starting
materials. The synthesis of 12(R)-HETE (1) and LTB4 (3)
were based on the retrosynthetic analysis shown in Fig. 2.
The chiral TES glycidol (7),14 a versatile C-3 building
block, was obtained from racemic glycidol with .99% ee
using Jacobsen's hydrolytic kinetic resolution with H2O in
the presence of 1% (S,S)-salen-Co catalyst (14) in Et2O at
room temperature,15 as shown in Scheme 1. Simple bulb to
bulb distillation gave 7 in 46% isolated yield (92%
theoretical yield).
In the interest of evaluating the biological and pharmaco-
logical properties of these compounds it was necessary to
obtain suf®cient quantities by chemical synthesis. The ®rst
synthesis of 12(S)-HETE (2) was reported by Corey et al.8
starting from S(2)-malic acid that was used later on as
starting material by other groups.9 d(1)-Mannitol and
The nucleophilic opening of the epoxide 7 with 1-heptynyl-
lithium in the presence of TMEDA, similar as described by
Nicolaou,16 was very slow. The protective group was
cleaved under those conditions and large quantities of the
dimerization product of 1-heptyne were isolated.
Better results were achieved using the Yamaguchi
method with BF3´Et2O at 2788C in THF.17 The reaction
was fast and only a small amount of deprotected
material was observed. The optical purity was measured
Keywords: eicosanoids; hydrolytic kinetic resolution; selective Swern
oxidation.
* Corresponding author. Department of Cell Biology, University of Medi-
cine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA. Tel.:
11-856-566-7016; fax: 11-856-566-6195; e-mail: spurbw@umdnj.edu
²
Deceased on 26 September 1997.
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00983-2

Â
A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
26
Figure 1.
by chiral HPLC [Column: OF-chiracel, mobile phase:
hexane/i-PrOH (90:10), lˆ265 nm, .99% ee] of the
dibenzoate derivative obtained from compound 16 after
cleavage of the TES ether. The secondary hydroxy group
in 16 was protected with triethylsilylchloride to give 5.
Selective Swern oxidation of the primary TES ether in the
presence of the secondary one produced directly the chiral
key intermediate 4 (Scheme 2), required for the synthesis of
12(R)-HETE (1) and LTB4 (3).15
phosphoranylidene)acetaldehyde (8)18 in benzene at 608C to
produce the a,b-unsaturated aldehyde 20 in 87% isolated
yield. Compound 20 was reacted with methyl 8-(triphenyl-
phosphoranylidene)-5(Z)-octenoate (9), generated in situ
from 22 with KHMDS, in THF/HMPA at 2788C to give
the 12(R)-HETE precursor 23. The critical step in the
synthesis was the selective reduction of the triple bond in
23 to the cis double bond in 25 in the presence of the
additional conjugated and isolated double bonds avoiding
over-reduction.19 Reaction conditions and solvents were
very critical. Compound 25 was obtained from 23 by
controlled hydrogenation (Lindlar catalyst, deactivated
with pyridine, in hexane). 12(R)-HETE methyl ester (27)
The synthesis of 12(R)-HETE (1) (Scheme 2) was accom-
plished, similarly as described by Rokach et al.,10f by Wittig
reaction of the aldehyde 4 with 3 equivalents of (triphenyl-
Figure 2.

Â
A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
27
Scheme 1.
Scheme 2.

Â
A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
28
Scheme 3.
was obtained in high yield by mild deprotection of the silyl
ether in 25 with pyridinium p-toluenesulfonate in acetone/
H2O (2 h) or in MeOH (1.5 h). Compound 27 was charac-
terized by 1H NMR, 13C NMR, APT, COSY, HETCOR and
optical rotation. Final hydrolysis of 27 with a 1N aqueous
solution of LiOH in THF/MeOH gave 12(R)-HETE (1)
identical in all aspects with an authentic sample (Upjohn-
Pharmacia).
(37), as outlined in Scheme 3, through intermediates 31 and
33 to give [14,15-2H2]-12(R)-HETE methyl ester (36). Mild
hydrolysis as previously described gave [14,15-2H2]-12(R)-
HETE (37).
Compound 30 was transformed to 2 following the same
steps as described for 37, as outlined in Scheme 3.
Compound 2 was identical with the material prepared by
the method described in Scheme 2.
The synthesis of the major platelet metabolite of
arachidonic acid, 12(S)-HETE (2), was achieved using a
similar route as described for its enantiomer 12(R)-HETE
(1) (Scheme 2). The chiral TES-glycidol (13) was obtained
with .99% ee using Jacobsen's hydrolytic kinetic resolu-
tion with 1% (R,R)-salen-Co catalyst (15) (Scheme 1).
The synthesis of LTB4 (3) was accomplished by Emmons±
Horner reaction of aldehyde 4 with Nicolaou's chiral
C1±C10 phosphonate 10.16 (Scheme 4) The reaction of 4
with 10 produced unexpectedly the 8E,10Z-diene, however,
the crude product could be easily isomerized with a catalytic
amount of iodine in CH2Cl2 at room temperature to give 38
(.95% E,E). Lindlar hydrogenation of 38 followed by
deprotection with TBAF gave LTB4 (3) directly, identical
in all aspects (1H NMR, 13C NMR, APT, COSY, HETCOR,
UV, optical rotation, HPLC, HPLC/API-ES/MS and
bioassay) with a sample prepared using Corey's route.20
1
Compound 2 was characterized by H NMR, 13C NMR,
APT, COSY, HETCOR and HPLC/API-ES/MS, and was
identical in all aspects with an authentic sample (Upjohn-
Pharmacia).
In order to avoid the dif®culties encountered in the Lindlar
reduction at a late stage we examined the reduction of the
triple bond to the cis double bond at the ®rst possible step.
The synthesis of [14,15-2H2]-12(R)-HETE (37) and 12(S)-
HETE (2) is outlined in Scheme 3. The di-TES ether 5 was
cleanly reduced in hexane with deuterium, Lindlar catalyst
and Et3N affording 29 in quantitative yield. In a similar way
intermediate 18 was reduced with hydrogen affording 30.
In summary, a short and ef®cient total synthesis of 12(S)-
HETE, 12(R)-HETE, [14,15-2H2]-12(R)-HETE and LTB4
has been accomplished from racemic glycidol. The key
steps are the Jacobsen hydrolytic kinetic resolution of
racemic TES-glycidol and the selective oxidation of the
primary TES ether in the presence of a secondary one.
The application of this method towards other natural
products will be reported in due course.
Compound 29 was transformed to [14,15-2H2]-12(R)-HETE

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
29
Scheme 4.
1. Experimental
reach room temperature and stirred until completion. The
mixture was diluted with CH2Cl2 and poured in ice-cold
H2O. Separation of the organic phase, washing with a satu-
rated solution of NaCl, drying over Na2SO4 and concentra-
tion under vacuo afforded crude 12 in quantitative yield.
The product was puri®ed by bulb to bulb distillation 60±
1.1. General remarks
All reactions that were moisture and air-sensitive were
carried out in ¯ame-dried glassware and under an argon
atmosphere. The progress of the reactions was checked by
thin layer chromatography (TLC) using E. Merck silica gel
60F glass plates (0.25 mm). The spots were visualized with
UV light, followed by heat staining with p-anisaldehyde in
EtOH/CH3COOH/H2SO4. Silica gel 60 from EM-Science
was used for ¯ash chromatography. HPLC analysis were
performed on a Hewlett-Packard liquid chromatograph
HP-1090 Series II with PV5 SDS (Solvent Delivery System)
and DAD (Diode Array Detector) equipped with heated
column compartment and automatic liquid injector, or on
a Waters HPLC system (M-6000A pump, M-730 Data
Module integrator, U6K Injector) and a Schoeffel SF-770
UV detector. For Chiral HPLC Chiracel OF, OD, OB
1
808C/1 mm affording 12 (15.7 g, 84%). H NMR (CDCl3,
300 MHz): d 3.8 (1H, ddd, Jˆ11.8, 3.3, 0.4 Hz, 1H of CH2±
OTES), 3.6 (1H, dd, Jˆ11.8, 5.0 Hz, 1H of CH2±OTES), 3.1
1
(1H, m, CH±O), 2.7 (1H, ddd, Jˆ5.1, 4.0, 0.4 Hz, H of
1
CH2±O±CH), 2.6 (1H, dd, Jˆ5.1, 2.8 Hz, H of CH2±O±
CH), 0.9 (9H, t, Jˆ7.8 Hz, CH3±CH2±Si), 0.6 (6H, q,
Jˆ7.8 Hz, CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d 63.6
(CH2±OTES), 52.3 (CH±O), 44.5 (CH2±O±CH), 6.5 (3C,
CH3±CH2±Si), 4.2 (3C, CH2±Si).
1.1.2. (R)-(Triethylsilyl)glycidyl ether (7). Compound 12
(12.2 g, 64.8 mmol) was dissolved in Et2O (25 ml) and
(S,S)-(salen)Co(III)(AcO) (14) (0.21 g, 0.32 mmol) was
added. The mixture was cooled to 08C and H2O (0.64 ml,
35.6 mol) was added dropwise. The reaction was allowed to
reach room temperature and stirred for 20 h. The Et2O was
evaporated and the residue was puri®ed by bulb to bulb
distillation 50±558C/0.6 mm affording 7 (5.6 g, 46%
yield). [a]2D5ˆ1.9 (cˆ1.08, CHCl3). 1H NMR (CDCl3,
1
columns (Daicel Chemical Ltd.) have been used. H NMR
and 13C NMR data were recorded on a 300 MHz Varian
Gemini 2000 Broadband High-Resolution NMR. IR spectra
were measured on a Perkin±Elmer Paragon 1000 FT-IR
spectrometer. UV Spectra were obtained using a Hewlett
Packard HP-8453 UV±Visible Spectrophotometer. Optical
rotation was measured on a Perkin±Elmer Polarimeter 343.
Mass Spectra were obtained using Hewlett Packard HP-
59987A API-Electrospray (Atmospheric Pressure Ioniza-
tion Electrospray) interface coupled to a Mass Spectrometer
Hewlett Packard HP-5989B MS. High Resolution Mass
Spectra (HRMS) were obtained at the University of
Pennsylvania Mass Spectrometry Service Center on a VG
Micromass using Electrospray Ionization Mode. Micro-
analysis were performed by Micro-Analysis, Inc.,
Wilmington, Delaware.
1
300 MHz): d 3.8 (1H, ddd, Jˆ11.8, 3.3, 0.4 Hz, H of
1
CH2±OTES), 3.6 (1H, dd, Jˆ11.8, 5.0 Hz, H of CH2±
OTES), 3.1 (1H, m, CH±O), 2.8 (1H, ddd, Jˆ5.1, 4.0,
1
0.4 Hz, H of CH2±O±CH), 2.6 (1H, dd, Jˆ5.1, 2.8 Hz,
1H of CH2±O±CH), 0.9 (9H, t, Jˆ7.8 Hz, CH3±CH2±Si),
0.6 (6H, q, Jˆ7.8 Hz, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 63.6 (CH2±OTES), 52.3 (CH±O), 44.5
(CH2±O±CH), 6.5 (3C, CH3±CH2±Si), 4.3 (3C, CH2±Si).
1.1.3. (R)-1-[(Triethylsilyl)oxy]-4-decyn-2-ol (16). A solu-
tion of 1-heptyne (3.5 ml, 26.8 mmol) in THF (20 ml) at
2788C was treated with a 2.5 M solution of n-butyllithium
in hexane (10.7 ml, 26.8 mmol). The solution was brought
to 08C and kept at that temperature for 15 min. The reaction
was cooled again to 2788C and then the TES protected
glycidol 7 (2.4 g, 12.7 mmol) in THF (5 ml) was added
1.1.1. (Triethylsilyl)glycidyl ether (12). To a solution of
glycidol (11) (7.4 g, 0.10 mol), Et3N (15.9 ml, 0.11 mol)
and 4-dimethylaminopyridine (50 mg, 0.41 mmol) in
CH2Cl2 (50 ml) at 08C was added dropwise chlorotriethyl-
silane (15.9 ml, 94.7 mmol). The reaction was allowed to

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
30
followed by BF3´Et2O (3.4 ml, 26.8 mmol). After 30 min
stirring the reaction was quenched by the addition of a satu-
rated solution of NH4Cl. The reaction was brought to room
temperature and diluted with Et2O. The phases were sepa-
rated and the organic layer was washed with brine, dried
over Na2SO4 and concentrated under vacuo. The crude
product 16, that contained small amount of the unprotected
diol, was used without further puri®cation for the next step.
A small sample was puri®ed by ¯ash chromatography for
analytical purpose. 1H NMR (CDCl3, 300 MHz): d 3.8±3.7
(2H, m, CH±OH, 1H of CH2±OTES), 3.7±3.5 (1H, m, 1H of
CH2±OTES), 2.6±2.5 (1H, br. s, OH), 2.4±2.3 (2H, m,
CH2±CH±OH), 2.2±2.1 [2H, tt, Jˆ7.0, 2.4 Hz, CH2±
(CH2)3±CH3], 1.5±1.4 [2H, m, CH2±(CH2)2±CH3], 1.4±
1.2 [4H, m, (CH2)2±CH3], 1.0±0.9 (9H, t, Jˆ8.0 Hz,
CH3±CH2±Si), 0.9±0.8 (3H, t, Jˆ7.2 Hz, CH3), 0.6 (6H,
q, Jˆ8.0 Hz, CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d
82.6 (uC), 75.6 (uC), 70.5 (CH±OH), 65.4 (CH2±
OTES), 31.0 (CH2±CH2±CH3), 28.6 [CH2±(CH2)2±CH3],
23.3 (CH2±CH±OH), 22.1 (CH2±CH3), 18.6 [CH2±
(CH2)3±CH3], 13.8 (CH3), 6.5 (3C, CH3±CH2Si), 4.2 (3C,
CH2±Si). Enantiomeric excess was determined to be .99%
by chiral HPLC of the dibenzoate derivative obtained
from compound 16 after cleavage of the TES ether
[Column: OF-chiracel, mobile phase: hexane/i-PrOH
(90:10), lˆ265 nm].
tion of Et3N (1.05 ml, 7.5 mmol). The mixture was allowed
to reach room temperature, diluted with CH2Cl2 and washed
with ice-cold H2O and brine. After drying and concentrating
the crude was puri®ed by ¯ash chromatography affording
1
aldehyde 4 (96 mg, 68%). H NMR (CDCl3, 300 MHz): d
9.6 (1H, d, Jˆ1.8 Hz, CHO), 4.0 (1H, m, CH±OTES),
2.6±2.4 (2H, m, CH2±CH±OTES), 2.2±2.0 [2H, m, CH2±
(CH2)3±CH3], 1.5±1.4 [2H, m, CH2±(CH2)2±CH3], 1.4±1.2
[4H, m, (CH2)2±CH3], 1.0±0.8 (12H, m, CH3, CH3±CH2±
Si), 0.6 (6H, m, CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d
202.2 (CHO), 83.0 (uC), 76.0 (CH±OTES), 74.4 (uC),
30.9 (CH2±CH2±CH3), 28.3 [CH2±(CH2)2±CH3], 23.4
(CH2±CH±OTES), 22.0 (CH2±CH3), 18.5 [CH2±(CH2)3±
CH3], 13.7 (CH3), 6.4 (3C, CH3±CH2±Si), 4.6 (3C, CH2±
Si). IR (®lm): 2955, 2933, 2875, 1741, 1459, 1239, 1122,
1077, 1007, 744, 730 cm21
.
1.1.6. (R)-4-[(Triethylsilyl)oxy]-2(E)-dodecen-6-ynal (20).
To the aldehyde 4 (96 mg, 0.34 mmol) in benzene (5 ml) was
added (triphenylphosphoranylidene)acetaldehyde (8) (0.30 g,
1.0 mmol). The reaction mixture was brought to 608C and
stirred for 2 h. The solvent was evaporated under vacuo and
the crude product was puri®ed by ¯ash chromatography
[SiO2, hexane/EtOAc (98:2) (1% Et3N)] affording 20
(91 mg, 87%). [a]D25ˆ245.3 (cˆ1.03, CH2Cl2). H NMR
1
(CDCl3, 300 MHz): d 9.6 (1H, d, Jˆ7.8 Hz, CHO), 6.9
(1H, dd, Jˆ15.3, 4.2 Hz, vCH±CH±OTES), 6.3 (1H, ddd,
Jˆ15.3, 7.8, 1.5 Hz, vCH±CHO), 4.5 (1H, dddd, Jˆ8.4,
5.7, 4.2, 1.5 Hz, CH±OTES), 2.6±2.5 (1H, ddt AB system,
1.1.4. (R)-1,2-Bis[(triethylsilyl)oxy]-4-decyne (5). To a
solution of mono-protected compound 16 (3.6 g,
12.7 mmol) and imidazole (4.6 g, 67.6 mmol) in DMF
(15 ml) at 08C was added Et3N (5.1 ml, 36.6 mmol)
followed by chlorotriethylsilane (4.5 ml, 26.7 mmol).
After 30 min stirring, the reaction was quenched over ice-
cold H2O layered with hexane/EtOAc (9:1). The organic
layer was separated, washed four times with ice-cold H2O
and once with brine. After drying and concentrating under
vacuo the crude was puri®ed by ¯ash chromatography with
hexane/EtOAc (98:2) (0.5% Et3N) and 5 (3.2 g, 64% two-
1
Jˆ16.5, 5.7, 2.4 Hz, H of CH2±CH±OTES), 2.4±2.3 (1H,
ddt AB system, Jˆ16.5, 8.4, 2.4 Hz, 1H of CH2±CH±OTES),
2.1 [2H, tt, Jˆ7.2, 2.4 Hz, CH2±(CH2)3±CH3], 1.5±1.4 [2H,
m, CH2±(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.0±
0.8 (12H, m, CH3, CH3±CH2±Si), 0.6 (6H, m, CH2±Si). 13
C
NMR (CDCl3, 75.5 MHz): d 193.6 (CHO), 158.3 (vCH±
CH±OTES), 131.2 (vCH±CHO), 83.4 (uC), 75.1 (uC),
70.8 (CH±OTES), 31.0 (CH2±CH2±CH3), 28.4 [CH2±
(CH2)2±CH3], 28.0 (CH2±CH±OTES), 22.1 (CH2±CH3),
18.6 [CH2±(CH2)3±CH3], 13.8 (CH3), 6.6 (3C, CH3±CH2±
Si), 4.6 (3C, CH2±Si). IR (®lm): 2956, 2934, 2915, 2876,
2808, 2719, 1696, 1459, 1107, 1006, 975, 744, 729 cm21.
1
steps) was obtained. [a]2D5ˆ2.0 (cˆ1, CH2Cl2). H NMR
(CDCl3, 300 MHz): d 3.8 (1H, m, CH±OTES), 3.7±3.5
(2H, 2 dd AB system, Jˆ9.9, 5.7 Hz, CH2±OTES), 2.5±
1
2.4 (1H, ddt AB system, Jˆ16.5, 6.0, 2.4 Hz, H of CH2±
CH±OTES), 2.3±2.2 (1H, ddt AB system, Jˆ16.5, 5.7,
2.4 Hz, 1H of CH2±CH±OTES), 2.1 [2H, tt, Jˆ6.9,
2.4 Hz, CH2±(CH2)3±CH3], 1.5±1.4 [2H, m, CH2±
(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.0±0.8
(21H, m, CH3±CH2±Si, CH3), 0.7±0.5 (12H, m, CH2±Si).
13C NMR (CDCl3, 75.5 MHz): d 81.6 (uC), 77.0 (uC),
72.5 (CH±OTES), 66.4 (CH2±OTES), 31.1 (CH2±CH2±
CH3), 28.7 [CH2±(CH2)2±CH3], 24.6 (CH2±CH±OTES),
22.2 (CH2±CH3), 18.7 [CH2±(CH2)3±CH3], 13.8 (CH3),
6.7 (3C, CH3±CH2±Si), 6.6 (3C, CH3±CH2±Si), 4.9 (3C,
CH2±Si), 4.3 (3C, CH2±Si). IR (®lm): 2955, 2935, 2912,
2875, 1459, 1415, 1239, 1123, 1081, 1005, 815, 743,
1.1.7. (R)-12-[(Triethylsilyl)oxy]-5(Z),8(Z),10(E)-eicosa-
trien-14-ynoic acid methyl ester (23). To a suspension of
the phosphonium iodide salt 22 (0.20 g, 0.40 mmol) in THF
(1.5 ml) at 2788C was added dropwise a 0.5 M solution of
potassium bis(trimethylsilyl)amide in toluene (0.84 ml,
0.42 mmol). The mixture was stirred for 30 min and alde-
hyde 20 (72.0 mg, 0.23 mmol) in THF (1.5 ml) followed by
HMPA (0.25 ml) were added. After 30 min stirring at
2788C the mixture was brought to 08C and added to a
saturated solution of NH4Cl layered with hexane/EtOAc
(9:1). The phases were separated and the organic layer
was washed with brine. After drying over Na2SO4 and
concentrating under vacuo the crude was puri®ed by ¯ash
chromatography affording 23 (88 mg, 86%). [a]2D5ˆ219.2
672 cm21
.
1
1.1.5. (R)-2-[(Triethylsilyl)oxy]-4-decynal (4). To
a
(cˆ0.83, acetone). H NMR (d6-benzene, 300 MHz): d 6.9
2708C solution of oxalyl chloride (0.19 ml, 2.2 mmol) in
CH2Cl2 (2 ml) was added dropwise DMSO (0.31 ml,
4.4 mmol). After 15 min stirring the di-TES ether 5
(0.20 g, 0.5 mmol) in CH2Cl2 (2 ml) was added. The stirring
was continued at 2708C for 20 min followed by 20 min at
2408C. The reaction was quenched at 2708C by the addi-
(1H, ddt, Jˆ15.2, 11.1, 1.2 Hz, CHvCH±CH±OTES),
6.2±6.1 (1H, br. t, Jˆ11.1 Hz, vCH±CHvCH±CH±
OTES), 6.0 (1H, dd, Jˆ15.2, 6.0 Hz, vCH±CH±OTES),
5.6±5.3 [3H, m, vCH±CH2±CHvCH±(CH2)3±COO], 4.5
(1H, m, CH±OTES), 3.4 (3H, s, CH3O), 3.0 [2H, br. t,
Jˆ7.4 Hz, CH2±CHvCH±(CH2)3±COO], 2.7±2.6 (1H,

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
31
ddt AB system, Jˆ16.2, 6.0, 2.4 Hz, 1H of CH2±CH±
OTES), 2.6±2.5 (1H, ddt AB system, Jˆ16.2, 7.0, 2.4 Hz,
1H of CH2±CH±OTES), 2.2 [4H, m, CH2±(CH2)3±CH3,
CH2±COO], 2.0 [2H, m, CH2±(CH2)2±COO], 1.8±1.6
(2H, quint, Jˆ7.2 Hz, CH2±CH2±COO), 1.6±1.5 [2H, m,
CH2±(CH2)±COO], 1.5±1.2 [4H, m, (CH2)2±CH3], 1.1 (9H,
t, Jˆ8.0 Hz, CH3±CH2±Si), 0.9 (3H, t, Jˆ7.9 Hz, CH3), 0.7
(6H, q, Jˆ7.9 Hz, CH2±Si). 13C NMR (d6-benzene,
75.5 MHz): d 173.2 (COO), 136.5 (vCH±CH±OTES),
130.1 (vCH), 129.6 [vCH±(CH2)3±COO], 128.7
(vCH), 128.6 (vCH±CHvCH±CH±OTES), 125.3
(CHvCH±CH±OTES), 82.3 (uC), 77.1 (uC), 72.6
(CH±OTES), 50.7 (CH3±O), 33.2 (CH2±COO), 31.2
(CH2±CH2±CH3), 29.4 (CH2±CH±OTES), 28.9 [CH2±
(CH2)2±CH3], 26.6 [CH2±(CH2)2±COO], 26.2 (vCH±
CH2±CHv), 24.9 (CH2±CH2±COO), 22.3 (CH2±CH3),
19.0 [CH2±(CH2)3±CH3], 13.9 (CH3), 6.9 (3C, CH3±
CH2±Si), 5.2 (3C, CH2±Si). IR (®lm): 3011, 2953, 2933,
2875, 1741, 1458, 1435, 1240, 1155, 1107, 1073, 1005, 984,
951, 743, 727 cm21. HRMS (ESI) calcd for C27H46O3SiNa
(M1Na)1: 469.3114, found (M1Na)1: 469.3106.
hexane/EtOAc (9:1) affording 12(R)-HETE methyl ester
(47 mg, 84%). [a]D25ˆ212 (cˆ0.9, acetone). {Ref.12d
[a]2D0ˆ211.4 (cˆ1.0, acetone)}. UV (CH3CN) lmax
1
237 nm. H NMR (CDCl3, 300 MHz): d 6.6±6.5 (1H, ddt,
Jˆ15.3, 11.1, 1.2 Hz, CHvCH±CH±OH), 6.0 (1H, br. t,
Jˆ11.1 Hz, vCH±CHvCH±CH±OH), 5.7 (1H, dd,
Jˆ15.3, 6.0 Hz, vCH±CH±OH), 5.6±5.5 [1H, m, vCH±
(CH2)4±CH3], 5.4±5.3 [4H, m, vCH±CH2±CHvCH±
(CH2)3±COO, CHvCH±(CH2)4±CH3], 4.2 (1H, m, CH±
OH), 3.6 (3H, s, CH3O), 2.9 (2H, m, vCH±CH2±CHv),
2.4±2.2 (4H, t and m, Jˆ7.5 Hz, CH2±COO, CH2±CH±
OH), 2.2±2.0 [4H, m, CH2±(CH2)2±COO, CH2±(CH2)3±
CH3], 2.0±1.9 (1H, br. s, OH), 1.8±1.6 (2H, m, CH2±
CH2±COO), 1.4±1.2 [6H, m, (CH2)3±CH3], 0.9 (3H, t,
Jˆ6.8 Hz, CH3). 13C NMR (CDCl3, 75.5 MHz): d 174.2
(COO), 136.0 (vCH±CH±OH), 133.7 [vCH±(CH2)4±
CH3], 130.3, 129.4, 128.5 [vCH±CH2±CHvCH±
(CH2)3±COO], 128.1 (vCH±CHvCH±CH±OH), 125.5
(CHvCH±CH±OH), 124.4 [CHvCH±(CH2)4±CH3],
72.1 (CH±OH), 51.4 (CH3±O), 35.4 (CH2±CH±OH), 33.4
(CH2±COO), 31.5 (CH2±CH2±CH3), 29.2 [CH2±(CH2)2±
CH3], 27.4 [CH2±(CH2)3±CH3], 26.6 [CH2±(CH2)2±
COO], 26.1 (vCH±CH2±CHv), 24.7 (CH2±CH2±COO),
22.5 (CH2±CH3), 13.9 (CH3).
1.1.8. (R)-12-[(Triethylsilyl)oxy]-5(Z),8(Z),10(E),14(Z)-
eicosatetraenoic acid methyl ester (25). To a solution of
alkyne 23 (88 mg, 0.20 mmol) in hexane (5 ml) under argon
were added pyridine (92 mL) and Lindlar catalyst (130 mg).
The argon atmosphere was exchanged by hydrogen and the
mixture was stirred for 36 h. Filtration of the catalyst,
evaporation of the solvent and puri®cation by ¯ash chroma-
tography with hexane/EtOAc (95:5) (1% Et3N) afforded 25
(75 mg, 85%). 1H NMR (CDCl3, 300 MHz): d 6.4 (1H, ddt,
Jˆ15.0, 11.1, 1.2 Hz, CHvCH±CH±OTES), 6.0 (1H, br. t,
Jˆ11.1 Hz, vCH±CHvCH±CH±OTES), 5.7±5.6 (1H,
dd, Jˆ15.0, 6.3 Hz, vCH±CH±OTES), 5.5±5.2 [5H, m,
vCH±CH2±CHvCH±(CH2)3±COO, CHvCH±(CH2)4±
CH3], 4.2 (1H, m, CH±OTES), 3.6 (3H, s, CH3O), 2.9
(2H, m, vCH±CH2±CHv), 2.3 (2H, t, Jˆ7.5 Hz, CH2±
COO), 2.3±2.2 (2H, m, CH2±CH±OTES), 2.1 [2H, m,
CH2±(CH2)2±COO], 2.0 [2H, m, CH2±(CH2)3±CH3], 1.7
(2H, quint, Jˆ7.5 Hz, CH2±CH2±COO), 1.4±1.2 [6H, m,
(CH2)3±CH3], 1.0±0.9 (9H, m, CH3±CH2±Si), 0.9 (3H, t,
Jˆ6.9 Hz, CH3), 0.6 (6H, m, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 174.1 (COO), 137.0 (vCH±CH±OTES),
132.1 [vCH±(CH2)4±CH3], 129.5 (CHvCH±CHvCH±
1.1.10. 12(R)-HETE (1). To a solution of 27 (47 mg,
0.14 mmol) in THF (10 ml) at 08C under an argon
atmosphere was added 1N LiOH (2.8 ml, 2.8 mmol).
MeOH (1.2 ml) was added to achieve a homogeneous solu-
tion. The mixture was stirred for 2.5 h and quenched by the
addition of solid carbon dioxide. The mixture was concen-
trated under vacuo, diluted with EtOAc and layered with
phosphate buffer pH 5.6. The phases were separated, the
aqueous layer was re-extracted with EtOAc and the
combined organic layers were dried (Na2SO4) and concen-
trated under vacuo affording 12(R)-HETE (1) (38 mg, 85%).
[a]2D5ˆ211.7 (cˆ0.77, acetone). UV (CH3CN) lmax
237 nm. 1H NMR (CDCl3, 300 MHz): d 6.6 (1H, ddt,
Jˆ15.3, 11.1, 1.2 Hz, CHvCH±CH±OH), 6.0 (1H, br. t,
Jˆ11.1 Hz, vCH±CHvCH±CH±OH), 5.7 (1H, dd,
Jˆ15.3, 6.3 Hz, vCH±CH±OH), 5.6±5.5 [1H, dtt,
Jˆ11.1, 7.2, 1.5 Hz, vCH±(CH2)4±CH3], 5.5±5.3 [4H,
m,
vCH±CH2±CHvCH±(CH2)3±COO,
CHvCH±
(CH2)4±CH3], 4.3±4.2 (1H, m, CH±OH), 3.0±2.8 (2H, m,
vCH±CH2±CHv), 2.4±2.3 (4H, m, CH2±COO, CH2±
CH±OH), 2.1 [2H, m, CH2±(CH2)2±COO], 2.1±2.0 [2H,
m, CH2±(CH2)3±CH3], 1.7 (2H, m, CH2±CH2±COO),
1.4±1.2 [6H, m, (CH2)3±CH3], 0.9±0.8 (3H, t, Jˆ6.8 Hz,
CH3). 13C NMR (CDCl3, 75.5 MHz): d 178.1 (COO), 135.4
(vCH±CH±OH), 133.7 [vCH±(CH2)4±CH3], 130.3,
CH±OTES),
129.3
[vCH±(CH2)3±COO],
128.7
[CHvCH±(CH2)3±COO], 128.4 (vCH±CHvCH±CH±
OTES), 125.2 [CHvCH±(CH2)4±CH3], 124.5 (CHvCH±
CH±OTES), 73.1 (CH±OTES), 51.3 (CH3±O), 36.5 (CH2±
CH±OTES), 33.4 (CH2±COO), 31.5 (CH2±CH2±CH3),
29.2 [CH2±(CH2)2±CH3], 27.4 [CH2±(CH2)3±CH3], 26.5
[CH2±(CH2)2±COO], 26.0 (vCH±CH2±CHv), 24.8
(CH2±CH2±COO), 22.5 (CH2±CH3), 13.9 (CH3), 6.7 (3C,
CH3±CH2±Si), 5.0 (3C, CH2±Si). IR (®lm): 3011, 2953,
2929, 2874, 1741, 1456, 1239, 1071, 1005, 743,
727 cm21. Anal. Calcd for C27H48O3Si: C, 72.26; H,
10.78. Found: C, 72.69; H, 10.90.
129.4,
128.4
[vCH±CH2±CHvCH±(CH2)3±COO],
127.8 (vCH±CHvCH±CH±OH), 125.6 (CHvCH±CH±
OH), 124.3 [CHvCH±(CH2)4±CH3], 72.1 (CH±OH), 35.3
(CH2±CH±OH), 33.1 (CH2±COO), 31.4 (CH2±CH2±CH3),
29.2 [CH2±(CH2)2±CH3], 27.4 [CH2±(CH2)3±CH3], 26.4
[CH2±(CH2)2±COO], 26.1 (vCH±CH2±CHv), 24.5
(CH2±CH2±COO), 22.4 (CH2±CH3), 13.9 (CH3). HPLC/
API-ES/MS (m/z): 319 [M12(R)-HETE2H1]2.
1.1.9. 12(R)-HETE methyl ester (27). To compound 25
(75 mg, 0.17 mmol) in MeOH (10 ml) was added pyridi-
nium p-toluenesulfonate (15 mg). The mixture was stirred
for 1.5 h at room temperature and then quenched by the
addition of Et3N. The solvent was evaporated under vacuo
and crude 27 was puri®ed by ¯ash chromatography with
1.1.11. (S)-(Triethylsilyl)glycidyl ether (13). Compound
12 (6.0 g, 31.9 mol) was dissolved in Et2O (5 ml) and
(R,R)-(salen)Co(III)(AcO) (15) (0.10 g, 0.15 mmol) was
added. The mixture was cooled to 08C and H2O (0.32 ml,

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
32
17.5 mmol) was added dropwise. The reaction was allowed
to reach room temperature and then stirred for 20 h. The
Et2O was evaporated and the residue was puri®ed by bulb
to bulb distillation 50±558C/0.6 mm affording 13 (2.7 g,
45% yield). [a]D25ˆ22.2 (cˆ1.52, CHCl3) {Ref.13a
[a]2D0ˆ22.20 (cˆ0.64, CHCl3)}. 1H NMR (CDCl3,
1.1.14. (S)-2-[(Triethylsilyl)oxy]-4-decynal (19). Follow-
ing the same procedure as described for the preparation of
4, the di-TES 18 (0.30 g, 0.75 mmol) in CH2Cl2 (4 ml) was
converted to 19. Crude 19 was used without further
puri®cation for the next step.
1
300 MHz): d 3.8 (1H, ddd, Jˆ11.8, 3.3, 0.4 Hz, H of
1.1.15. (S)-4-[(Triethylsilyl)oxy]-2(E)-dodecen-6-ynal (21).
To the crude aldehyde 19, obtained in the previous reaction,
in benzene (10 ml) was added (triphenylphosphoranyl-
idene)acetaldehyde (8) (0.45 g, 1.5 mmol). The reaction
mixture was brought to 608C and stirred for 2 h. The solvent
was evaporated under vacuo and the crude product was puri-
®ed by ¯ash chromatography [hexane/EtOAc (98:2) (1%
Et3N)] affording 21 (0.14 g, 61%). 1H NMR (CDCl3,
300 MHz): d 9.6 (1H, d, Jˆ7.8 Hz, CHO), 6.9 (1H, dd,
Jˆ15.3, 4.2 Hz, vCH±CH±OTES), 6.3 (1H, ddd, Jˆ15.3,
7.8, 1.5 Hz, vCH±CHO), 4.5 (1H, dddd, Jˆ8.4, 5.7, 4.2,
1.5 Hz, CH±OTES), 2.6±2.5 (1H, ddt AB system, Jˆ16.5,
1
CH2±OTES), 3.6 (1H, dd, Jˆ11.8, 5.0 Hz, H of CH2±
OTES), 3.1±3.0 (1H, m, CH±O), 2.8±2.7 (1H, ddd,
Jˆ5.1, 4.0, 0.4 Hz, 1H of CH2±O±CH), 2.6 (1H, dd,
1
Jˆ5.1, 2.8 Hz, H of CH2±O±CH), 0.9 (9H, t, Jˆ7.8 Hz,
CH3±CH2±Si), 0.6 (6H, q, Jˆ7.8 Hz, CH2±Si). 13C NMR
(CDCl3, 75.5 MHz): d 63.6 (CH2±OTES), 52.3 (CH±O),
44.4 (CH2±O±CH), 6.4 (3C, CH3±CH2±Si), 4.2 (3C,
CH2±Si).
1.1.12. (S)-1-[(Triethylsilyl)oxy]-4-decyn-2-ol (17). The
TES protected glycidol 13 (2.0 g, 10.6 mmol) was trans-
formed in 17 following the same procedure as for the
preparation of compound 16. Crude 17 (2.9 g) was obtained
and used for the next step without further puri®cation. A
small sample was puri®ed by ¯ash chromatography for
1
5.7, 2.4 Hz, H of CH2±CH±OTES), 2.4±2.3 (1H, ddt AB
1
system, Jˆ16.5, 8.4, 2.4 Hz, H of CH2±CH±OTES), 2.1
[2H, tt, Jˆ7.2, 2.4 Hz, CH2±(CH2)3±CH3], 1.5±1.4 [2H, m,
CH2±(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.0±0.8
(12H, m, CH3, CH3±CH2±Si), 0.6 (6H, m, CH2±Si). 13C
NMR (CDCl3, 75.5 MHz): d 193.3 (CHO), 158.0 (vCH±
CH±OTES), 131.2 (vCH±CHO), 83.5 (uC), 75.2 (uC),
70.9 (CH±OTES), 31.0 (CH2±CH2±CH3), 28.5 [CH2±
(CH2)2±CH3], 28.1 (CH2±CH±OTES), 22.1 (CH2±CH3),
18.7 [CH2±(CH2)3±CH3], 13.8 (CH3), 6.6 (3C, CH3±CH2±
Si), 4.8 (3C, CH2±Si). IR (®lm): 2956, 2934, 2914, 2876,
2808, 2719, 1696, 1459, 1239, 1107, 1007, 975, 745,
730 cm21. Anal. Calcd for C18H32O2Si2´0.2H2O: C, 69.26;
H, 10.46. Found: C, 68.83; H, 9.96.
1
analytical purpose. [a]2D5ˆ9.2 (cˆ1.75, CH2Cl2). H NMR
1
(CDCl3, 300 MHz): d 3.8±3.6 (2H, m, CH±OH, H of
CH2±OTES), 3.6±3.5 (1H, m, 1H of CH2±OTES), 2.5
(1H, br. s, OH), 2.5±2.3 (2H, m, CH2±CH±OH), 2.2±2.1
[2H, tt, Jˆ7.0, 2.4 Hz, CH2±(CH2)3±CH3], 1.5±1.4 [2H, m,
CH2±(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.0±0.9
(9H, t, Jˆ8.0 Hz, CH3±CH2±Si), 0.9±0.8 (3H, t, Jˆ7.2 Hz,
CH3), 0.6 (6H, q, Jˆ8.0 Hz, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 82.6 (uC), 75.6 (uC), 70.5 (CH±OH), 65.4
(CH2±OTES), 31.0 (CH2±CH2±CH3), 28.6 [CH2±(CH2)2±
CH3], 23.3 (CH2±CH±OH), 22.1 (CH2±CH3), 18.6 [CH2±
(CH2)3±CH3], 13.8 (CH3), 6.5 (3C, CH3±CH2±Si), 4.2 (3C,
CH2±Si). Enantiomeric excess was determined to be .99%
by chiral HPLC of the dibenzoate derivative obtained
from compound 17 after cleavage of the TES ether
[Column: OF-chiracel, mobile phase: hexane/i-PrOH
(90:10), lˆ265 nm].
1.1.16. (S)-12-[(Triethylsilyl)oxy]-5(Z),8(Z),10(E)-eicosa-
trien-14-ynoic acid methyl ester (24). Wittig reaction of
aldehyde 21 (0.10 g, 0.32 mmol) with the phosphorane 9,
obtained in situ from the phosphonium iodide salt 22
(0.30 g, 0.56 mmol), under the same conditions as described
for the preparation of compound 23, afforded 24 (0.13 g,
87%) after ¯ash chromatography puri®cation. [a]2D5ˆ21.3
1
1.1.13. (S)-1,2-Bis[(triethylsilyl)oxy]-4-decyne (18). Follow-
ing the same procedure that for the preparation of 5, 17 (2.7 g,
9.5 mmol) was transformed in 18. After drying and concen-
trating under vacuo the product was puri®ed by ¯ash
chromatography with hexane/EtOAc (98:2) (0.5% Et3N)
affording 18 (2.8 g, 66% two-steps). [a]2D5ˆ21.9 (cˆ1.19,
(cˆ1, acetone). H NMR (d6-benzene, 300 MHz): d 6.9
(1H, ddt, Jˆ15.2, 11.1, 1.2 Hz, CHvCH±CH±OTES),
6.2±6.1 (1H, br. t, Jˆ11.1 Hz, vCH±CHvCH±CH±
OTES), 6.0 (1H, dd, Jˆ15.2, 6.0 Hz, vCH±CH±OTES),
5.6±5.3 [3H, m, vCH±CH2±CHvCH±(CH2)3±COO], 4.5
(1H, m, CH±OTES), 3.4 (3H, s, CH3O), 3.0 [2H, br. t,
Jˆ7.4 Hz, CH2±CHvCH±(CH2)3±COO], 2.7±2.6 (1H,
ddt AB system, Jˆ16.2, 6.0, 2.4 Hz, 1H of CH2±CH±
OTES), 2.6±2.5 (1H, ddt AB system, Jˆ16.2, 7.0, 2.4 Hz,
1H of CH2±CH±OTES), 2.2 [4H, m, CH2±(CH2)3±CH3,
CH2±COO], 2.0 [2H, m, CH2±(CH2)2±COO], 1.8±1.6
(2H, quint, Jˆ7.2 Hz, CH2±CH2±COO), 1.6±1.5 [2H, m,
CH2±(CH2)±COO], 1.5±1.2 [4H, m, (CH2)2±CH3], 1.1 (9H,
t, Jˆ8.0 Hz, CH3±CH2±Si), 0.9 (3H, t, Jˆ7.9 Hz, CH3), 0.7
(6H, q, Jˆ7.9 Hz, CH2±Si). 13C NMR (CDCl3, 75.5 MHz):
d 174.1 (COO), 135.9 (vCH±CH±OTES), 129.8 (vCH),
129.3 [vCH±(CH2)3±COO], 128.6 (vCH), 128.2 (vCH±
CHvCH±CH±OTES), 124.8 (CHvCH±CH±OTES), 82.2
(uC), 76.6 (uC), 72.1 (CH±OTES), 51.3 (CH3±O), 33.3
(CH2±COO), 31.0 (CH2±CH2±CH3), 28.9 (CH2±CH±
OTES), 28.6 [CH2±(CH2)2±CH3], 26.4 [CH2±(CH2)2±
COO], 25.9 (vCH±CH2±CHv), 24.7 (CH2±CH2±COO),
22.1 (CH2±CH3), 18.7 [CH2±(CH2)3±CH3], 13.8 (CH3), 6.7
1
CH2Cl2). H NMR (CDCl3, 300 MHz): d 3.8 (1H, m, CH±
OTES), 3.7±3.5 (2H, 2 dd AB system, Jˆ9.9, 5.7 Hz,
CH2±OTES), 2.5±2.4 (1H, ddt AB system, Jˆ16.5, 6.0,
2.4 Hz, 1H of CH2±CH±OTES), 2.3±2.2 (1H, ddt AB
1
system, Jˆ16.5, 5.7, 2.4 Hz, H of CH2±CH±OTES), 2.1
[2H, tt, Jˆ6.9, 2.4 Hz, CH2±(CH2)3±CH3], 1.5±1.4 [2H, m,
CH2±(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.0±0.8
(21H, m, CH3±CH2±Si, CH3), 0.7±0.5 (12H, m, CH2±Si). 13C
NMR (CDCl3, 75.5 MHz): d 81.6 (uC), 77.0 (uC), 72.5
(CH±OTES), 66.3 (CH2±OTES), 31.1 (CH2±CH2±CH3),
28.7 [CH2±(CH2)2±CH3], 24.6 (CH2±CH±OTES), 22.2
(CH2±CH3), 18.8 [CH2±(CH2)3±CH3], 13.9 (CH3), 6.7
(6C, CH3±CH2±Si), 4.9 (3C, CH2±Si), 4.3 (3C, CH2±Si).
IR (®lm): 2955, 2935, 2912, 2876, 1459, 1415, 1239,
1123, 1081, 1005, 815, 743, 673 cm21. Anal. Calcd for
C22H46O2Si2: C, 66.26; H, 11.63. Found: C, 66.53; H,
11.58.

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
33
(3C, CH3±CH2±Si), 4.8 (3C, CH2±Si). IR (®lm): 3011,
2953, 2933, 2875, 1741, 1457, 1435, 1239, 1155, 1107,
1072, 1005, 984, 951, 743, 727 cm21. Anal. Calcd for
C27H46O3Si: C, 72.59; H, 10.38. Found: C, 72.30; H, 10.76.
(CHvCH±CH±OH), 124.4 [CHvCH±(CH2)4±CH3],
72.0 (CH±OH), 51.3 (CH3±O), 35.4 (CH2±CH±OH), 33.4
(CH2±COO), 31.4 (CH2±CH2±CH3), 29.2 [CH2±(CH2)2±
CH3], 27.4 [CH2±(CH2)3±CH3], 26.6 [CH2±(CH2)2±
COO], 26.1 (vCH±CH2±CHv), 24.7 (CH2±CH2±COO),
22.4 (CH2±CH3), 13.8 (CH3).
1.1.17. (S)-12-[(Triethylsilyl)oxy]-5(Z),8(Z),10(E),14(Z)-
eicosatetraenoic acid methyl ester (26). The alkyne 24
(67.0 mg, 0.15 mmol) was dissolved in hexane (4 ml)
under argon and pyridine (70 mL) followed by Lindlar
catalyst (100 mg) were added. The argon atmosphere was
exchanged by hydrogen and the mixture was stirred for 36 h.
Filtration of the catalyst, evaporation of the solvent and
puri®cation by ¯ash chromatography with hexane/EtOAc
(95:5) (1% Et3N) afforded 26 (61 mg, 90%). 1H NMR
(CDCl3, 300 MHz): d 6.4 (1H, ddt, Jˆ15.3, 11.1, 1.2 Hz,
CHvCH±CH±OTES), 6.0 (1H, br. t, Jˆ11.1 Hz, vCH±
CHvCH±CH±OTES), 5.7±5.6 (1H, dd, Jˆ15.3, 6.3 Hz,
vCH±CH±OTES), 5.5±5.2 [5H, m, vCH±CH2±
CHvCH±(CH2)3±COO, CHvCH±(CH2)4±CH3], 4.2
(1H, m, CH±OTES), 3.6 (3H, s, CH3O), 2.9 (2H, m,
vCH±CH2±CHv), 2.3 (2H, t, Jˆ7.5 Hz, CH2±COO),
2.3±2.2 (2H, m, CH2±CH±OTES), 2.1 [2H, m, CH2±
(CH2)2±COO], 2.0 [2H, m, CH2±(CH2)3±CH3], 1.7 (2H,
quint, Jˆ7.5 Hz, CH2±CH2±COO), 1.4±1.2 [6H, m,
(CH2)3±CH3], 1.0±0.9 (9H, m, CH3±CH2±Si), 0.9 (3H, t,
Jˆ6.8 Hz, CH3), 0.6 (6H, m, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 174.1 (COO), 137.0 (vCH±CH±OTES),
132.1 [vCH±(CH2)4±CH3], 129.5 (CHvCH±CHvCH±
1.1.19. 12(S)-HETE (2). Compound 28 (15.0 mg,
0.045 mmol) was converted to 2 using the same conditions
as for the preparation of 1 affording 12(S)-HETE (13 mg,
90%). UV (CH3CN) lmax 237 nm. 1H NMR (CDCl3,
300 MHz): d 6.6 (1H, br. dd, Jˆ15.3, 11.0 Hz, CHvCH±
CH±OH), 6.0 (1H, br. t, Jˆ11.0 Hz, vCH±CHvCH±CH±
OH), 5.7 (1H, dd, Jˆ15.3, 6.3 Hz, vCH±CH±OH),
5.6±5.5 [1H, dtt, Jˆ11.1, 7.2, 1.5 Hz, vCH±(CH2)4±
CH3], 5.5±5.3 [4H, m, vCH±CH2±CHvCH±(CH2)3±
COO, CHvCH±(CH2)4±CH3], 4.3±4.2 (1H, m, CH±OH),
3.0±2.8 (2H, m, vCH±CH2±CHv), 2.4±2.3 (4H, m, CH2±
COO, CH2±CH±OH), 2.1 [2H, m, CH2±(CH2)2±COO],
2.1±2.0 [2H, m, CH2±(CH2)3±CH3], 1.7 (2H, m, CH2±
CH2±COO), 1.4±1.2 [6H, m, (CH2)3±CH3], 0.9±0.8 (3H,
t, Jˆ6.8 Hz, CH3). 13C NMR (CDCl3, 75.5 MHz): d 178.2
(COO), 135.4 (vCH±CH±OH), 133.7 [vCH±(CH2)4±
CH3], 130.3, 129.4, 128.4 [vCH±CH2±CHvCH±
(CH2)3±COO], 127.8 (vCH±CHvCH±CH±OH), 125.6
(CHvCH±CH±OH), 124.3 [CHvCH±(CH2)4±CH3],
72.1 (CH±OH), 35.3 (CH2±CH±OH), 33.5 (CH2±COO),
31.4 (CH2±CH2±CH3), 29.2 [CH2±(CH2)2±CH3], 27.4
[CH2±(CH2)3±CH3], 26.4 [CH2±(CH2)2±COO], 26.2
(vCH±CH2±CHv), 24.6 (CH2±CH2±COO), 22.4
(CH2±CH3), 13.9 (CH3). HPLC/API-ES/MS (m/z): 319
[M12(S)-HETE -H1]2.
CH±OTES),
129.3
[vCH±(CH2)3±COO],
128.7
[CHvCH±(CH2)3±COO], 128.3 (vCH±CHvCH±CH±
OTES), 125.2 [CHvCH±(CH2)4±CH3], 124.4 (CHvCH±
CH±OTES), 73.0 (CH±OTES), 51.4 (CH3±O), 36.4 (CH2±
CH±OTES), 33.4 (CH2±COO), 31.5 (CH2±CH2±CH3),
29.2 [CH2±(CH2)2±CH3], 27.4 [CH2±(CH2)3±CH3], 26.5
[CH2±(CH2)2±COO], 26.0 (vCH±CH2±CHv), 24.7
(CH2±CH2±COO), 22.5 (CH2±CH3), 13.9 (CH3), 6.8 (3C,
CH3±CH2±Si), 4.9 (3C, CH2±Si). IR (®lm): 3011, 2953,
1.1.20. (S)-1,2-Bis[(triethylsilyl)oxy]-4(Z)-decene (30). To
a solution of alkyne 18 (0.30 g, 0.75 mmol) in hexane
(10 ml) under argon was added Lindlar catalyst (50 mg)
followed by Et3N (50 mL). The atmosphere of argon was
exchanged by hydrogen and the mixture was vigorously
stirred for 1 h. The catalyst was ®ltered and the solvent
evaporated under vacuo. The crude product 30 was used
directly in the next step. [a]2D5ˆ22.3 (cˆ1 crude product,
2931, 2875, 1743, 1457, 1239, 1073, 1005, 743, 727 cm21
.
1.1.18. 12(S)-HETE methyl ester (28). To compound 26
(66 mg, 0.15 mmol) in MeOH (7 ml) was added pyridinium
p-toluenesulfonate (10 mg). The mixture was stirred for
1.5 h at room temperature and then quenched by the addi-
tion of Et3N. The solvent was evaporated under vacuo and
the crude was puri®ed by ¯ash chromatography with
hexane/EtOAc (9:1) affording 12(S)-HETE methyl ester
(45 mg, 90%). [a]D25ˆ11.4 (cˆ1.1, acetone). {Ref.10f
[a]2D0ˆ13 (cˆ1.5, acetone)}. UV (CH3CN) lmax 237 nm.
1H NMR (CDCl3, 300 MHz): d 6.5 (1H, ddt, Jˆ15.0,
11.1, 1.2 Hz, CHvCH±CH±OH), 6.0±5.9 (1H, br. t,
Jˆ11.1 Hz, vCH±CHvCH±CH±OH), 5.7 (1H, dd,
Jˆ15.0, 6.0 Hz, vCH±CH±OH), 5.6±5.5 [1H, m, vCH±
(CH2)4±CH3], 5.4±5.3 [4H, m, vCH±CH2±CHvCH±
(CH2)3±COO, CHvCH±(CH2)4±CH3], 4.2 (1H, m, CH±
OH), 3.6 (3H, s, CH3O), 2.9 (2H, m, vCH±CH2±CHv),
2.4±2.2 (4H, t and m, Jˆ7.5 Hz, CH2±COO, CH2±CH±
OH), 2.2±2.0 [4H, m, CH2±(CH2)2±COO, CH2±(CH2)3±
CH3], 2.0±1.9 (1H, br. s, OH), 1.8±1.6 (2H, m, CH2±
CH2±COO), 1.4±1.2 [6H, m, (CH2)3±CH3], 0.9 (3H, t,
Jˆ6.8 Hz, CH3). 13C NMR (CDCl3, 75.5 MHz): d 174.1
(COO), 136.0 (vCH±CH±OH), 133.6 [vCH±(CH2)4±
CH3], 130.2, 129.4, 128.5 [vCH±CH2±CHvCH±
(CH2)3±COO], 128.1 (vCH±CHvCH±CH±OH), 125.4
1
CH2Cl2). H NMR (CDCl3, 300 MHz): d 5.5±5.3 (2H, m,
CHvCH), 3.7 (1H, m, CH±OTES), 3.6±3.4 (2H, m, CH2±
1
OTES), 2.4±2.3 (1H, br. dt, Jˆ14.4, 5.7 Hz, H of CH2±
1
CH±OTES), 2.3±2.1 (1H, br. dt, Jˆ14.4, 6.0 Hz, H of
CH2±CH±OTES), 2.0 [2H, m, CH2±(CH2)3±CH3], 1.4±
1.2 [6H, m, (CH2)3±CH3], 1.0±0.8 (21H, br. t and t,
Jˆ7.8 Hz, Jˆ6.9 Hz, CH3±CH2±Si, CH3), 0.7±0.5 (12H,
2q, Jˆ7.8 Hz, CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d
131.9 (vCH), 125.6 (vCH), 73.4 (CH±OTES), 66.8
(CH2±OTES), 32.3 (CH2±CH±OTES), 31.5 (CH2±CH2±
CH3), 29.3 [CH2±(CH2)2±CH3], 27.3 [CH2±(CH2)3±CH3],
22.5 (CH2±CH3), 13.9 (CH3), 6.7 (3C, CH3±CH2±Si), 6.6
(3C, CH3±CH2±Si), 4.9 (3C, CH2±Si), 4.3 (3C, CH2±Si).
1.1.21. (S)-2-[(Triethylsilyl)oxy]-4(Z)-decenal (32). The
di-TES 30 (0.20 g, 0.50 mmol) was oxidized following the
same Swern conditions as described for the preparation of 4.
The crude product 32 was used without further puri®cation
for the next step.
1.1.22. (S)-4-[(Triethylsilyl)oxy]-2(E),6(Z)-dodecadienal
(34). Wittig reaction of 32, obtained in the previous

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A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
34
reaction, with 8 afforded aldehyde 34 using the conditions
described for the preparation of 20. The crude was puri®ed
by ¯ash chromatography [hexane/EtOAc (98:2) (1% Et3N)]
affording 34 (91 mg, 59% two-steps). [a]2D5ˆ21.7 (cˆ0.94,
CH2Cl2). 1H NMR (CDCl3, 300 MHz): d 9.5 (1H, d,
Jˆ7.8 Hz, CHO), 6.8 (1H, dd, Jˆ15.5, 4.5 Hz, vCH±
CH±OTES), 6.4±6.2 (1H, ddd, Jˆ15.5, 7.8, 1.6 Hz,
vCH±CHO), 5.5 [1H, m, vCH±(CH2)4±CH3], 5.3 [1H,
m, CHvCH±(CH2)4±CH3], 4.4 (1H, m, CH±OTES), 2.4±
2.2 (2H, m, CH2±CH±OTES), 2.0 [2H, m, CH2±(CH2)3±
CH3], 1.4±1.2 [6H, m, (CH2)3±CH3], 1.0±0.9 (9H, t,
Jˆ7.8 Hz, CH3±CH2±Si), 0.9±0.8 (3H, t, Jˆ6.9 Hz,
CH3), 0.8 (6H, q, Jˆ7.8 Hz, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 193.6 (CHO), 159.5 (vCH±CH±OTES),
133.4 [vCH±(CH2)4±CH3], 130.8 (vCH±CHO), 123.6
[CHvCH±(CH2)4±CH3], 71.5 (CH±OTES), 35.4 (CH2±
CH±OTES), 31.4 (CH2±CH2±CH3), 29.1 [CH2±(CH2)2±
CH3], 27.4 [CH2±(CH2)3±CH3], 22.4 (CH2±CH3), 13.9
(CH3), 6.6 (3C, CH3±CH2±Si), 4.7 (3C, CH2±Si). IR
(®lm): 3011, 2956, 2929, 2876, 2858, 2808, 2719, 1695,
preparation of 4. The crude product 31 was used without
further puri®cation in the next step. 1H NMR (CDCl3,
300 MHz): d 9.6 (1H, d, Jˆ1.8 Hz, CHO), 3.9 (1H, td,
Jˆ6.3, 1.8 Hz, CH±OTES), 2.4±2.3 (2H, d, Jˆ6.3 Hz,
CH2±CH±OTES), 2.0±1.9 [2H, t, Jˆ7.4 Hz, CH2±(CH2)3±
CH3], 1.4±1.2 [6H, m, (CH2)3±CH3], 1.0±0.8 (12H, m, CH3,
CH3±CH2±Si), 0.6±0.4 (6H, m, CH2±Si). 13C NMR (CDCl3,
75.5 MHz): d 203.6 (CHO), 132.9 (t, Jˆ23 Hz, vCD), 122.6
(t, Jˆ23 Hz, vCD), 77.4 (CH±OTES), 31.4 (CH2±CH2±
CH3), 30.9 (CH2±CH±OTES), 29.0 [CH2±(CH2)2±CH3],
27.1 [CH2±(CH2)3±CH3], 22.4 (CH2±CH3), 13.8 (CH3), 6.4
(3C, CH3±CH2±Si), 4.8 (3C, CH2±Si).
1.1.26. 6,7-Dideuterio-4(R)-[(triethylsilyl)oxy]-2(E),6(Z)-
dodecadienal (33). Wittig reaction of 31, obtained in the
previous reaction, with 8 afforded aldehyde 33 using the
conditions described for the preparation of 20. The crude
was puri®ed by ¯ash chromatography [SiO2, hexane/EtOAc
(98:2) (1% Et3N)] affording 33 (90 mg, 59% two-steps). 1H
NMR (CDCl3, 300 MHz): d 9.6 (1H, d, Jˆ7.8 Hz, CHO),
6.8 (1H, dd, Jˆ15.6, 4.5 Hz, vCH±CH±OTES), 6.3 (1H,
ddd, Jˆ15.6, 7.8, 1.5 Hz, vCH±CHO), 4.4 (1H, dddd,
Jˆ6.9, 6.0, 4.5, 1.5 Hz, CH±OTES), 2.4 (2H, m, CH2±
CH±OTES), 2.0 [2H, m, CH2±(CH2)3±CH3], 1.4±1.2 [6H,
m, (CH2)3±CH3], 1.0±0.9 (9H, t, Jˆ7.9 Hz, CH3±CH2±Si),
0.9±0.8 (3H, t, Jˆ6.8 Hz, CH3), 0.6 (6H, q, Jˆ7.9 Hz,
CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d 193.5 (CHO),
159.3 (vCH±CH±OTES), 133.0 [t, Jˆ23 Hz, vCD±
(CH2)4±CH3], 131.0 (vCH±CHO), 123.2 [t, Jˆ23 Hz,
CDvCD±(CH2)4±CH3], 71.7 (CH±OTES), 35.4 (CH2±
CH±OTES), 31.5 (CH2±CH2±CH3), 29.1 [CH2±(CH2)2±
CH3], 27.3 [CH2±(CH2)3±CH3], 22.4 (CH2±CH3), 13.8
(CH3), 6.6 (3C, CH3±CH2±Si), 4.8 (3C, CH2±Si). IR
(®lm): 2956, 2928, 2876, 2856, 2807, 2718, 2249, 1695,
1459, 1239, 1139, 1104, 1005, 976, 744, 729 cm21. Anal.
Calcd for C18H32D2O2Si: C, 69.17; H, 11.61. Found: C,
69.11; H, 11.59.
1459, 1414, 1239, 1141, 1102, 1006, 955, 743, 729 cm21
.
Anal. Calcd for C18H34O2Si: C, 69.62; H, 11.03. Found: C,
68.95; H, 11.63.
1.1.23. (S)-12-[(Triethylsilyl)oxy]-5(Z),8(Z),10(E),14(Z)-
eicosatetraenoic acid methyl ester (26). Wittig reaction
of aldehyde 34 (71.4 mg, 0.23 mmol) with the phosphorane
9, obtained in situ from the phosphonium iodide salt 22
(0.20 g, 0.40 mmol), under the same conditions as described
for the preparation of compound 23, afforded 26 (85 mg,
82%) after ¯ash chromatography. [a]2D5ˆ13.4 (cˆ1.1,
acetone).
1.1.24. 4,5-Dideuterio-1,2(R)-bis[(triethylsilyl)oxy]-4(Z)-
decene (29). Following the same conditions used for the
transformation of 18 to 30, alkyne 5 (0.30 g, 0.75 mmol)
was reduced with deuterium in the presence of Lindlar
catalyst (100 mg) and Et3N (80 ml). After 30 min the start-
ing material was consumed, the reaction mixture was
®ltered and the solvent was evaporated affording 29 that
was used without further puri®cation in the next step.
[a]2D5ˆ22.12 (cˆ2.1, CH2Cl2). 1H NMR (CDCl3,
300 MHz): d 3.7 (1H, m, CH±OTES), 3.6±3.4 (2H, 2 dd
AB system, Jˆ9.9, 5.7 Hz, CH2±OTES), 2.4±2.3 (1H, dd
1.1.27. 14,15-Dideuterio-12(R)-[(triethylsilyl)oxy]-5(Z),8(Z),
10(E),14(Z)-eicosatetraenoic acid methyl ester (35).
Wittig reaction of aldehyde 33 (0.10 g, 0.32 mmol) with
the phosphorane 9, obtained in situ from the phosphonium
iodide salt 22 (0.27 g, 0.5 mmol), under the same conditions
as described for the preparation of compound 23, afforded
35 (0.11 g, 84%) after ¯ash chromatography puri®cation. 1H
NMR (d6-benzene, 300 MHz): d 6.8 (1H, br. dd, Jˆ15.3,
11.1 Hz, CHvCH±CH±OTES), 6.1 (1H, br. t, Jˆ11.1 Hz,
vCH±CHvCH±CH±OTES), 5.8 (1H, dd, Jˆ15.3, 6.3 Hz,
vCH±CH±OTES), 5.5±5.2 [3H, m, vCH±CH2±
CHvCH±(CH2)3±COO], 4.4±4.3 (1H, m, CH±OTES),
3.4 (3H, s, CH3O), 3.0±2.9 (2H, m, vCH±CH2±CHv),
2.6±2.4 (2H, 2 dd AB system, Jˆ14.1, 6.6 Hz, CH2±CH±
OTES), 2.2±2.1 (2H, t, Jˆ7.5 Hz, CH2±COO), 2.1 [2H, m,
CH2±(CH2)3±CH3], 2.1±1.9 [2H, m, CH2±(CH2)2±COO],
1.7±1.6 (2H, m, CH2±CH2±COO), 1.5±1.2 [6H, m,
(CH2)3±CH3], 1.2±1.0 (9H, t, Jˆ7.8 Hz, CH3±CH2±Si),
0.9 (3H, t, Jˆ6.8 Hz, CH3), 0.8±0.6 (6H, q, Jˆ7.8 Hz,
CH2±Si). 13C NMR (d6-benzene, 75.5 MHz): d 173.1
(COO), 137.5 (vCH±CH±OTES), 129.8, 129.6, 128.7
[vCH±CH2±CHvCH±(CH2)3±COO], 127.9 (vCH±
CHvCH±CH±OTES), 124.9 (CHvCH±CH±OTES),
73.5 (CH±OTES), 50.7 (CH3±O), 36.8 (CH2±CH±OTES),
33.3 (CH2±COO), 31.7 (CH2±CH2±CH3), 29.5 [CH2±
1
AB system, Jˆ14.4, 5.7 Hz, H of CH2±CH±OTES), 2.2±
1
2.1 (1H, dd AB system, Jˆ14.4, 6.0 Hz, H of CH2±CH±
OTES), 2.0 [2H, br. t, Jˆ6.9 Hz, CH2±(CH2)3±CH3], 1.4±
1.2 [6H, m, (CH2)3±CH3], 1.0±0.9 [21H, br. t, Jˆ7.8 Hz, t,
Jˆ6.9 Hz, (CH3±CH2)3±Si, CH3], 0.7±0.5 (12H, 2q,
Jˆ7.8 Hz, CH2±Si). 13C NMR (CDCl3, 75.5 MHz): d
131.4 (t, Jˆ23 Hz, vCD), 125.2 (t, Jˆ23 Hz, vCD),
73.4 (CH±OTES), 66.8 (CH2±OTES), 32.2 (CH2±CH±
OTES), 31.5 (CH2±CH2±CH3), 29.3 [CH2±(CH2)2±CH3],
27.2 [CH2±(CH2)3±CH3], 22.5 (CH2±CH3), 13.9 (CH3),
6.7 (3C, CH3±CH2±Si), 6.6 (3C, CH3±CH2±Si), 4.9 (3C,
CH2±Si), 4.3 (3C, CH2±Si). IR (®lm): 2955, 2934, 2913,
2876, 2248, 1630, 1459, 1415, 1239, 1121, 1087, 1005, 811,
742, 728 cm21. Anal. Calcd for C22H46D2O2Si2: C, 65.60; H,
12.51. Found: C, 64.83; H, 12.18.
1.1.25. 4,5-Dideuterio-2(R)-[(triethylsilyl)oxy]-4(Z)-dece-
nal (31). The di-TES 29 (0.20 g, 0.50 mmol) was oxidized
following the same Swern conditions as described for the

Â
A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
35
(CH2)2±CH3], 27.6 [CH2±(CH2)3±CH3], 26.7 [CH2±
(CH2)2±COO], 26.3 (vCH±CH2±CHv), 24.9 (CH2±
CH2±COO), 22.7 (CH2±CH3), 14.0 (CH3), 6.9 (3C,
CH3±CH2±Si), 5.4 (3C, CH2±Si). The 13C signals corre-
sponding to the carbons CDvCD were not observed due
to their low intensity. IR (®lm): 3011, 2953, 2929, 2875,
2247, 1742, 1456, 1435, 1239, 1071, 1005, 983, 950, 742,
solution of LDA in cyclohexane (0.53 ml, 0.79 mmol) was
added dropwise. After 2 min aldehyde (0.19 g,
4
0.67 mmol) in THF (2 ml) was added. The reaction was
stirred for 1 h at 2788C and then was allowed to reach
room temperature before quenching with NH4Cl aq/Et2O.
The organic phase was separated, washed with brine, dried
(Na2SO4) and concentrated under vacuo. The crude product
was ®ltered through silica affording a mixture of cis and
trans isomers at the C10±C11 double bond.
726 cm21
. HRMS (ESI) calcd for C27H46D2O3SiNa
(M1Na)1: 473.3396, found (M1Na)1: 473.3408.
1.1.28. 14,15-Dideuterio-12(R)-HETE methyl ester (36).
To compound 35 (50 mg, 0.11 mmol) in MeOH (5 ml) was
added pyridinium p-toluenesulfonate (10 mg). The mixture
was stirred for 1.5 h at room temperature and then quenched
by the addition of Et3N. The solvent was evaporated under
vacuo and the crude was puri®ed by ¯ash chromatography
with hexane/EtOAc (9:1) affording 36 (34 mg, 92%). UV
(CH3CN) lmax 237 nm. 1H NMR (CDCl3, 300 MHz): d 6.5
(1H, ddt, Jˆ15.3, 11.1, 1.2 Hz, CHvCH±CH±OH), 6.0
(1H, br. t, Jˆ11.1 Hz, vCH±CHvCH±CH±OH), 5.7
(1H, dd, Jˆ15.3, 6.3 Hz, vCH±CH±OH), 5.4±5.3 [3H,
m, vCH±CH2±CHvCH±(CH2)3±COO], 4.2 (1H, m,
CH±OH), 3.6 (3H, s, CH3O), 2.9 (2H, m, vCH±CH2±
CHv), 2.4±2.2 (4H, m, CH2±COO, CH2±CH±OH),
2.2±2.0 [4H, m, CH2±(CH2)2±COO, CH2±(CH2)3±CH3],
1.8±1.6 (2H, m, CH2±CH2±COO), 1.4±1.2 [6H, m,
(CH2)3±CH3], 0.9 (3H, t, Jˆ6.8 Hz, CH3). 13C NMR
(CDCl3, 75.5 MHz): d 174.2 (COO), 136.0 (vCH±CH±
OH), 133.2 [t, Jˆ23 Hz, vCD±(CH2)4±CH3], 130.3,
The crude mixture was dissolved in CH2Cl2 (10 ml) and
treated with a catalytic amount of I2. After stirring at
room temperature for 30 min the reaction was quenched
by addition of a concentrated solution of Na2S2O3 (1 ml).
Separation of phases, drying over Na2SO4, concentrating
and ¯ash chromatography [hexane/EtOAc (98:2)] afforded
1
38 (0.23 g, 49%). H NMR (CDCl3, 300 MHz): d 7.8±7.6
(4H, m, Ar), 7.5±7.3 (6H, m, Ar), 6.4±6.1 (2H, m, vCH±
CHvCH±CH±OTES), 5.8 (1H, dd, Jˆ13.8, 5.7 Hz,
vCH±CH±OTES), 5.4 (1H, m, vCH±CuC±CH±
OTBDPS), 4.5±4.4 (1H, m, CH±OTBDPS), 4.3±4.2 (1H,
m, CH±OTES), 3.6 (3H, s, CH3O), 2.5±2.2 (4H, m, CH2±
COO, CH2±CH±OTES), 2.2±2.1 [2H, m, CH2±(CH2)3±
CH3], 1.8±1.6 [4H, m, (CH2)2±CH2±COO], 1.5±1.4 [2H,
m, CH2±(CH2)2±CH3], 1.4±1.2 [4H, m, (CH2)2±CH3], 1.1
[9H, s, (CH3)3C], 1.0±0.9 [9H, t, Jˆ7.8 Hz, (CH3±CH2)3Si],
0.9 (3H, t, Jˆ6.9 Hz, CH3), 0.6 [6H, q, Jˆ7.8 Hz, (CH3±
CH2)3Si]. 13C NMR (CDCl3, 75.5 MHz): d 174.0 (COO),
141.1 (CHvCH±Cu), 138.1 (vCH±CH±OTES), 136.2,
136.0 (4C, ArCH), 133.9, 133.7 (2C, ArC), 129.8, 129.6
(2C, ArCH), 129.1 (CHvCH±CH±OTES), 127.7, 127.4
(4C, ArCH), 110.7 (vCH±Cu), 92.7 (Cu), 84.6 (Cu),
82.4 (Cu), 76.6 (Cu), 71.9 (CH±OTES), 64.0 (CH±
OTBDPS), 51.4 (CH3O), 37.6 [CH2±(CH2)2±COO], 33.7
(CH2±COO), 31.0 (CH2±CH2±CH3), 28.8, 28.6 [CH2±
CH±OTES, CH2±(CH2)2±CH3], 26.9 [(CH3)3C], 22.1
(CH2±CH3), 20.4 (CH2±CH2±COO), 19.2 (C), 18.7
[CH2±(CH2)3±CH3], 13.9 (CH3), 6.7 [(CH3±CH2)3Si], 4.8
[(CH3±CH2)3Si]. IR (®lm): 3070, 3047, 2954, 2931, 2874,
2858, 1741, 1460, 1428, 1361, 1241, 1171, 1149, 1111,
1080, 1005, 985, 822, 740, 701 cm21. HRMS (ESI) calcd
for C43H62O4Si2Na (M1Na)1: 721.4084, found (M1Na)1:
721.4115.
129.3,
128.4
[vCH±CH2±CHvCH±(CH2)3±COO],
128.0 (vCH±CHvCH±CH±OH), 125.4 (CHvCH±CH±
OH), 123.9 [t, Jˆ23 Hz, CDvCD±(CH2)4±CH3], 72.0
(CH±OH), 51.4 (CH3±O), 35.2 (CH2±CH±OH), 33.4
(CH2±COO), 31.4 (CH2±CH2±CH3), 29.2 [CH2±(CH2)2±
CH3], 27.2 [CH2±(CH2)3±CH3], 26.5 [CH2±(CH2)2±
COO], 26.0 (vCH±CH2±CHv), 24.7 (CH2±CH2±COO),
22.5 (CH2±CH3), 13.9 (CH3). IR (®lm): 3457 (br), 3009,
2953, 2927, 2856, 2248, 1739, 1437, 1156, 984,
950 cm21
.
HRMS (ESI) calcd for C21H32D2O3Na
(M1Na)1: 359.2531, found (M1Na)1: 359.2539.
1.1.29. [14,15-2H2]-12(R)-HETE (37). Compound 36
(1.6 mg, 4.8 mmol) was converted to 37 using the same
conditions as for the preparation of
[14,15-2H2]-12(R)-HETE (1.4 mg, 91%). UV (CH3CN)
lmax 237 nm. H NMR (CD3CN, 300 MHz): d 6.6±6.5
1 affording
1.1.31. 5(S)-[(tert-Butyldiphenylsilyl)oxy]-12(R)-[(triethyl-
silyl)oxy]-6(Z),8(E),10(E),14(Z)-eicosatetraenoic
1
acid
(1H, br. dd, Jˆ15.3, 11.1 Hz, CHvCH±CH±OH), 6.0
(1H, br. t, Jˆ11.1 Hz, vCH±CHvCH±CH±OH), 5.7
(1H, dd, Jˆ15.3, 6.3 Hz, vCH±CH±OH), 5.5±5.3 [3H,
m, vCH±CH2±CHvCH±(CH2)3±COO], 4.2±4.1 (1H, m,
CH±OH), 2.9 (2H, m, vCH±CH2±CHv), 2.4±2.0 (8H, m,
CH2±CH±OH, CH2±CH2±CH2±COO, CH2±(CH2)3±CH3],
1.7±1.5 (2H, m, CH2±CH2±COO), 1.4±1.2 [6H, m,
(CH2)3±CH3], 0.9 (3H, t, Jˆ6.8 Hz, CH3). IR (®lm): 3369
(br), 3009, 2955, 2927, 2857, 2248, 1709, 1456, 1365, 1245,
1159, 1048, 983, 950 cm21. HRMS (ESI) calcd for
C20H30D2O3Na (M1Na)1: 345.2375, found (M1Na)1:
345.2390.
methyl ester (39). Compound 38 (30 mg, 0.043 mmol)
was dissolved in hexane (10 ml) under an argon atmosphere
and Lindlar catalyst (50 mg) was added. The argon
atmosphere was exchanged by hydrogen and the mixture
was stirred until TLC check showed completion. Dilution
of the crude reaction with Et2O, ®ltration of the catalyst,
concentration and puri®cation by ¯ash chromatography
[hexane/EtOAc (96:4)] afforded 39 (27 mg, 89%). 1H
NMR (d6-benzene, 300 MHz): d 7.8±7.7 (4H, m, Ar),
7.3±7.2 (6H, m, Ar), 6.1±6.0 (1H, m, CHvCH±CH±
OTES), 5.8 (2H, m, CHvCH±CHvCH±CH±OTES),
5.8±5.7 (1H, m, CHvCH±CH±OTBDPS), 5.7±5.6 (1H,
dd, Jˆ14.9, 6.8 Hz, vCH±CH±OTES), 5.5 [2H, m,
CHvCH±(CH2)4±CH3], 5.5±5.4 (1H, dd, Jˆ10.5, 9.3 Hz,
vCH±CH±OTBDPS), 4.7±4.6 (1H, m, CH±OTBDPS),
4.2±4.1 (1H, m, CH±OTES), 3.2 (3H, s, CH3O), 2.5±2.2
(2H, m, CH2±CH±OTES), 2.1±1.9 [4H, m, CH2±COO,
1.1.30. 5(S)-[(tert-Butyldiphenylsilyl)oxy]-12(R)-[(triethyl-
silyl)oxy]-8(E),10(E)-eicosadien-6,14-diynoic acid methyl
ester (38). Phosphonate 10 (0.40 g, 0.74 mmol) was
dissolved in THF (7 ml) and cooled to 2788C. A 1.5 M

Â
A. Rodrõguez et al. / Tetrahedron 57 (2001) 25±37
36
S. E.; Lindgren, J. A.; Rouzer, C. A.; Serhan, C. N. Science
1987, 237, 1171±1176.
CH2±(CH2)3±CH3], 1.7±1.4 [4H, m, (CH2)2±CH2±COO],
1.4±1.2 [6H, m, (CH2)3±CH3], 1.2 [9H, s, (CH3)3C], 1.0
[9H, t, Jˆ7.8 Hz, (CH3±CH2)3Si], 0.9±0.8 (3H, t,
Jˆ6.9 Hz, CH3), 0.6 [6H, q, Jˆ7.8 Hz, (CH3±CH2)3Si].
13C NMR (d6-benzene, 75.5 MHz): d 173.0 (COO), 137.8
(vCH±CH±OTES), 136.5, 136.4 (4C, ArCH), 134.7, 134.5
(2C, ArC), 134.2 (vCH±CH±OTBDPS), 133.8 (CHv),
132.2 [vCH±(CH2)4±CH3], 129.9, 129.8 (2C, ArCH),
129.9 (CHvCH±CH±OTES), 128.9 (CHvCH±CH±
OTBDPS), 127.8 (CHv), unde®ned (interference with
d6-benzene signal) (4C, ArCH), 125.5 [CHvCH±(CH2)4±
CH3], 73.5 (CH±OTES), 69.8 (CH±OTBDPS), 50.7
(CH3O), 37.9 [CH2±(CH2)2±COO], 36.9 (CH2±CH±
OTES), 33.7 (CH2±COO), 31.7 (CH2±CH2±CH3), 29.5
[CH2±(CH2)2±CH3], 27.7 [CH2±(CH2)3±CH3], 27.1
[(CH3)3C], 22.8 (CH2±CH3), 20.6 (CH2±CH2±COO), 19.4
(C), 14.1 (CH3), 7.0 [(CH3±CH2)3Si], 5.3 [CH3±CH2)3Si].
IR (®lm): 3071, 3048, 2957, 2929, 2875, 2857, 1742, 1460,
1428, 1260, 1110, 1076, 821, 801, 740, 702 cm21. HRMS
(ESI) calcd for C43H66O4Si2Na (M1Na)1: 725.4397, found
(M1Na)1: 725.4415.
2. Woollard, P. M. Biochem. Biophys. Res. Commun. 1986, 136,
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(Weinheim) 1985, 318, 225±228. (b) Hanzawa, Y.; Kawagoe,
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1942±1943.
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315. (b) Yadagiri, P.; Lumin, S.; Mosset, P.; Capdevila, J.;
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1 1982, 545±552. (b) Bestmann, H, J.; Pecher, B.; Riemer, C.
Synthesis 1991, 731±734. (c) Le Merrer, Y.; Gravier, C.;
Languin-Micas, D.; Depezay, J. C. Tetrahedron Lett. 1986,
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1.1.32. Leukotriene B4 (3). To a solution of 39 (15 mg,
0.021 mmol) in THF (2 ml) at 08C was added a 1.0 M solu-
tion of TBAF in THF (0.4 ml, 0.40 mmol). After 15 h the
reaction mixture was diluted with EtOAc (50 ml). Washing
with brine, drying over Na2SO4 and concentrating afforded
crude 3 that was puri®ed by ¯ash chromatography affording
LTB4 (3) (4.5 mg, 63%). [a]2D5ˆ12.6 (cˆ0.1, CHCl3)
{Ref.18b [a]2D0ˆ12.6 (cˆ0.46, CDCl3)}. UV (MeOH) lmax
260, 270, 281 nm. 1H NMR (CDCl3, 300 MHz): d 6.5 (1H,
dd, Jˆ13.5, 11.1 Hz, H-8), 6.4±6.2 (2H, m, H-9, H-10), 6.1
(1H, t, Jˆ11.1 Hz, H-7), 5.8 (1H, dd, Jˆ14.7, 6.3 Hz, H-
11), 5.6±5.5 (1H, m, H-15), 5.5±5.3 (2H, m, H-14, H-6), 4.6
(1H, m, H-5), 4.2 (1H, m, H-12), 2.5±2.3 (4H, m, H-2,
H-13), 2.1±2.0 (2H, m, H-16), 1.8±1.5 (4H, m, H-3, H-4),
1.4±1.2 (6H, m, H-17, H-18, H-19), 0.9 (3H, t, Jˆ6.9 Hz,
H-20). 13C NMR (CDCl3, 75.5 MHz): d 174.1 (C-1), 136.9
(C-11), 134.2, 134.0 (C-9, C-15), 133.7 (C-6), 130.3, 130.2
(C-7, C-10), 127.6 (C-8), 124.1 (C-14), 71.9 (C-12), 67.6
(C-5), 36.7 (C-4), 35.3 (C-13), 33.8 (C-2), 31.4 (C-18), 29.2
(C-17), 27.4 (C-16), 22.4 (C-19), 20.7 (C-3), 13.9 (C-20).
HPLC/API-ES/MS (m/z): 335 [MLTB42H1]2.
11. (a) Nicolaou, K. C.; Ladduwahetty, T.; Taffer, I. M.; Zipkin,
R. E. Synthesis 1986, 344±347. (b) Nicolaou, K. C.; Ramphal,
J. Y.; Abe, Y. Synthesis 1989, 898±901. (c) Djuric, S. W.;
Miyashiro, J. M.; Penning, T. D. Tetrahedron Lett. 1988, 29,
3459±3462.
12. (a) Kobayashi, Y.; Shimazaki, T.; Sato, F. Tetrahedron Lett.
1987, 28, 5849±5852. (b) Shimazaki, T.; Kobayashi, Y.; Sato,
F. Chem. Lett. 1988, 1785±1788. (c) Yamaguchi, M.; Hirao, I.
Tetrahedron Lett. 1983, 24, 391±394. (d) Chemin, D.;
Gueugnot, S.; Linstrumelle, G. Tetrahedron 1992, 48,
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13. Han, X.; Corey, E. J. Org. Lett. 2000, 2 (16), 2543±2544.
14. (a) Mori, Y.; Asai, M.; Okumura, A.; Furukawa, H.
Tetrahedron 1995, 51, 5299±5314. (b) Hansen, R. H. Chem.
Rev. 1991, 91, 437±475.
Acknowledgements
Financial support of this research in part by Laboratorios
Lasa S.A., Barcelona (Spain), and the Department of Cell
Biology UMDNJ-SOM is gratefully acknowledged. We
would like to thank Upjohn & Pharmacia for kindly provid-
ing us with standards of HETEs and leukotrienes for
comparison.
Â
15. (a) Rodrõguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161±5164. (b) Tokunaga, M.;
Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997,
277, 936±938. (c) Furrow, M. E.; Schaus, S. E.; Jacobsen,
E. N. J. Org. Chem. 1998, 63, 6776±6777. (d) Jacobsen,
E. N.; Kakiuchi F.; Konsler R. G.; Larrow, J. F.; Tokunaga,
M. Tetrahedron Lett. 1997, 38, 773±776. (e) Wu, M. H.;
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(f) Brandes, B. D.; Jacobsen, E. N. Tetrahedron: Asymmetry
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