An efficient total synthesis of leukotriene B4

Article abstract of DOI:10.1039/c5ob00473j

Lipid mediators have attracted great interest from scientists within the chemical, medicinal, and pharmaceutical research community. One such example is leukotriene B₄ which has been the subject of many pharmacological studies. Herein, we report a convergent and stereoselective synthesis of this potent lipid mediator in 5% yield over 10 steps in the longest linear sequence from commercial starting materials. The key steps were a stereocontrolled acetate-aldol reaction with Nagao's chiral auxiliary and a Z-selective Boland reduction. All spectroscopic data were in agreement with those previously reported.

Full text of DOI:10.1039/c5ob00473j

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An efficient total synthesis of leukotriene B4†
Karoline Gangestad Primdahl, Jørn Eivind Tungen, Marius Aursnes,
Trond Vidar Hansen and Anders Vik*
Cite this: DOI: 10.1039/c5ob00473j
Lipid mediators have attracted great interest from scientists within the chemical, medicinal, and pharma-
ceutical research community. One such example is leukotriene B4 which has been the subject of many
pharmacological studies. Herein, we report a convergent and stereoselective synthesis of this potent lipid
mediator in 5% yield over 10 steps in the longest linear sequence from commercial starting materials. The
key steps were a stereocontrolled acetate–aldol reaction with Nagao’s chiral auxiliary and a Z-selective
Boland reduction. All spectroscopic data were in agreement with those previously reported.
Received 10th March 2015,
Accepted 30th March 2015
DOI: 10.1039/c5ob00473j
www.rsc.org/obc
Introduction
Leukotriene B4 (LTB4, 1) is a highly potent pro-inflammatory
lipid mediator that promotes accumulation and activation of
leukocytes at sites of inflammation.1 In the first phase of acute
inflammation, this dihydroxylated polyunsaturated fatty acid
plays an important role, allowing leukocytes to cross from the
bloodstream and into the tissue at the site of injury or infec-
tion. LTB4 (1) mediates its biological effects through two G
protein-coupled receptors, BLT1 and BLT2.2 BLT1 appears to
mediate the major activities of LTB4 on leukocytes and is
important in inflammation, whereas BLT2 may be involved in
various aspects of cancer progression.3 The structure of LTB4
(1) was reported by Borgeat and Samuelsson in 1979.4 Shortly
thereafter the first total synthesis by Corey and co-workers
established the stereochemistry of the conjugated triene to be
6Z,8E,10E.5 The name leukotriene was coined to reflect two
attributes of this class of lipid mediators. The first relates to
those white blood cells, like the polymorphonuclear leuko-
cytes, that synthesize this class of eicosanoids, while the
second part of the name reflects the conjugated triene present
in the leukotrienes.6 LTB4 (1) is produced by enzymatic conver-
sion of arachidonic acid (2) as outlined in Fig. 1. First, inser-
Fig. 1 Outline of the biosynthesis of leukotriene B4 (1).
and E4. The latter three belongs to the cysteinyl leukotriene
class of natural products. These are formed by the addition of
glutathione on LTA4 (4) to form first LTC4, which is further
converted successively by peptidases to LTD4, and then LTE4.
Enzymatic hydrolysis of LTA4 (4) by LTA4 hydrolase produces
LTB4 (1). On the other hand, nonenzymatic hydrolysis of LTA4
(4) produces two all trans isomers of LTB4 (1) and two 4,5-di-
hydroxy eicosatetraenoic acids,7 all of which are lacking signifi-
cant biological activity.8 Further metabolism of LTB4 (1)
produces 20-OH and 20-COOH leukotriene B4,9 and these
metabolites have significantly lower biological activity than
LTB4 (1).10
tion of molecular oxygen at the 5-position of
2 by
5-lipoxygenase (5-LO) produces 5-(S)-hydroperoxyeicosatetrae-
noic acid (5-HPETE, 3), which is converted to leukotriene A4
(LTA4, 4) by the second catalytic activity of 5-LO, see Fig. 1.
LTA4 (4) is the precursor of LTB4, as well as leukotriene C4, D4
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo,
PO Box 1068 Blindern, N-0316 Oslo, Norway. E-mail: anders.vik@farmasi.uio.no,
k.g.primdahl@farmasi.uio.no, j.e.tungen@farmasi.uio.no,
marius.aursnes@farmasi.uio.no, t.v.hansen@farmasi.uio.no; Fax: +47 22855947;
Tel: +47 22857451
Although several syntheses of LTB4 (1) have been reported
in the literature,11 this highly potent lipid mediator is still of
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00473j
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was directly converted in a Colvin rearrangement to give the
terminal alkyne 13 in 57% yield over two steps.12d Oxidation
with Dess–Martin periodinane afforded the aldehyde 14,
which was treated with methyl (triphenylphosphoranylidene)
acetate to afford the α,β-unsaturated ester 15 in 88% yield.
Various procedures for the 1,4-reduction of the α,β-unsaturated
ester 15 were attempted. Tsuda and co-workers have reported
that selective 1,4-reductions of α,β-unsaturated esters may be
achieved using DIBAL-H in the presence of MeCu in a mixture
of HMPA and THF as the solvent.14 In our experiments, this
procedure gave low conversion of the starting material 15. We
then tried this reduction using the Stryker reagent.15 This gave
the ester 7 in 41% yield. Reduction using magnesium in
methanol16 proved to be the best method of those attempted,
affording ester 7 in 60% yield from 15.
Fig. 2 Retrosynthetic analysis of leukotriene B4 (1).
Aldehyde 6 was prepared in six steps from salt 16 essentially
as previously reported (Scheme 2).12a,b Commercially available
pyridinium-1-sulfonate (16) was treated with aqueous potassium
hydroxide to yield potassium salt 17,17 which was first treated
with PPh3/Br2 in dichloromethane, and then with p-TsOH in
diethyl ether, to form (2E,4E)-5-bromopenta-2,4-dienal 9 in 75%
yield over two steps.18 The aldehyde 9 was reacted with thiazoli-
dinone 819 in an acetate–aldol reaction to produce intermediate
1820 in a 15.3 : 1 diastereomeric ratio. Purification by chromato-
graphy yielded diastereomeric pure 18 in 92% yield. Next, pro-
tection of the secondary alcohol to give 19, followed by removal
of the chiral auxiliary with DIBAL-H afforded aldehyde 6 which
was used immediately in the next step.
interest to the scientific community. The stability of the conju-
gated Z,E,E-triene found in 1 is a challenge for all synthesis of
1. This moiety is prone to undergo isomerization in the pres-
ence of light, oxygen and acidic conditions. The instability of
the Z,E,E-triene is further intensified by the presence of two
chiral allylic alcohols, rendering this moiety prone to water
elimination. Based on our success with the acetate–aldol reac-
tion in recent synthesis of some lipid mediators,12 we were
motivated to demonstrate this strategy in an efficient and con-
vergent synthesis of LTB4 (1). The retrosynthetic analysis,
shown in Fig. 2, allows the installment of the sensitive Z,E,E-
triene at a late stage of the synthesis.
Regarding the assembly of the fragments, aldehyde 6 was
reacted in a Z-selective Wittig reaction with the ylide of com-
mercially available hexyltriphenylphosphonium bromide (5),
to afford vinyl bromide 20 in 74% yield from 19 (Scheme 3).
With NaHMDS as base, low temperatures and HMPA as a co-
solvent in the Wittig-reaction, only the Z-isomer could be
Results and discussion
Our synthesis of LTB4 (1) commenced with the preparation of
terminal alkyne 7 in six steps and 24% overall yield from com-
mercially available (S)-(−)-α-hydroxy-γ-butyrolactone (10), as
outlined in Scheme 1. Protection of 10 using TBS-triflate13 in
the presence of 2,6-lutidine in dichloromethane at −78 °C
afforded the protected alcohol 11. Reduction of the lactone in
11 with DIBAL-H produced the corresponding lactol 12 which
1
detected by H or 13C NMR analyses after purification.12a The
vinyl bromide 20 was reacted in a Sonogashira cross-coupling
Scheme 1 Synthesis of the terminal alkyne 7.
Scheme 2 Synthesis of the aldehyde 6.
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odinane (1.3 g, 3.0 mmol, 1.3 eq.) in dry CH2Cl2 (15 mL). The
mixture was stirred at room temperature for four hours before
it was quenched with a solution of sat. aq. Na2S2O3 (16 mL)
and sat. aq. NaHCO3 (16 mL). The layers were separated and
the aq. layer was extracted with Et2O (3 × 16 mL). The com-
bined organic layers were washed with brine (9.0 mL), dried
over MgSO4 and concentrated in vacuo. The crude product was
passed through a silica plug using hexane–EtOAc 8 : 2 as an
eluent to afford aldehyde 14 as a colorless oil. Yield: 0.41 g
(81%). TLC (hexane–EtOAc 8 : 2, KMnO4 stain): Rf = 0.40. Spec-
troscopic and physical data were in agreement with those
reported in the literature.25 1H NMR (300 MHz, CDCl3) δ 9.82
(t, J = 2.1 Hz, 1H), 4.86 (ddd, J = 6.9, 5.0, 2.2 Hz, 1H), 2.75 (m,
2H), 2.49 (d, J = 2.2 Hz, 1H), 0.88 (s, 9H), 0.16 (s, 3H), 0.13 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 200.18, 83.85, 73.85, 58.19,
51.45, 25.75 (3C), 18.19, −4.48, −5.09.
Scheme 3 Synthesis of leukotriene B4 (1).
Methyl (S,E)-5-((tert-butyldimethylsilyl)oxy)hept-2-en-6-ynoate
(15)
reaction21 with terminal alkyne 7 at room temperature in the
presence of catalytic Pd(PPh3)4 and CuI using diethyl amine as
a solvent. This afforded the conjugated dienyne 21 in 85%
yield. Removal of the two TBS-groups was achieved with five
equivalents of TBAF in THF at 0 °C to give the corresponding
diol 22 in 57% yield. The conjugated alkyne 22 was then
stereoselectively reduced. We first attempted a modified
Lindlar hydrogenation reaction.22 This gave a low yield of the
desired Z,E,E-triene 23 that was contaminated with by-pro-
ducts which we were unable to remove by chromatography.
The Boland reduction23 was then attempted. Gratifyingly, this
produced chemically pure LTB4 methyl ester (23) in an accepta-
ble 53% yield after chromatography. Finally, saponification of
the methyl ester 23 with dilute aqueous LiOH in a mixture of
methanol and THF at 0 °C followed by workup with aqueous
NaH2PO4 afforded LTB4 (1) in 78% yield (Scheme 3). All spec-
troscopic data of 1 were in agreement with those previously
reported.11a,c,d,24
To a solution of aldehyde 14 (0.27 g, 1.3 mmol, 1.0 eq.) in
CH2Cl2 (8.0 mL) was added methyl (triphenylphosphoranyli-
dene)acetate (0.56 g, 1.7 mmol, 1.3 eq.). After stirring for three
hours the solvent was removed in vacuo. The residue was
passed through a silica plug using hexane–EtOAc 8 : 2 as the
eluent to give the α,β-unsaturated methyl ester 15 as a colorless
oil. Yield: 0.30 g (88%); TLC (hexane–EtOAc 9 : 1, KMnO4
stain): Rf = 0.48; [α]2D0 = −42 (c = 0.20, MeOH); 1H NMR
(400 MHz, CDCl3) δ 6.97 (dt, J = 15.6, 7.3 Hz, 1H), 5.91 (dt, J =
15.8, 1.5 Hz, 1H), 4.45 (td, J = 6.2, 2.1 Hz, 1H), 3.73 (s, 3H),
2.57 (ddd, J = 7.5, 6.2, 1.4 Hz, 2H), 2.43 (d, J = 2.1 Hz, 1H), 0.89
(s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 166.78, 144.08, 123.95, 84.35, 73.28, 61.73, 51.62, 41.45,
25.83 (3C), 18.31, −4.47, −4.98. HRMS (TOF ES+): exact mass
calculated for C14H24O3Si2Na [M + Na]+: 291.1392, found
291.1388.
Methyl (S)-((tert-butyldimethylsilyl)oxy)hept-6-ynoate (7)
Magnesium turnings (0.27 g, 11 mmol, 10 eq.) (pre-dried in an
oven at 120 °C) were added to a solution of the α,β-unsaturated
methyl ester 15 (0.33 g, 1.2 mmol, 1.0 eq.) in MeOH (9.0 mL).
The mixture was stirred for two hours. The crude product was
passed through a short silica plug using hexane–EtOAc 8 : 2 as
the eluent before the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
(hexane–EtOAc 98 : 2) to afford the title compound 7 as a clear
oil. Yield: 0.20 g (60%). Spectroscopic and physical data were
in agreement with those reported in the literature.26 TLC
(hexane–EtOAc 9 : 1, KMnO4 stain): Rf = 0.48; [α]2D0 = −36 (c =
0.20, MeOH); 1H NMR (400 MHz, CDCl3) δ 4.37 (td, J = 6.0,
2.1 Hz, 1H), 3.67 (s, 3H), 2.35 (m, 3H), 1.83–1.66 (m, 4H), 0.90
(s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 173.97, 85.31, 72.46, 62.51, 51.63, 37.90, 33.81, 25.90 (3C),
Conclusions
In summary, a short and efficient total synthesis of the potent
inflammatory lipid mediator leukotriene B4 (1) has been
achieved over 10 steps (longest linear sequence) using 19 syn-
thetic operations in a non-optimized 5% overall yield. Our syn-
thesis of leukotriene B4 (1) compares well with those
previously reported.11 In particular, the acetate–aldol reaction
was central for this synthesis.
Experimental
(S)-3-((tert-Butyldimethylsilyl)oxy)pent-4-ynal (14)
A solution of alcohol 13 (0.52 g, 2.4 mmol, 1.0 eq.) in CH2Cl2 20.76, 18.33, −4.44, −4.96. HRMS (TOF ES+): exact mass calcu-
(8.0 mL) was added to a stirring solution of Dess–Martin peri- lated for C14H26O3SiNa [M + Na]+: 293.1548, found 293.1552.
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(R,1E,3E,7Z)-1-Bromo-5-((tert-butyldimethylsilyl)oxy)trideca-
1,3,7-trien-5-yl (20)
δ 174.05, 141.30, 139.48, 132.33, 128.51, 124.97, 110.48, 93.07,
83.77, 72.94, 63.27, 51.63, 38.09, 36.42, 33.88, 31.70, 29.44,
27.60, 26.03 (3C), 25.97 (3C), 22.73, 20.95, 18.43, 18.39, 14.23,
−4.27, −4.34, −4.60, −4.85. HRMS (TOF ES+): exact mass calcu-
lated for C33H60O4Si2Na [M + Na]+: 599.3930, found 599.3963.
Commercially available hexyltriphenylphosphonium bromide
(5) (1.8 g, 4.2 mmol, 2.0 eq.) was added to THF (40 mL) and
HMPA (5.0 mL), and the mixture was cooled to −78 °C before
NaHMDS (7.0 mL, 0.6 M in toluene, 2.0 eq.) was added drop-
wise. The resulting mixture was stirred for one hour. Then a
solution of freshly prepared aldehyde 6 in THF (5.0 mL) was
added dropwise at −78 °C. The solution was allowed to slowly
warm up to room temperature in the dry ice/acetone bath over
24 hours before it was quenched with aq. phosphate buffer
(30 mL, pH = 7.2). Et2O (50 mL) was added and the layers were
separated. The aq. layer was extracted with Et2O (2 × 50 mL)
and the combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. The crude product was purified by flash
chromatography on silica gel (hexane–EtOAc 97 : 3) to afford
the title compound 20 as a yellow oil. Yield: 0.60 g (74% yield
over two steps from 19). TLC (hexane–EtOAc, KMnO4 stain):
Rf = 0.66; [α]2D0 = −17 (c = 0.10, MeOH); 1H NMR (400 MHz,
CDCl3) δ 6.68 (dd, J = 13.5, 10.9 Hz, 1H), 6.27 (d, J = 13.5 Hz,
1H), 6.14–6.03 (m, 1H), 5.72 (dd, J = 15.2, 5.8 Hz, 1H),
5.50–5.41 (m, 1H), 5.38–5.29 (m, 1H), 4.14 (q, J = 5.8 Hz, 1H),
2.31–2.19 (m, 1H), 2.00 (q, J = 6.9 Hz, 2H), 1.38–1.23 (m, 6H),
0.93–0.86 (m, 12H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR
(400 MHz, CDCl3) δ 138.15, 137.20, 132.40, 126.54, 124.86,
108.17, 72.76, 36.30, 31.71, 29.44, 27.60, 26.02 (3C), 22.74,
18.42, 14.23, −4.37, −4.60. HRMS (CI+): exact mass calculated
for C19H35BrOSi [M + 1]+: 387.1719, found 387.1708.
Methyl (5S,6Z,8E,10E,12R,14Z)-5,12-dihydroxyicosa-8,10,14-
triene-6-ynoate (22)
TBAF (0.67 mL, 1.0 M in THF, 0.66 mmol, 5.0 eq.) was added
to a solution of 21 (76 mg, 0.13 mmol, 1.0 eq.) in THF (3.5 mL)
at 0 °C. The reaction was stirred for five hours at 0 °C, before it
was quenched with phosphate buffer (pH = 7.2, 2.0 mL). Brine
(3.5 mL) and CH2Cl2 (7.0 mL) were added and the layers were
separated. The aq. layer was extracted with CH2Cl2 (2 × 7.0 mL)
and the combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexane–EtOAc 6 : 4) to afford the
diol 22 as a pale yellow oil. Yield: 26 mg (57%). Spectroscopic
and physical data of 22 were in agreement with those reported
in the literature.26,27 TLC (hexane–EtOAc 4 : 6, KMnO4 stain):
Rf = 0.39; [α]2D0 = −10 (c = 0.05, MeOH); 1H NMR (300 MHz,
CD3OD) δ 6.55 (dd, J = 15.5, 10.8 Hz, 1H), 6.27 (dd, J = 15.3,
10.9 Hz, 1H), 5.81 (dd, J = 15.2, 6.3 Hz, 1H), 5.66 (d, J = 15.5,
1H), 5.43 (m, 2H), 4.45 (dd, J = 6.5, 1.7 Hz, 1H), 4.12 (q, J =
6.2 Hz, 1H) 3.66 (s, 3H), 2.38 (t, J = 7.0 Hz, 2H), 2.29 (m, 2H),
2.04 (q, J = 6.8 Hz, 2H), 1.84–1.62 (m, 4H) 1.40–1.25 (m, 6H),
0.90 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 175.62,
142.53, 139.92, 133.19, 130.24, 125.85, 111.64, 93.66, 84.37,
72.80, 62.88, 52.01, 38.23, 36.25, 34.38, 32.67, 30.40, 28.38,
23.64, 21.93, 14.45; HRMS (TOF ES+): exact mass calculated for
C21H32O4Na [M + Na]+: 371.2198, found 371.2205.
Methyl (5S,8E,10E,12R,14Z)-5,12-bis((tert-butyldimethylsilyl)-
oxy)icosa-8,10,14-trien-6-ynoate (21)
Methyl (5S,6Z,8E,10E,12R,14Z)-5,12-dihydroxy-6,8,10,14-
icosatetraenoate (23)
To a solution of vinyl bromide 20 (0.29 g, 0.74 mmol, 1.0 eq.)
in Et2NH (3.3 mL) and benzene (0.6 mL), Pd(PPh3)4 (26 mg,
0.02 mmol, 3.0 mol%) was added and the reaction was stirred The Zn(Cu/Ag) mixture was prepared as described by Boland
for 45 min in the dark. CuI (7.0 mg, 0.04 mmol, 5.0 mol%) in et al.23 Zinc dust (1.8 g) was stirred under argon for 15 min.
a minimum amount of Et2NH was added followed by dropwise Cu(OAc)2 (0.18 g) was then added and the reaction mixture was
addition of alkyne 7 (0.20 mg, 0.74 mmol, 1.0 eq.) in Et2NH stirred for 15 min, before AgNO3 (0.18 g) was added and the
(1.5 mL). After stirring for 20 hours at room temperature, the solution was stirred for an additional 30 minutes. The mixture
reaction was quenched by addition of saturated aq. NH4Cl was filtered and washed successively with H2O, MeOH,
(20 mL). Et2O (15 mL) was added and the layers were separ- acetone and Et2O before it was transferred to a flask contain-
ated. The aq. layer was extracted with Et2O (2 × 20 mL) and the ing the reaction solvents (MeOH–H2O, 1 : 1, 7.4 mL). A solution
combined organic layers were dried (Na2SO4) and evaporated of alkyne 22 (26 mg, 0.080 mmol) in MeOH–H2O (1 : 1, 1.0 mL)
in vacuo. The crude product was purified by flash chromato- was added and the mixture was stirred at room temperature
graphy on silica gel (hexane–EtOAc 98 : 2) to afford the title and in the dark for five hours. The reaction mixture was fil-
compound 21 as a yellow oil in 85% yield (0.36 g). Spectro- tered through a pad of Celite and washed with Et2O. Water was
scopic and physical data were in agreement with those added to the filtrate, and the organic layers were separated and
reported in the literature.26 TLC (hexane–EtOAc 95 : 5, KMnO4 the aq. layer was extracted with Et2O (2 × 5.0 mL). The com-
stain): Rf = 0.28; [α]2D0 = −33 (c = 0.14, MeOH); 1H NMR bined organic layers were washed with brine and dried
(400 MHz, CDCl3) δ 6.51 (dd, J = 15.5, 10.8 Hz, 1H), 6.18 (dd, (Na2SO4). The solvent was removed in vacuo and the crude
J = 15.2, 10.9 Hz, 1H), 5.77 (dd, J = 15.2, 5.9 Hz, 1H), 5.57 (d, product was purified by column chromatography on silica gel
J = 15.6 Hz, 1H), 5.45 (m, 1H), 5.34 (m, 1H), 4.50 (t, J = 5.2 Hz, (hexane–EtOAc 1 : 1) to afford the methyl ester 23 in 54% yield
1H), 4.17 (q, J = 6.0 Hz, 1H), 3.67 (s, 3H), 2.35 (t, J = 7.2 Hz, (14 mg). Spectroscopic and physical data for 23 were in agree-
2H), 2.25 (m, 2H), 2.00 (q, J = 7.2 Hz, 2H), 1.75 (m, 4H), ment with those reported in the literature.11c,26,27 TLC
1.27–1.10 (m, 6H), 0.82–0.74 (m, 21H), 0.13 (s, 3H), 0.11 (heptane–EtOAc 2 : 8, KMnO4 stain): Rf = 0.60; [α]2D0 = 5.6 (c =
(s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) 0.050, CCl4); UV (MeOH) λmax 261, 270, 281 nm; 1H NMR
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(600 MHz, CD3OD) δ 6.54 (m, 1H), 6.27 (m, 2H), 6.08 (t, J =
11.1 Hz, 1H), 5.75 (dd, J = 14.5, 6.6 Hz, 1H), 5.53–5.32 (m, 3H),
4.56 (q, J = 8.0 Hz, 1H), 4.12 (q, J = 6.6 Hz, 1H), 3.65 (s, 3H),
2.39–2.21 (m, 4H), 2.04 (q, J = 6.9 Hz, 2H), 1.70–1.58 (m, 2H),
1.50–1.28 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (151 MHz,
CD3OD) δ 175.75, 138.11, 135.10, 135.08, 133.08, 131.33,
130.56, 128.65, 126.00, 73.14, 68.12, 51.99, 37.91, 36.36, 34.61,
32.68, 30.41, 28.39, 23.65, 22.01, 14.43; HRMS (TOF ES+): exact
mass calculated for C21H34O4Na [M + Na]+: 373.2354, found
373.2362.
4 P. Borgeat and B. Samuelsson, J. Biol. Chem., 1979, 254,
2643.
5 E. J. Corey, A. Marfat, G. Goto and F. Brion, J. Am. Chem.
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7865.
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and B. Samuelsson, FEBS Lett., 1981, 130, 107;
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(5S,6Z,8E,10E,12R,14Z)-5,12-Dihydroxy-6,8,10,15-
icosatetraenoic acid (LTB4, 1)
To a solution of methyl ester 23 (5.1 mg, 0.014 mmol, 1 eq.) in
THF–MeOH–H2O (2 : 2 : 1, 1.7 mL), solid LiOH (10 mg,
0.43 mmol, 31 eq.) was added at 0 °C. The reaction mixture
was stirred at 0 °C for three hours and then allowed to warm
up to room temperature. The solution was acidified with sat.
aq. NaH2PO4 (1.9 mL). EtOAc (2.0 mL) was added and the
layers were separated. The aq. layer was extracted with EtOAc
(2 × 2.0 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (CH2Cl2–MeOH 95 : 5) to
afford LTB4 (1) in 78% yield (3.8 mg). Spectroscopic and physi-
cal data were in agreement with those reported in the litera-
10 A. W. Ford-Hutchinson, A. Rackham, R. Zamboni,
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ture.11a,c,d,24 TLC (CH2Cl2–MeOH 95 : 5, KMnO4 stain): Rf
=
0.10; [α]2D0 = 12 (c = 0.050, CHCl3); UV (MeOH) λmax 261, 270,
1
281 nm; H NMR (600 MHz, CD3OD) δ 6.54 (dd, J = 14.1, 11.7
Hz, 1H), 6.33–6.19 (m, 2H), 6.08 (t, J = 11.2 Hz, 1H), 5.74 (dd,
J = 14.7, 6.6 Hz, 1H), 5.51–5.31 (m, 3H), 4.60–4.53 (m, 1H),
4.11 (q, J = 6.5 Hz, 1H), 2.36–2.21 (m, 4H), 2.04 (q, J = 7.2 Hz,
2H), 1.70–1.59 (m, 2H), 1.51–1.42 (m, 1H), 1.38–1.25 (m, 7H),
0.90 (t, J = 6.9 Hz, 3H); 13C NMR (151 MHz, CD3OD) δ 180.19,
138.00, 135.25, 135.00, 133.07, 131.41, 130.49, 128.78, 126.01,
73.15, 68.26, 38.28, 36.46, 36.35, 32.68, 30.42, 28.39, 23.65,
22.63, 14.43; HRMS (TOF ES+): exact mass calculated for
C20H32O4Na [M + Na]+: 359.2198, found 359.2203.
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Acknowledgements
The School of Pharmacy, University of Oslo is gratefully
acknowledged for Ph.D. scholarships to K. G. P. and J. E. T.
The Norwegian Research Council is acknowledged for a post-
doctoral research grant to M. A.
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