Practical, Asymmetric Synthesis of 16-Hydroxyeicosa-5(Z),8(Z),
11(Z),14(Z)-tetraenoic Acid (16-HETE), an Endogenous Inhibitor
of Neutrophil Activity
Y. Krishna Reddy,
a
L. Manmohan Reddy,
a
Jorge H. Capdevila
b
and J. R. Falck
a,
*
a
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
b
Departments of Medicine and Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Received 20 May 2003; revised 5 August 2003; accepted 6 August 2003
Abstract—An asymmetric synthesis of 16-HETE, an endogenous inhibitor of neutrophil activity, was achieved in six steps from
R-(À)-glycidyl benzyl ether in 28% overall yield.
# 2003 Elsevier Ltd. All rights reserved.
16-Hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid
(16-HETE, 1),
1
a metabolite of the cytochrome P450
branch of the arachidonate cascade,
2
has attracted con-
siderable attention as a vasodilator
3
and as the first
endogenous lipidic inhibitor of human neutrophil adhe-
sion and aggregation.
4
The latter activity may be useful
for therapeutic intervention in acute ischemic brain
injury.
5
However, progress in exploring the pharmacol-
ogy of 1 has been trammeled by its limited availability
from natural sources
6
and its co-occurrence, in most
instances,
7
with structurally similar regioisomers.
Herein, we report a practical, asymmetric synthesis
8,9
of
both enantiomers of 1. Importantly, this strategy is
amenable to escalation of scale and also provides access
to stable- or radio-isotopically labeled 1 without alter-
ing the synthetic route.
10
In a one pot procedure (Scheme 1), n-propyl Grignard
was added under copper catalysis to commercial R-(À)-
glycidyl benzyl ether (2) at low temperature and the
newly generated alcoholate
11
was quenched with ben-
zoyl chloride affording benzoate 3.
12
Debenzylation via
catalytic hydrogenation and Swern oxidation provided
aldehyde 4.
13
Condensation of 4 with 13-carboxytrideca-
3(Z),6(Z),9(Z) - trien - 1 - ylidenetriphenylphosphorane
10
(9) and diazomethane esterification yielded methyl ester
5.
9
Adduct 5 was most conveniently resolved chromato-
graphically
14
from a minor amount of Á
14,15
-trans iso-
mer ( $5%) following solvolytic conversion to methyl
16(R)-HETE (6).
8
The enantiomer, methyl 16(S)-HETE
(8), was secured via Mitsunobu inversion of 6 and
methanolysis of the resultant benzoate 7. Saponification
(NaOH, THF/H
2
O, 23
C, 6–10h, 90–95%) of 5–8 and
extractive isolation furnished the corresponding free
acids as colorless oils.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.08.005
Bioorganic & Medicinal Chemistry Letters 13 (2003) 3719–3720
Scheme 1. Reagents and conditions: (a) n-PrMgCl, 10mol% CuCN,
THF, À20to 0
C, 12 h; (b) PhC(O)Cl, 0–23
C, 12 h; (c) 10% Pd/C,
H
2
(1 atm), EtOAc, 23
C, 4 h; (d) DMSO, (COCl)
2
,CH
2
Cl
2
, À78
C,
1h;Et
3
N, À78 to 23
C, 1 h; (e) 9, LiN(SiMe
3
)
2
, THF/HMPA (4:1),
À78
C, 1.5 h; CH
2
N
2
, 1 h; (f) NaOMe, MeOH, 23
C, 8 h; (g)
PhCO
2
H, DEAD, Ph
3
P, THF, 23
C, 4 h.
*Corresponding author. Tel.: +1-214-648-2406; fax: +1-214-648-
6455; e-mail: j.falck@utsouthwestern.edu