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,
L. Manmohan Reddy,
Jorge H. Capdevila
and J. R. Falck
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
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.
a metabolite of the cytochrome P450
branch of the arachidonate cascade,
has attracted con-
siderable attention as a vasodilator
and as the ﬁrst
endogenous lipidic inhibitor of human neutrophil adhe-
sion and aggregation.
The latter activity may be useful
for therapeutic intervention in acute ischemic brain
However, progress in exploring the pharmacol-
ogy of 1 has been trammeled by its limited availability
from natural sources
and its co-occurrence, in most
with structurally similar regioisomers.
Herein, we report a practical, asymmetric synthesis
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.
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
was quenched with ben-
zoyl chloride aﬀording benzoate 3.
catalytic hydrogenation and Swern oxidation provided
Condensation of 4 with 13-carboxytrideca-
3(Z),6(Z),9(Z) - trien - 1 - ylidenetriphenylphosphorane
(9) and diazomethane esteriﬁcation yielded methyl ester
Adduct 5 was most conveniently resolved chromato-
from a minor amount of Á
mer ( $5%) following solvolytic conversion to methyl
The enantiomer, methyl 16(S)-HETE
(8), was secured via Mitsunobu inversion of 6 and
methanolysis of the resultant benzoate 7. Saponiﬁcation
C, 6–10h, 90–95%) of 5–8 and
extractive isolation furnished the corresponding free
acids as colorless oils.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
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,
(1 atm), EtOAc, 23
C, 4 h; (d) DMSO, (COCl)
N, À78 to 23
C, 1 h; (e) 9, LiN(SiMe
, THF/HMPA (4:1),
C, 1.5 h; CH
, 1 h; (f) NaOMe, MeOH, 23
C, 8 h; (g)
H, DEAD, Ph
P, THF, 23
C, 4 h.
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