Practical, asymmetric synthesis of 16-hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid (16-HETE), an endogenous inhibitor of neutrophil activity

Article abstract of DOI:10.1016/j.bmcl.2003.08.005

An asymmetric synthesis of 16-HETE, an endogenous inhibitor of neutrophil activity, was achieved in six steps from R-(-)-glycidyl benzyl ether in 28% overall yield.

Full text of DOI:10.1016/j.bmcl.2003.08.005

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3719–3720
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. Capdevilab and J. R. Falcka,*
aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
bDepartments 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 vasodilator3 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 sources6 and its co-occurrence, in most
instances,7 with structurally similar regioisomers.
Herein, we report a practical, asymmetric synthesis8,9 of
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,
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
H2 (1 atm), EtOAc, 23 ꢁC, 4 h; (d) DMSO, (COCl)2, CH2Cl2, À78 ꢁC,
1 h; Et3N, À78 to 23 ꢁC, 1 h; (e) 9, LiN(SiMe3)2, THF/HMPA (4:1),
À78 ꢁC, 1.5 h; CH2N2, 1 h; (f) NaOMe, MeOH, 23 ꢁC, 8 h; (g)
PhCO2H, DEAD, Ph3P, THF, 23 ꢁC, 4 h.
catalytic hydrogenation and Swern oxidation provided
aldehyde 4.13 Condensation of 4 with 13-carboxytrideca-
3(Z),6(Z),9(Z) - trien - 1 - ylidenetriphenylphosphorane10
(9) and diazomethane esterification yielded methyl ester
5.9 Adduct 5 was most conveniently resolved chromato-
graphically14 from a minor amount of Á14,15-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/H2O, 23 ꢁC, 6–10h, 90–95%) of 5–8 and
extractive isolation furnished the corresponding free
acids as colorless oils.
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 alcoholate11 was quenched with ben-
zoyl chloride affording benzoate 3.12 Debenzylation via
*Corresponding author. Tel.: +1-214-648-2406; fax: +1-214-648-
6455; e-mail: j.falck@utsouthwestern.edu
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.08.005

3720
Y. K. Reddy et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3719–3720
7. Tsao, C.-C.; Foley, J.; Coulter, S. J.; Maronpot, R.;
Acknowledgements
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279.
8. Chiral synthesis: Heckmann, B.; Mioskowski, C.; Lumin,
S.; Falck, J. R.; Wei, S.; Capdevila, J. H. Tetrahedron Lett.
1996, 37, 1425.
9. Racemic synthesis: Ivanov, I. V.; Romanov, S. G.; Groza,
N. V.; Nigam, S.; Kuhn, H.; Myagkova, G. I. Bioorg. Med.
Chem. 2002, 10, 2335.
10. Phosphorane 9 is prepared from either commercial unla-
beled or isotopically labeled arachidonic acid: Yu, M.;
Alonso-Galicia, M.; Sun, C.-W.; Roman, R. J.; Ono, N.; Hir-
ano, H.; Ishimoto, T.; Reddy, Y. K.; Katipally, K. R.; Reddy,
K. M.; Gopal, V. R.; Yu, J.; Takhi, M. J. R.; Falck, J. R.
Bioorg. Med. Chem. 2003, 11, 2803.
Supported financially by the USPHS NIH (DK38226,
GM37922) and the Robert A. Welch Foundation. The
authors are grateful to Dr. Naoya Ono for his critical
review of the manuscript.
References and Notes
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3. Macica, C.; Balazy, M.; Falck, J. R.; Mioskowski, C.;
Carroll, M. A. Am. J. Physiol. 1993, 265, G735.
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Balazy, M. Neurosurgery 2000, 47, 1410.
5. Bednar, M. M.; Gross, C. E.; Balazy, M.; Falck, J. R.
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12. 1H NMR (400 MHz, CDCl3) of 3: d 0.88 (t, J=6.6 Hz,
3H), 1.24–1.42 (m, 4H), 1.70–1.80 (m, 2H), 3.60–3.70 (m, 2H),
4.57 (ABq, J=10.3, 29.4 Hz, 2H), 5.32 (quintet, J=4.4 Hz,
1H), 7.24–7.34 (m, 5H), 7.45 (t, J=7.5 Hz, 2H), 7.56 (t, J=7.5
Hz, 1H), 8.06 (d, J=7.5 Hz, 2H).
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14. HPLC: microsorb silica (10Â250mm), 0.4% 2-propanol/
hexane, 6 mL/min flow rate, UV detection at 206 nm, Rt
ꢀ34.5 min.