A practical, stereospecific route to 18-, 19-, and 20-hydroxyeicosa-5(Z), 8(Z),11(Z),14(Z)-tetraenoic acids (18-, 19-, and 20-HETEs)

Article abstract of DOI:10.1016/j.tetlet.2004.01.151

Suzuki-Miyaura cross-coupling of cis-vinylbromide 6, obtained in three steps from diol 4, with functionalized boranes provides a practical, stereospecific route to the title CYP P450 eicosanoids.

Full text of DOI:10.1016/j.tetlet.2004.01.151

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2563–2565
A practical, stereospecific route to 18-, 19-, and 20-hydroxyeicosa-
5(Z),8(Z),11(Z),14(Z)-tetraenoic acids (18-, 19-, and 20-HETEs)
V. Raj Gopal,a S. G. Jagadeesh,a Y. Krishna Reddy,a A. Bandyopadhyay,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 5 January 2004; revised 28 January 2004; accepted 30 January 2004
Abstract—Suzuki–Miyaura cross-coupling of cis-vinylbromide 6, obtained in three steps from diol 4, with functionalized boranes
provides a practical, stereospecific route to the title CYP P450 eicosanoids.
Ó 2004 Elsevier Ltd. All rights reserved.
Recent investigations have demonstrated that 18-, 19-,
and 20-hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic
acids (1–3, respectively), metabolites of the cytochrome
P450 branch of the arachidonic acid cascade,1 are pow-
erful mediators of ion transport2 and vascular reactiv-
ity.3 Since 1–3 are available from natural sources in only
minute amounts, several asymmetric total syntheses have
been published.4;5 Notably, all of these approaches utilize
a Wittig condensation to generate the critical D14;15-ole-
fin. This often affords poor yields and invariably results
in mixtures of cis/trans-isomers that require tedious
chromatographic separation. Herein, we describe a
convenient, stereocontrolled route to 1–3 based on the
Suzuki–Miyaura cross-coupling of a readily available
cis-vinylbromide with suitably functionalized boranes.
Our strategy is amenable to large scale operations as well
as the preparation of stable- or radio-isotopically labeled
products using commercial precursors.
Low temperature cleavage of diol 44a;6 using lead tetra-
acetate generated a somewhat labile b,c-unsaturated
aldehyde4g;6 that was subjected to Corey–Fuchs olefin-
ation without delay (Scheme 1).7 Tin hydride reduction8
of the resultant dibromide 59 provided cis-vinylbromide
6 in good overall yield. None of the isomeric trans-olefin
could be detected by NMR analysis. Subsequent
Suzuki–Miyaura cross-coupling10 of 6 at room temper-
ature with the boranes arising from addition of 9-BBN
to olefins 15, 19, and 20 smoothly led to adducts 7, 9,
and 11, respectively. Mild acidic hydrolysis of 7 afforded
methyl 18(R)-hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tet-
raenoate4d;f (8) whereas fluoride mediated desilylation of
Scheme 1. Reagents and conditions: (a) Pb(OAc)4, CH2Cl2, )20 °C,
40 min; (b) PPh3, CBr4, CH2Cl2, 0 °C, 2 h; (c) n-Bu3SnH, C6H6,
Pd(PPh3)4, 23 °C, 14 h; (d) 15/19/20 (1.5 equiv), 9-BBN-H, THF, 23 °C,
3 h; Cs2CO3 (1.5 equiv), Ph3As (10 mol %), Pd(dppf)Cl2 (15 mol%),
THF/DMF/H2O (1:3.5:0.8), 23 °C, 6 h; (e) PTSA (cat.), MeOH, 65 °C,
6 h; (f) n-Bu4NF (2 equiv), THF, 23 °C, 12 h.
Keywords: Eicosanoids; Suzuki reactions; Lipids; Biologically active
compounds.
* Corresponding author. Tel.: +1-214-648-2406; fax: +1-214-648-6455;
e-mail: j.falck@utsouthwestern.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.151

2564
V. R. Gopal et al. / Tetrahedron Letters 45 (2004) 2563–2565
Schwartzman, M. Biochem. Biophys. Res. Commun. 1988,
and 11 furnished methyl 19(R)-hydroxyeicosa-
9
5(Z),8(Z),11(Z),14(Z)-tetraenoate4c (10) and methyl 20-
hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoate4g (12),
respectively. Saponification (NaOH, THF/H2O, 23 °C,
6–8 h, 94–98%) of the foregoing esters and extractive
isolation gave free acids (R)-1, (R)-2, and 3 as colorless
oils identical in all respects with authentic material.4
152, 1269; (d) Falck, J. R.; Sun, L.; Lee, S. G.; Heckmann,
B.; Mioskowski, C.; Karara, A.; Capdevila, J. Tetrahedron
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Yu, M.; Alonso-Galicia, M.; Sun, C.-W.; Roman, R. J.;
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Takhi, M.; Falck, J. R. Bioorg. Med. Chem. 2003, 11,
2803.
2-Deoxy-a-D-glucosides 15 and 16 (Eq. 1) were conve-
niently accessed via Ph3PÆHBr catalyzed11 addition of
( )-1-penten-3-ol (13) to commercial 3,4,6-tri-O-benzyl-
5. Alternative approaches: (a) chromatographic resolution,
Oliw, E. H. J. Chromatogr. 1990, 526, 525; (b) Enzymatic
incubation, Prabhune, A.; Fox, S. R.; Ratledge, C.
Biotechnol. Lett. 2002, 24, 1041; (c) Polyacetylene alkyl-
ation, Romanov, S. G.; Ivanov, I. V.; Groza, N. V.; Kuhn,
H.; Myagkova, G. I. Tetrahedron 2002, 58, 8483.
D
-glucal (14) and chromatographic separation of the
diastereomers over silica gel [EtOAc/hexane (15:85),
Rf ꢀ 0:53 and 0.46, respectively].
6. Ryan, W. J.; Banner, K. W.; Wiley, J. L.; Martin, B. R.;
Razdan, R. K. J. Med. Chem. 1997, 40, 3617.
7. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
8. Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J.
Org. Chem. 1996, 61, 5716.
9. Physical and spectral data for 5: 1H NMR (CDCl3,
400 MHz) d 6.36 (t, 1H, J ¼ 7:3 Hz), 5.54–5.30 (m, 6H),
3.67 (s, 3H), 2.92–2.78 (m, 6H), 2.32 (t, 2H, J ¼ 7:3 Hz),
2.18–2.06 (m, 2H), 1.71 (quintet, 2H, J ¼ 7:3 Hz); 13C
NMR (CDCl3, 75 MHz) d 174.11, 136.68, 130.45, 129.19,
128.82, 128.76, 127.63, 124.31, 89.50, 51.62, 33.55, 31.54,
26.71, 25.92, 25.78, 24.89. 6: 1H NMR (CDCl3, 400 MHz)
d 6.17 (dt, J ¼ 1:5, 7.0 Hz, 1H) 6.07 (ddd, J ¼ 7:0, 7.0,
7.0 Hz, 1H), 5.50–5.32 (m, 6H), 3.66 (s, 3H), 2.98 (t,
J ¼ 6:4 Hz, 2H), 2.86 (t, J ¼ 6:1 Hz, 2H), 2.81 (t,
J ¼ 5:4 Hz, 2H), 2.32 (t, J ¼ 7:3 Hz, 2H), 2.18–2.06 (m,
2H), 1.70 (quintet, J ¼ 7:3 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 173.96, 133.02, 129.75, 129.09, 128.85, 128.48,
ð1Þ
Olefins 19 and 20 were prepared in excellent yields by
silylation of commercial (R)-())-4-penten-2-ol (17,
Aldrich Chem. Co.) and 4-penten-1-ol (18), respectively,
using standard reaction conditions (Eq. 2).
ð2Þ
127.83, 125.54, 108.05, 51.49, 33.46, 28.38, 26.63, 25.84,
23
D
25.70, 24.83. 7: ½aꢁ +45.44 (c 1.25, CHCl3); 1H NMR
Enantiomers (S)-1 and (S)-2 were obtained analogously
and in comparable yields from 16 and (S)-(+)-4-penten-
2-ol (Aldrich Chem. Co.), respectively.
(CDCl3, 400 MHz) d 7.35–7.25 (m, 13H), 7.18–7.16 (m,
2H), 5.40–5.30 (m, 8H), 5.04 (d, J ¼ 3:0 Hz, 1H), 4.88 (d,
J ¼ 10:9 Hz, 1H), 4.69–4.62 (m, 3H), 4.50 (dd, J ¼ 10:6,
5.8 Hz, 2H), 4.01–3.95 (m, 1H), 3.86 (br d, J ¼ 9:4 Hz,
1H), 3.79 (dd, J ¼ 10:3, 3.6 Hz, 1H), 3.65 (s, 3H), 3.64–
3.51 (m, 3H), 2.84–2.70 (m, 6H), 2.31 (t, J ¼ 7:6 Hz, 2H),
2.24 (dd, J ¼ 12:8, 4.9 Hz, 1H), 2.12–2.04 (m, 4H), 1.76–
1.66 (m, 3H), 1.57–1.49 (m, 4H), 0.87 (t, J ¼ 7:3 Hz, 3H);
13C NMR (CDCl3, 75 MHz) d 174.14, 138.90, 138.67,
138.32, 130.01, 129.10, 128.94, 128.48, 128.44, 128.32,
128.25, 128.18, 128.12, 127.98, 127.71, 127.63, 96.60,
78.58, 78.27, 77.93, 75.12, 73.58, 71.90, 71.15, 69.05,
Acknowledgements
Supported financially by the USPHS NIH (GM37922
and 31278) and the Robert A. Welch Foundation.
51.60, 36.16, 33.54, 32.72, 30.51, 27.45, 26.66, 25.75, 24.89,
23
References and notes
22.95, 10.04. Adduct of 6 with 16: ½aꢁ +57.1(c 0.9,
CHCl3); 1H NMR (CDCl3, 400 MHz) dD 7.38–7.22 (m,
13H), 7.20–7.14 (m, 2H), 5.46–5.27 (m, 8H), 5.08 (d,
J ¼ 2:7 Hz, 1H), 4.89 (d, J ¼ 10:6 Hz, 1H), 4.61–4.71 (m,
3H), 4.50 (dd, J ¼ 10:3, 8.8 Hz, 2H), 4.04–3.94 (m, 1H),
3.88–3.83 (m,1H), 3.80 (dd, J ¼ 10:3, 3.6 Hz, 1H), 3.66 (s,
3H), 3.65–3.55 (m, 3H), 2.88–2.72 (m, 6H), 2.32 (t,
J ¼ 7:6 Hz, 2H), 2.24 (dd, J ¼ 12:8, 4.9 Hz, 1H), 2.18–
2.02 (m, 4H), 1.76–1.66 (m, 3H), 1.62–1.44 (m, 4H), 0.87
(t, J ¼ 7:3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 174.13,
138.89, 138.69, 138.29, 130.01, 129.05, 128.96, 128.51,
128.47, 128.42, 128.33, 128.26, 128.12, 128.04, 128.03,
127.98, 127.70, 127.68, 127.65, 127.61, 95.98, 78.54, 77.93,
77.34, 75.06, 73.56, 71.90, 71.22, 69.01, 51.59, 36.06, 34.10,
1. Review: Capdevila, J. H.; Harris, R. C.; Falck, J. R. Cell.
Mol. Life Sci. 2002, 59, 780.
2. (a) Ito, O.; Roman, R. J. Hypertension 1999, 33, 419; (b)
Silverstein, D. M.; Barac-Nieto, M.; Falck, J. R.; Spitzer,
A. Prost. Leuk. Essent. Fat. Acids 1998, 58, 209; (c) Zou,
A. P.; Drummond, H. A.; Roman, R. J. Prost. Leuk.
Essent. Fat. Acids 1996, 27, 631; (d) Macica, C.; Balazy,
M.; Falck, J. R.; Mioskowski, C.; Carroll, M. A. Am. J.
Physiol. 1993, 265, G735.
3. (a) Roman, R. J. Physiol. Rev. 2002, 82, 131–185; (b)
Carroll, M. A.; Balazy, M.; Margiotta, P.; Huang, D.-D.;
Falck, J. R.; McGiff, J. C. Am. J. Physiol. 1996, 271, R863.
4. (a) Manna, S.; Falck, J. R.; Chacos, N.; Capdevila, J.
Tetrahedron Lett. 1983, 24, 33; (b) Corey, E. J.; Iguchi, S.;
Albright, J. O.; De, B. Tetrahedron Lett. 1983, 24, 37; (c)
Escalante, B.; Falck, J. R.; Yadagiri, P.; Sun, L.; Laniado-
33.52, 32.17, 26.65, 26.35, 25.71, 25.47, 24.88, 23.52, 22.12,
23
D
9.18. 9: ½aꢁ +16.5 (c 1.25 CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.68–7.66 (m, 4H), 7.43–7.34 (m, 6H), 5.40–
5.30 (m, 8H), 3.84 (sextet, J ¼ 5:8 Hz, 1H), 3.66 (s, 3H),

V. R. Gopal et al. / Tetrahedron Letters 45 (2004) 2563–2565
2565
2.83–2.74 (m, 6H), 2.31 (t, J ¼ 7:7 Hz, 2H), 2.10 (q,
J ¼ 6:4 Hz, 2H), 1.95 (q, J ¼ 5:5 Hz, 2H), 1.70 (quintet,
J ¼ 7:3 Hz, 2H), 1.50–1.30 (m, 4H), 1.06–1.05 (m, 12H);
13C NMR (CDCl3, 75 MHz) d 174.25, 136.08, 135.10,
134.76, 130.45, 129.65, 129.57, 129.14, 129.06, 128.72,
128.39, 128.09, 127.92, 127.66, 127.58, 69.67, 51.68, 39.20,
(CDCl3, 75 MHz) d 138.96, 138.72, 137.90, 128.52, 128.47,
128.16, 127.99, 127.75, 127.73, 127.65, 118.13, 94.08,
78.65, 78.09, 78.05, 75.18, 73.58, 71.92, 71.12, 69.13,
23
D
35.14, 28.49, 10.09. 16: ½aꢁ +92.3 (c 2.0, CHCl3); 1H
NMR (CDCl3, 400 MHz) d 7.37–7.25 (m, 13H), 7.18–7.16
(m, 2H), 5.80–5.72 (m, 1H), 5.18–5.04 (m, 3H), 4.89 (d,
J ¼ 10:7 Hz, 1H), 4.74–4.64 (m, 3H), 4.50 (t, J ¼ 10:9 Hz,
2H), 4.04–3.91 (m, 2H), 3.84–3.77 (m, 2H), 3.67–3.59 (m,
2H), 2.29 (dd, J ¼ 12:8, 4.9 Hz, 1H), 1.74 (td, 1H,
J ¼ 12:5, 3.7 Hz, 1H), 1.63–1.47 (m, 2H), 0.86 (t,
J ¼ 7:3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 139.06,
138.97, 138.73, 128.54, 128.49, 128.47, 128.17, 128.05,
127.76, 127.67,115.58, 96.55, 79.41, 78.55, 77.97, 75.19,
33.63, 27.39, 27.24, 26.75, 25.81, 25.40, 24.97, 23.42, 19.47.
23
D
10: ½aꢁ )2.96 (c 1.55, CHCl3); 1H NMR (CDCl3,
400 MHz) d 5.43–5.33 (m, 8H), 3.80 (sextet, J ¼ 5:8 Hz,
1H), 3.66 (s, 3H), 2.84–2.79 (m, 6H), 2.32 (t, J ¼ 7:4 Hz,
2H), 2.10 (quintet, J ¼ 7:3 Hz, 4H), 1.70 (quintet,
J ¼ 7:6 Hz, 2H), 1.50–1.38 (m, 4H), 1.19 (d, J ¼ 6:1 Hz,
3H); 13C NMR (CDCl3, 75 MHz) d 174.30, 130.15, 129.12,
129.04, 128.59, 128.37, 128.32, 128.20, 128.15, 68.18,
51.70, 39.06, 33.62, 27.32 26.73, 25.93, 25.83, 25.81,
25.79, 24.95, 23.70. 11: 1H NMR (CDCl3, 400 MHz) d
7.67–7.65 (m, 4H), 7.44–7.35 (m, 6H), 5.41–5.30 (m, 8H),
3.66–3.63 (m, 5H), 2.84–2.77 (m, 6H), 2.31 (t, J ¼ 7:3 Hz,
2H), 2.12–2.02 (m, 4H), 1.69 (quintet, J ¼ 7:6 Hz, 2H),
1.58–1.53 (m, 2H), 1.40–1.31 (m, 4H), 1.04 (s, 9H); 13C
NMR (CDCl3, 75 MHz) d 174.18, 135.73, 134.29, 133.88,
130.47, 129.66, 129.09, 129.03, 128.82, 128.71, 128.61,
128.34, 128.07, 127.82, 127.74, 64.07, 51.63, 33.58, 32.66,
29.88, 29.56, 27.40, 27.04, 26.71, 25.80, 25.78, 25.65, 24.94,
73.58, 71.98, 71.00, 68.80, 35.93, 27.23, 9.45. 19: ½aꢁ23 +9.18
D
(c 0.35, acetone); 1H NMR (CDCl3, 400 MHz) d 7.69–7.61
(m, 4H), 7.42–7.34 (m, 6H), 5.81–5.71 (m, 1H), 4.99–4.93
(m, 2H), 3.88 (sextet, J ¼ 6:0 Hz, 1H), 2.25–2.15 (m, 2H),
1.06 (t, 3H, J ¼ 7:3 Hz), 1.05 (s, 9H); 13C NMR (CDCl3,
75 MHz) d 136.10, 136.08, 135.33, 134.94, 134.66, 129.73,
129.66, 127.71, 127.65, 117.00, 69.41, 44.16, 27.23, 23.05,
19.47. 20: 1H NMR (CDCl3, 400 MHz) d 7.75–7.67 (m,
4H), 7.50–7.35 (m, 6H), 5.88–5.78 (m, 1H), 5.10–4.90 (m,
2H), 3.70 (t, 2H, J ¼ 7:3 Hz), 2.14–2.12 (m, 2H), 1.72–1.62
(m, 2H), 1.08 (s, 9H); 13C NMR (CDCl3, 75 MHz) d
138.70, 135.78, 134.25, 129.74, 127.82, 114.77, 63.47,
32.03, 30.28, 27.09, 19.44.
23
D
1
19.28. 15: ½aꢁ +71.35 (c 2.0, CHCl3); H NMR (CDCl3,
400 MHz) d 7.37–7.15 (m, 15H), 5.63–5.47 (m, 1H), 5.20–
5.16 (m, 2H), 5.02 (d, J ¼ 3:3 Hz, 1H), 4.88 (d,
J ¼ 10:9 Hz, 1H), 4.69–4.62 (m, 3H), 4.53–4.49 (m, 2H),
4.04–3.89 (m, 2H), 3.85–3.77 (m, 2H), 3.70–3.59 (m, 2H),
2.33 (dd, J ¼ 12:8, 4.8 Hz, 1H), 1.73 (td, J ¼ 12:8, 3.9 Hz,
1H), 1.63 (m, 2H), 0.88 (t, J ¼ 7:3 Hz, 3H); 13C NMR
10. Lee, C. B.; Chou, T.-C.; Zhang, X.-G.; Wang, Z.-G.;
Kuduk, S. D.; Chappell, M. D.; Stachel, S. J.; Danishef-
sky, S. J. J. Org. Chem. 2000, 65, 6525.
11. Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org.
Chem. 1990, 55, 5812.