A concise synthesis of 12(S),20-dihydroxyeicosa-5(Z),8(Z),10(E),14(Z)- tetraenoic acid, an endogenous vasoconstrictor

Article abstract of DOI:10.1016/j.tetlet.2004.07.130

12(S),20-DiHETE, prepared by a combination of Evans-Crimmins asymmetric alkylation, Sonogashira alkynation, and Suzuki-Miyaura cross-coupling, significantly sensitizes phenylephrine-induced vasoconstriction of rat renal interlobar arteries.

Full text of DOI:10.1016/j.tetlet.2004.07.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7111–7113
A concise synthesis of 12(S),20-dihydroxyeicosa-5(Z),
8(Z),10(E),14(Z)-tetraenoic acid, an endogenous vasoconstrictor
S. G. Jagadeesh,a L. Manmohan Reddy,a Alberto Nasjlettib and J. R. Falcka,
*
aDepartment of Biochemistry, University of Texas, Southwestern Medical Center, Dallas, TX 75390-9038, USA
bDepartment of Pharmacology, New York Medical College, Valhalla, NY 10595, USA
Received 28 June 2004; revised 9 July 2004; accepted 22 July 2004
Available online 13 August 2004
Abstract—12(S),20-DiHETE, prepared by a combination of Evans–Crimmins asymmetric alkylation, Sonogashira alkynylation,
and Suzuki–Miyaura cross-coupling, significantly sensitizes phenylephrine-induced vasoconstriction of rat renal interlobar arteries.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
126 at low temperature to give 37 (Scheme 1). Suzuki–
Miyaura cross-coupling of 3 with the alkylborane gener-
ated from 5-(tert-butyldiphenylsilyl-oxy)pent-1-ene8 (8)
via in situ addition of 9-BBN was best accomplished
using Buchwaldꢁs catalytic system.9 The resultant ad-
duct, 4, was converted to E-vinyl iodide 5 by sequential
lithium borohydride reduction, Swern oxidation, and
Takai iodoo¨lefination.10 Sonogashira11 alkylation of 5
with methyl non-5(Z)-8-ynoate12 (9) and semihydrogen-
ation13 over P-2 nickel smoothly evolved 6 and com-
pleted the synthesis of the carbon framework. Bis-
desilylation generated methyl ester 7 from which 1 was
obtained by saponification.
Recent studies from these and other laboratories have
documented the structure and biosynthesis of a variety
of ꢀdual pathway metabolitesꢁ arising from secondary
oxidation of a primary eicosanoid by cyclooxygenase,
lipoxygenase, or cytochrome P450.1 These novel biosyn-
thetic paradigms significantly increase structural diver-
sity and the range of biological activities.2
A
prominent example of this class of autacoids, 12(S),20-
dihydroxyeicosa-5(Z),8(Z),10(E),14(Z)-tetraenoic acid
(1), has attracted wide attention for its effects on vascu-
lar regulation and inflammation.1a–f To expedite contin-
uing pharmacological investigations, we describe herein
a concise, asymmetric synthesis3 of 1 by a triply conver-
gent strategy (Fig. 1). Additionally, 1 was evaluated for
its ability to sensitize phenylephrine-induced vasocon-
striction of rat renal interlobar arteries.4
The somewhat labile allylic iodide 12 was prepared by
modification of the procedures published by Wei and
Taylor (Scheme 2).14 Specifically, Michael addition of
chloride anion to commercial ethyl propynoate (10) pro-
ceeded stereoselectively giving 11, which was subse-
quently reduced with LiAlH4. The newly generated
alcohol was transformed into the corresponding iodide
using a mixture of KI/BF3 ÆEt2O.
Access to the central chiral retron (Fig. 1) was conven-
iently achieved by asymmetric alkylation of glycolate
oxazolidinone 25 with 1-chloro-3-iodoprop-1(Z)-ene
CO2H
CO2R'
HO
PGO
X
+
OH
OPG
R2B
+
1
X'
Figure 1. Retrosynthetic analysis.
*
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.2004.07.130

7112
S. G. Jagadeesh et al. / Tetrahedron Letters 45 (2004) 7111–7113
Weissmann, R. R.; Oglesby, T. D.; Gorman, R. R. J.
Allergy Clin. Immun. 1984, 74, 338–342; (d) Marcus, A. J.;
Safier, L. B.; Ullman, H. L.; Islam, N.; Broekman, M. J.;
von Schacky, C. J. Clin. Invest. 1987, 79, 179–187; (e) Hill,
E.; Murphy, R. C. Dev. Oncol. 1993, 71, 265–270; (f)
Marcus, A. J.; Safier, L. B.; Ullman, H. L.; Broekman, M.
J.; Islam, N.; Oglesby, T. D.; Gorman, R. R. Proc. Nat.
Acad. Sci. U.S.A. 1984, 81, 903–907; (g) Okita, R. T.;
Soberman, R. J.; Bergholte, J. M.; Masters, B. S. S.;
Hayes, R.; Murphy, R. C. Mol. Pharm. 1987, 32, 706–709;
(h) Wong, P. Y. K.; Westlund, P.; Hamberg, M.;
Granstroem, E.; Chao, P. H. W.; Samuelsson, B. J. Biol.
Chem. 1984, 259, 2683–2686; (i) Hatzelmann, A.; Ullrich,
V. Eur. J. Biochem. 1988, 173, 445–452; (j) OꢁFlaherty, J.
T.; Wykle, R. L.; Redman, J.; Samuel, M.; Thomas, M. J.
Immunol. 1986, 137, 3277–3283.
O
O
O
O
TBDPSO
N
O
a
b
N
O
75%
71%
TBDPSO
H
Ph
H
Ph
O
2
3
Cl
TBDPSO
O
I
TBDPSO
N
O
c-e
41%
H
Ph
OTBDPS
OTBDPS
4
5
CO2R
R'O
f,g
61%
2. Reviews: (a) Marcus, A. J. Prog. Hemost. Throm. 1986, 8,
127–142; (b) Sraer, J.; Bens, M.; Oudinet, J. P.; Baud, L.
Adv. Exp. Med. Biol. 1989, 259, 23–47.
OR '
6: R = Me, R' = TBDPS
7: R = Me, R' = H
1: R = R' = H
3. Prior chemical syntheses: (a) Falck, J. R.; Chauhan, K.;
Rosolowsky, M.; Campbell, W. B. Bioorg. Med. Chem.
Lett. 1994, 4, 2113–2116; (b) Manna, S.; Viala, J.;
Yadagiri, P.; Falck, J. R. Tetrahedron Lett. 1986, 27,
2679–2682; (c) Leblanc, Y.; Fitzsimmons, B. J.; Adams, J.;
Perez, F.; Rokach, J. J. Org. Chem. 1986, 51, 789–793.
4. Notably, the enantiomer of 1, that is, 12(R),20-DiHETE is
not a vasorelaxant in canine arteries (see Ref. 1a).
5. Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett.
2000, 2, 2165–2167.
(h)
82%
(i) 90%
Scheme 1. Reagents and conditions: (a) Na(TMS)2N, THF/PhCH3
(2:1), ꢀ90 to ꢀ78°C, 2h; 12, ꢀ90 to ꢀ78°C, 6h; (b) 8, 9-BBN, THF,
23°C, 2h; Pd(OAc)2 (1mol%)/Buchwald ligand (2mol%), K3PO4,
THF, 65°C, 18h; (c) LiBH4, Et2O, 0°C, 8h, 83%; (d) (COCl)2/DMSO/
Et3N, CH2Cl2, ꢀ78 to 0°C, 6h, 70%; (e) CHI3/CrCl2, THF, 23°C, 6h,
71%; (f) 9, CuI/Pd(Ph3P)4/n-BuNH2, C6H6, 23°C, 5h, 76%; (g) P-2 Ni/
H2 (1atm), EtOH, 1.5h, 80%; (h) n-Bu4NF, THF, 0°C, 8h; (i) NaOH,
THF/H2O (3:1), 23°C, 7h.
6. Auge, J.; David, S. Tetrahedron Lett. 1983, 24, 4009–4012.
7. Spectral and physical data for new compounds. Com-
23
pound 2: IR (neat) 1782, 1721, 1113cmꢀ1; ½aꢁD ꢀ 46:4 (c
1
1.0, CHCl3); H NMR (CDCl3 + TMS, 400MHz) d 7.22
Cl
b,c
Cl
a
CO2Et
CO2Et
10
I
(td, 4H, J = 7.6, 1.6Hz), 7.46–7.36 (m, 6H), 7.32–7.24 (m,
3H), 7.12 (dd, 2H, J = 6.1, 1.6Hz), 4.87 (q, 2H,
J = 9.5Hz), 4.64–4.57 (m, 1H), 4.18 (t, 1H, J = 9.1Hz),
4.14 (dd, 1H, J = 8.8, 3.0Hz), 3.19 (dd, 1H, J = 13.4,
3.0Hz), 2.70 (dd, 1H, J = 13.4, 9.1Hz), 1.13 (s, 9H); 13C
NMR (CDCl3, 75MHz) d 171.18, 153.43, 135.90, 135.84,
135.07, 133.08, 130.09, 130.06, 129.60, 129.13, 127.96,
127.94, 127.55, 67.18, 64.74, 54.84, 37.72, 26.99, 19.55.
84%
75%
11
12
Scheme 2. Reagents and conditions: (a) LiCl, AcOH/CH3CN, 82°C,
12h; (b) LiAlH4, Et2O, 0°C, 4h, 84%; (c) KI/BF3 ÆEt2O, dioxane,
23°C, 5h, 62%.
23
2. Bioassay
Compound 3: ½aꢁD ꢀ 74:9 (c 1.09, CHCl3); IR (neat) 1781,
1713, 1113, 701cmꢀ1
;
1H NMR (CDCl3 + TMS,
400MHz) d 7.71 (dd, 2H, J = 7.6, 1.2Hz), 7.61 (dd, 2H,
J = 8.0, 1.2Hz), 7.44–7.32 (m, 6H), 7.31–7.22 (m, 3H),
7.16 (dd, 2H, J = 6.7, 1.2Hz), 6.18 (app dt, 1H,
J = 7.0Hz), 6.12–6.05 (m, 1H), 5.51 (t, 1H, J = 5.2Hz),
4.12–4.04 (m, 1H), 3.96 (dd, 1H, J = 8.8, 2.7Hz), 3.79 (t,
1H, J = 8.5Hz), 3.07 (dd, 1H, J = 13.4, 3.2Hz), 2.94–2.83
(m, 1H), 2.78–2.68 (m, 1H), 2.56 (dd, 1H, J = 13.4,
9.7Hz), 1.14 (s, 9H); 13C NMR (CDCl3, 75MHz) d
172.53, 152.68, 136.49, 136.09, 135.21, 133.45, 133.33,
130.04, 129.92, 129.60, 129.12, 127.82, 127.66, 127.52,
126.41, 120.66, 69.89, 66.59, 54.82, 37.77, 32.66, 27.15,
Ring segments of rat renal interlobar arteries bathed
in Krebsꢁ buffer were mounted on a wire-myograph.
Phenylephrine
increases of isometric tension with an EC50
elicited
concentration
dependent
=
0.49 0.04lmol/L (Rmax = 4.19 0.42mN/mm). Com-
pound 1 (10lmol/L) resulted in a significant (P < 0.05)
sensitization of the arteries to phenylephrine (EC50
=
0.16 0.07lmol/L) without changing Rmax
.
23
19.54. Compound 4: ½aꢁD ꢀ 45:3 (c 1.17, CHCl3); IR (neat)
Acknowledgements
1782, 1712cmꢀ1 1H NMR (CDCl3 + TMS, 400MHz) d
;
7.74–7.60 (m, 8H), 7.42–7.20 (m, 15H), 7.09 (d, 2H,
J = 7.7Hz), 5.66–5.52 (m, 2H), 5.43 (t, 1H, J = 5.1Hz),
4.06–3.80 (m, 1H), 3.95–3.89 (m, 1H), 3.73 (t, 1H,
J = 8.2Hz), 3.62 (t, 2H, J = 6.6Hz), 3.03 (dd, 1H,
J = 13.3, 2.9Hz), 2.64–2.48 (m, 3H), 2.10–2.00 (m, 2H),
1.60–1.50 (m, 3H), 1.40–1.30 (m, 4H), 1.11 (s, 9H), 1.03 (s,
9H); 13C NMR (CDCl3, 75MHz) d 173.46, 152.58, 136.55,
136.22, 135.76, 135.25, 134.34, 133.76, 133.54, 133.38,
129.87, 129.77, 129.67, 129.59, 129.05, 127.77, 127.67,
127.57, 127.48, 123.95, 70.84, 66.37, 64.14, 54.76, 37.85,
33.11, 32.72, 29.59, 27.62, 27.18, 27.08, 25.74, 19.54, 19.41;
Supported financially by the USPHS NIH (DK38226,
HL34300, GM31278) and the Robert A. Welch
Foundation.
References and notes
1. (a) Rosolowsky, M.; Falck, J. R.; Campbell, W. B.
Biochim. Biophys. Acta 1996, 1300, 143–150; (b) Hajjar, D.
P.; Marcus, A. J.; Etingin, O. R. Biochem. 1989, 28,
8885–8891; (c) Marcus, A. J.; Safier, L. B.; Broekman, M.
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23
MS (APCI) m/z 860 (M + Na)+. Compound 5:½aꢁD ꢀ 26 (c
0.5, CHCl3); IR (neat) 2857, 1427, 1111, 700cmꢀ1 1H
;

S. G. Jagadeesh et al. / Tetrahedron Letters 45 (2004) 7111–7113
7113
NMR (CDCl3 + TMS, 400MHz) d 7.70–7.59 (m, 8H),
7.44–7.33 (m, 12H), 6.46 (dd, 1H, J = 14.3, 6.4Hz), 5.96
(d, 1H, J = 14.3Hz), 5.42–5.33 (m, 1H), 5.27–5.18 (m, 1H),
4.07 (q, 1H, J = 6.7Hz), 3.63 (t, 2H, J = 6.4Hz), 2.28–2.12
(m, 2H), 1.88–1.76 (m, 2H), 1.56–1.49 (m, 2H), 1.32–1.20
(m, 4H), 1.05 (s, 9H), 1.04 (s, 9H); 13C NMR (CDCl3,
75MHz) d 148.26, 136.29, 136.26, 135.98, 134.54, 134.20,
133.88, 133.06, 130.18, 130.15, 129.92, 128.00, 124.08,
77.86, 76.13, 64.36, 35.66, 32.92, 29.70, 27.73, 27.40, 27.31,
J = 15.2, 6.1Hz), 5.60–5.50 (m, 1H), 5.48–5.30 (m, 4H),
4.23 (q, 1H, J = 6.1Hz), 3.67 (s, 3H), 3.63 (t, 2H,
J = 6.4Hz), 2.92 (t, 2H, J = 6.4Hz), 2.40–2.26 (m, 4H),
2.16–2.02 (m, 4H), 1.90–1.65 (m, 4H), 1.62–1.52 (m, 2H),
1.46–1.32 (m, 4H); 13C NMR (CDCl3, 75MHz) d 174.41,
136.00, 133.38, 130.45, 129.46, 128.52, 128.07, 125.53,
124.87, 72.21, 63.10, 51.77, 35.55, 33.63, 32.80, 29.51,
27.53, 26.76, 26.30, 25.54, 24.92; MS (APCI) m/z 373
(M + Na)+. Compound 11: 1H NMR (CDCl3 +
TMS,400MHz) d 6.70 (d, 1H, J = 8.2Hz), 6.19 (d, 1H,
J = 8.2Hz), 4.24 (q, 2H, J = 7.4Hz), 1.31 (t, 3H, J =
7.0Hz). Compound 12: 1H NMR (CDCl3 + TMS,
400MHz) d 6.13 (m, 2H), 4.00 (d, 2H, J = 7.7Hz).
8. Gopal, V. R.; Jagadeesh, S. G.; Reddy, Y. K.; Bandyo-
padhyay, A.; Capdevila, J. H.; Falck, J. R. Tetrahedron
Lett. 2004, 45, 2563–2565.
9. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. Engl. 2004, 43, 1871–1876.
10. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408–7410.
11. Tykwinski, R. R. Angew. Chem., Int. Ed. Engl. 2003, 42,
1566–1568.
12. Chemin, D.; Gueugnot, S.; Linstrumelle, G. Tetrahedron
1992, 48, 4369–4378.
13. Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38,
2226–2230.
23
25.87, 19.73, 19.64. Compound 6: ½aꢁD ꢀ 6:55 (c 0.9,
CHCl3); IR (neat) 1738, 1428, 1111cm1; 1H NMR
(CDCl3 + TMS, 400MHz) d 7.70–7.62 (m, 8H), 7.44–
7.30 (m, 12H), 6.23 (dd, 1H, J = 15.2, 10.3Hz), 5.87 (t, 1H,
J = 10.9Hz), 5.62 (dd, 1H, J = 12.2, 6.7Hz), 5.40–5.21 (m,
5H), 4.21 (q, 1H, J = 5.5Hz), 3.64–3.60 (m, 5H), 2.76 (t,
2H, J = 6.1Hz), 2.28 (t, 3H, J = 7.3Hz), 2.23–2.14 (m,
1H), 2.10–2.00 (m, 2H), 1.81 (q, 2H, J = 7.0Hz), 1.68 (q,
2H, J = 7.6Hz), 1.66–1.48 (m, 2H), 1.32–1.18 (m, 4H),
1.06 (s, 9H), 1.04 (s, 9H); 13C NMR (CDCl3, 75MHz) d
174.25, 136.18, 136.14, 135.78, 134.56, 134.35, 134.29,
132.07, 129.77, 129.70, 129.57, 129.30, 128.80, 128.42,
127.79, 127.68, 127.59, 125.21, 124.87, 74.01, 64.16, 51.68,
36.23, 33.62, 32.72, 29.51, 27.54, 27.24, 27.09, 26.73, 26.17,
25.66, 24.95, 19.56, 19.43; MS (APCI) m/z 849 (M + Na)+.
23
Compound 7: ½aꢁD ꢀ 2:5 (c 2.0, CHCl3); IR (neat)
3392, 2930, 1727, 1437, 1216cmꢀ1
;
1H NMR
(CDCl3 + TMS, 400MHz) d 6.60 (dd, 1H, J = 15.2,
10.9Hz), 5.99 (t, 1H, J = 10.6Hz), 5.72 (dd, 1H,
14. Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 616–
620.