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.
J.; Ullman, H. L.; Islam, N.; Sorrell, T. C.; Serhan, C. N.;
23
MS (APCI) m/z 860 (M + Na)+. Compound 5:½aꢁD ꢀ 26 (c
0.5, CHCl3); IR (neat) 2857, 1427, 1111, 700cmꢀ1 1H
;