Epoxygenase eicosanoids: Synthesis of tetrahydrofuran-diol metabolites and their vasoactivity

Article abstract of DOI:10.1016/j.bmcl.2007.01.096

Eight members of a recently identified family of tetrahydrofuran-diols (THFDs), originating from epoxyeicosatrienoic acids (EETs), were prepared stereospecifically from d-(+)-glucose. The THFDs potently induced relaxation of pre-contracted bovine arteries

Full text of DOI:10.1016/j.bmcl.2007.01.096

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2634–2638
Epoxygenase eicosanoids: Synthesis
of tetrahydrofuran-diol metabolites and their vasoactivity
J. R. Falck,a,* L. Manmohan Reddy,a Kihwan Byun,a
William B. Campbellb and Xiu-Yu Yib
aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
bDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Received 22 December 2006; revised 27 January 2007; accepted 30 January 2007
Available online 2 February 2007
Abstract—Eight members of a recently identified family of tetrahydrofuran-diols (THFDs), originating from epoxyeicosatrienoic
acids (EETs), were prepared stereospecifically from D-(+)-glucose. The THFDs potently induced relaxation of pre-contracted bovine
arteries.
Ó 2007 Elsevier Ltd. All rights reserved.
Arachidonic acid is metabolized by the cytochrome P450
epoxygenase pathway into four regioisomeric epoxyei-
cosatrienoic acids (EETs),1 whose varied contributions
to homeostasis and pathophysiology have attracted con-
siderable attention.2 Secondary metabolism results in
even greater structural diversity by converting the EETs
into vic-diols,3 S-glutathione adducts,4 or more highly
oxygenated products5 including a family of bioactive tet-
rahydrofuran-diols (THFDs).6–8 It is unclear, at present,
if the THFDs originate from completely enzymatic pro-
cesses9 or from spontaneous, nonenzymatic epoxide ann-
ulations (e.g., Eq. 1).10 To expedite current structural and
pharmacological investigations, we report herein the syn-
thesis of eight isomers of defined stereochemistry starting
from an inexpensive member of the chiral pool and their
evaluations as vasomodulators. A structurally similar,
but biosynthetically distinct, class of endogenous arachid-
onate tetrahydrofuran-diols,11 known collectively as
isofurans,12 has also been described and representative
members prepared by chemical synthesis.13
Since the ‘mid-chain’ THFDs, that is, those derived
from transannular cyclizations between epoxides at the
original D8,9- and D11,12-olefins, were found to be the
most efficacious for increasing intracellular free Ca2+
in rat pulmonary alveolar cells,6b our initial synthetic ef-
forts focused on this system. Our strategy (Scheme 1)
utilized furanoside 1,14 readily obtained from D-(+)-glu-
cose, as a convenient starting point.15 Alkynylation of 1
using the dianion of commercial 5-hexynoic acid and
esterification of the adduct with diazomethane provided
the known homopropargylic alcohol 2.14 Benzoylation
of 2 followed by reductive allylation at the anomeric
center induced with BF3ÆEt2O according to the method
of Garcıa-Tellado16 afforded a chromatographically sep-
´
arable mixture (5:1) of 3 and its a-isomer 4 in good com-
bined yield.17 Sequential silylation of the newly liberated
alcohol, OsO4 dihydroxylation of the terminal olefin,
and cleavage of the resultant vic-diol converted 3 into
the somewhat labile aldehyde 5 which was immediately
subjected to Wittig cis-olefination using n-hexylidenetri-
phenylphosphorane in a non-polar solvent to minimize
b-elimination. Semi-hydrogenation of the acetylene over
P-2 nickel18 and fluoride-induced desilylation gave 6.
Saponification of the esters in 6 delivered 8(R),9(S),
11(R),12(S)-THFD (7) without incident, whereas Mits-
unobu inversion19 at C(11) prior to saponification led
to 8(R),9(S),11(S),12(S)-THFD (8).
ð1Þ
An analogous series of transformations as described in
Scheme 1, when applied to a-isomer 4, yielded 8(R),
9(S),11(R),12(R)-THFD (10) and 8(R),9(S),11(S),
12(R)-THFD (11) by way of methyl ester 9 (Scheme 2).
Keywords: Eicosanoids; Epoxygenase; Tetrahydrofuran; Vasorelaxa-
tion; EETs.
*
Corresponding author. Tel.: +1 214 648 2406; fax: +1 214 648
6455; e-mail: j.falck@UTSouthwestern.edu
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.096

J. R. Falck et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2634–2638
2635
Scheme 1. Reagents and conditions: (a) 5-hexynoic acid, n-BuLi (2 equiv), HMPA, 5 °C for 1 h, then 23 °C for 12 h; CH2N2, 5% MeOH/Et2O, 23 °C,
1 h, 60–65%; (b) PhC(O)Cl, DMAP, Et3N, CH2Cl2, 23 °C, 12 h, 97%; (c) Me3SiCH2CH@CH2/BF3ÆEt2O, CH2Cl2, 23 °C, 18 h, 82% (a-/b-isomers
combined); (d) t-BuMe2SiCl, ImH, DMF, 50 °C, 12 h, 95%; (e) OsO4 (2 mol %), NMO, t-BuOH, 23 °C, 12 h; (f) NaIO4/SiO2, CH2Cl2, 23 °C, 1.5 h;
(g) H3C(CH2)5PPh3Br, NaN(SiMe3)2, PhCH3/THF (1:1), ꢀ90 °C for 0.5 h, then warm to 23 °C overnight, 70% over three steps; (h) Ni(OAc)2,
NaBH4, (H2NCH2)2, H2 (1 atm), EtOH, 23 °C, 5 h, 85%; (i) n-Bu4NF, THF, 23 °C, 12 h, 70%; (j) LiOH, THF/H2O (3:1), 92%; (k) DEAD/PPh3/
PhCO2H, THF, 1 h, 0 °C, 93%.
Scheme 2. Reagents and conditions: (a) steps (d)–(i) from Scheme 1; (b) LiOH, THF/H2O (3:1), 23 °C, 10 h, 92–96%; (c) DEAD/PPh3/PhCO2H,
THF, 1 h, 0 °C, 90–93%.
Scheme 3. Reagents and conditions: (a) 5-hexynoic acid, n-BuLi (2 equiv), HMPA, 5 °C for 1 h, then 23 °C for 12 h; CH2N2, 5% MeOH/Et2O, 23 °C,
1 h, 60–65%; (b) PhC(O)Cl, DMAP, Et3N, CH2Cl2, 23 °C, 12 h, 93%; (c) Me3SiCH2CH@CH2/BF3ÆEt2O, CH2Cl2, 23 °C, 18 h, 80–82% (a-/b-isomers
combined); (d) steps (d)–(i) in Scheme 1; (e) LiOH, THF/H2O (3:1), 23 °C, 10 h, 92–96%; (f) DEAD/PPh3/PhCO2H, THF, 1 h, 0 °C, 90–93%.
Regrettably, all attempts to access the 8(S)-series of
THFDs via Mitsunobu inversion19 of alcohol 2 or the
derived 5(Z)-olefin were discouraged by a facile dehy-
dration. Only minor amounts of the desired 8(S)-ester
could be obtained. Oxidation/reduction sequences
through the corresponding ketone as a means of estab-
lishing the S-alcohol were also stymied by poor yields
and/or migration of the adjacent olefin. Consequently,
the known20 epimeric epoxide 12 (Scheme 3) was used
to prepare benzoates 13 and 17 following the now
well-established protocols from Scheme 1. After chroma-
tographic separation, 13 and 17 were elaborated into 14

2636
J. R. Falck et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2634–2638
References and notes
100
80
60
40
20
0
14,15-EET
a
compound 7
compound 8
compound 15
compound 16
1. Review: Capdevila, J. H.; Falck, J. R. Prostaglandins
Other Lipid Mediat. 2002, 68–69, 325.
2. (a) Inceoglu, B.; Schmelzer, K. R.; Morisseau, C.; Jinks, S.
L.; Hammock, B. D. Prostaglandins Other Lipid Mediat.
2007, 82, 42; (b) Olearczyk, J. J.; Imig, J. D. Curr.
Hypertens. Rev. 2005, 1, 235; (c) Fleming, I. Pharmacol.
Res. 2004, 49, 525; (d) Watanabe, H.; Vriens, J.; Prenen,
J.; Droogmans, G.; Voets, T.; Nilius, B. Nature 2003, 424,
434; (e) Jiang, J.-G.; Chen, C.-L.; Card, J. W.; Yang, S.;
Chen, J.-X.; Fu, X.-N.; Ning, Y.-G.; Xiao, X.; Zeldin, D.
C.; Wang, D. W. Cancer Res. 2005, 65, 4707.
-20
3. Zeldin, D. C.; Shouzou, W.; Falck, J. R.; Hammock, B.
D.; Snapper, J. R.; Capdevila, J. H. Arch. Biochem.
Biophys. 1995, 316, 443.
10-10
10-9
10-8
10-7
10-6
10-5
10-4
Concentration (M)
4. Spearman, M. E.; Prough, R. A.; Estabrook, R. W.;
Falck, J. R.; Manna, S.; Leibman, K. C.; Murphy, R. C.;
Capdevila, J. Arch. Biochem. Biophys. 1985, 242, 225.
5. Diepoxides: (a) Capdevila, J. H.; Mosset, P.; Yadagiri, P.;
Lumin, S.; Falck, J. R. Arch. Biochem. Biophys. 1988, 261,
122; Prostanoids: (b) Oliw, E. H. J. Biol. Chem. 1984, 259,
2716; Epoxy-alcohols: (c) Zhang, J. Y.; Prakash, C.;
Yamashita, K.; Blair, I. A. Biochem. Biophys. Res.
100
80
60
40
20
0
b
14,15-EET
compound 10
compound 11
´ ´
Commun. 1992, 183, 138; x-Oxidation: (d) le Quere, V.;
´
Plee-Gautier, E.; Potin, P.; Madec, S.; Salaun, J.-P.
J. Lipid Res. 2004, 45, 1446.
¨
6. (a) Moghaddam, M. F.; Motoba, K.; Borhan, B.; Pinot,
F.; Hammock, B. D. Biochim. Biophys. Acta 1996, 1290,
327; (b) Hammock, B. D.; Moghaddam, M. F.; Cheek, J.
M.; Borhan, B.; Fergusson, J.; Grant, D. F.; Greene, J. F.;
Matoba, K.; Zheng, J.; Sisemore, M. F. US 5,955,496
(A1), 1998; CAN 128:201056.
-20
10-10
10-9
10-8
10-7
10-6
10-5
10-4
Concentration (M)
7. THFDs from other fatty acids: (a) Hosokawa, M.; Hou,
C. T.; Weisleder, D. Appl. Environ. Microbiol. 2003, 69,
3868; (b) Nourooz-Zadeh, J.; Uematsu, T.; Borhan, B.;
Kurth, M. J.; Hammock, B. D. Arch. Biochem. Biophys.
1992, 294, 675; (c) Halarnkar, P. P.; Nourooz-Zadeh, J.;
Kuwano, E.; Jones, A. D.; Hammock, B. D. Arch.
Biochem. Biophys. 1992, 294, 586.
8. Bioactive plant THFDs: (a) Markaverich, B. M.; Alejan-
dro, M. A.; Markaverich, D.; Zitzow, L.; Casajuna, N.;
Camarao, N.; Hill, J.; Bhirdo, K.; Faith, R.; Turk, J.;
Crowley, J. R. Biochem. Biophys. Res. Commun. 2002, 291,
692; Marine alga (b) Murray, L. M.; Barrow, R. A.;
Capon, R. J. Aust. J. Chem. 1991, 44, 843; Marine alga: (c)
Yoda, H.; Maruyama, K.; Takabe, K. Tetrahedron:
Asymmetry 2001, 12, 1403.
Figure 1. Relaxation of pre-contracted bovine arteries by THFDs and
14,15-EET.
and 18, respectively. In turn, these intermediates were
advanced to 8(S),9(S),11(R),12(S)-THFD (15)8(S),
9(S), 11(S),12(S)-THFD (16) and 8(S),9(S),11(R),
12(R)-THFD (19)/8(S),9(S),11(S),12(R)-THFD (20),
accordingly.
The THFDs were tested for vasodilatory activity using
bovine coronary arteries preconstricted with the throm-
boxane-mimetic U-46619 (10–20 nM).21 All caused relax-
ation of the arteries when used from 10ꢀ8 to 10ꢀ5 M
(Fig. 1a and b). In the same assay, the endogenous dilator
14,15-epoxyeicosatrienoic acid (14,15-EET) also relaxed
coronary arteries over a similar concentration range.22
Notably, THFD 10 (ED50 = 3.0 0.11 lM) and 14,15-
EET (ED50 = 2.5 0.10 lM) were equally active, while
the other THFDs were less efficacious. These studies indi-
cate that, in this series, a trans-tetrahydrofuran skeleton
and 11(R)-hydroxyl are necessary for full agonist activity
with respect to the parent EETs. The physiological signif-
icance of these secondary metabolites and their utility as
EET mimetics are under investigation and the results will
be published in due course.
9. Glueck, S. M.; Fabian, W. M. F.; Faber, K.; Mayer, S. F.
Chem. Eur. J. 2004, 10, 3467.
10. (a) Piazza, G. J.; Nunez, A.; Foglia, T. A. J. Am. Oil
Chem. Soc. 2003, 80, 901; (b) Williams, D. R.; Grote, J.;
Harigaya, Y. Tetrahedron Lett. 1984, 25, 5231; (c) Orru,
R. V. A.; Groenendaal, B.; van Heyst, J.; Hunting, M.;
Wesseling, C.; Schmitz, R. F.; Mayer, S. F.; Faber, K.
Pure Appl. Chem. 2003, 75, 259; (d) Jan, S.-T.; Li, K.; Vig,
S.; Rudolph, A.; Uckun, F. M. Tetrahedron Lett. 1999, 40,
193.
11. Fessel, J. P.; Porter, N. A.; Moore, K. P.; Sheller, J. R.;
Roberts, L. J., II Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
16713.
12. Isofuran nomenclature Taber, D. F.; Fessel, J. P.; Rob-
erts, L. J., II Prostaglandins Other Lipid Mediat. 2004, 73,
47.
Acknowledgments
13. Taber, D. F.; Zhang, Z. J. Org. Chem. 2006, 71, 926.
14. (a) Just, G.; Luthe, C.; Oh, H. Tetrahedron Lett. 1980, 21,
1001; (b) Just, G.; Luthe, C. Can. J. Chem. 1980, 58, 1799.
15. As proof of principle that our strategy could be used
to prepare other members of this family, for example, iii,
Financial support was provided by the Robert A. Welch
Foundation and NIH (GM31278, DK38226, and HL-
51055). Dr. Elaine R. Fogel is thanked for helpful
discussions.

J. R. Falck et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2634–2638
2637
1-(Z)-heptene cuprate was added to epoxide 1 to give i
which ultimately evolved ii following the procedures in
Scheme 1.
(m, 2H), 4.09–4.16 (m, 2H), 5.35–5.57 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 14.26, 22.75, 24.65, 26.66, 27.63,
29.43, 31.02, 31.70, 31.96, 33.52, 33.76, 71.51, 75.73, 80.85,
86.31, 124.23, 126.32, 131.39, 133.41, 178.83; MS (AP-LC)
m/z 354 (M+, 100%).
D
Compound 8: TLC, EtOAc, Rf ꢁ 0.29; ½aꢂ23 15.3 (c 0.96,
CHCl3); 1H NMR (400 MHz, CDCl3) d 0.88 (t, J ꢁ 6.8 Hz,
3H), 1.24–1.40 (m, 6H), 1.65–1.78 (m, 2H), 2.00 (dd,
J ꢁ 3.2, 12.8 Hz, 1H), 2.04–2.26 (m, 7H), 2.34 (t,
J ꢁ 7.2 Hz, 2H), 2.38–2.51 (m, 2H), 3.61(td, J ꢁ 2.4,7.2 Hz,
1H), 3.88 (apparent t, J ꢁ 6.4 Hz, 1H), 5.40–5.55 (m, 4H);
13C NMR (75 MHz, CDCl3) d 14.27, 22.79, 24.65, 26.66,
27.17, 27.55, 29.50, 31.73, 31.94, 33.46, 34.31, 71.21, 72.01,
80.07, 83.77, 125.12, 125.93, 132.21, 132.71, 178.56; MS
(AP-LC) m/z 354 (M+, 100%).
´
16. Garcıa-Tellado, F.; de Armas, P.; Marrero-Tellado, J. J.
Angew. Chem. Int. Ed. 2000, 39, 2727.
D
17. Compound 3: TLC, EtOAc/hexane (1:1), Rf ꢁ 0.40; ½aꢂ23
ꢀ34.2 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) d
1.74 (apparent p, J ꢁ 7.2 Hz, 2H), 1.91 (br s, 1H), 2.01
(ddd, J ꢁ 3.2, 6.4, 13.2 Hz, 1H), 2.11–2.23 (m, 5H), 2.37 (t,
2H, J ꢁ 7.6 Hz), 2.60–2.70 (m, 2H), 3.64 (s, 3H), 3.87 (td,
J ꢁ 3.2, 6.4 Hz, 1H), 4.15 (t, J ꢁ 2.4 Hz, 1H), 4.70 (dt,
J ꢁ 6.0, 6.4 Hz, 1H), 4.99–5.06 (m, 2H), 5.24 (apparent q,
J ꢁ 6.0 Hz, 1H), 5.70–5.82 (m, 1H), 7.42 (apparent t,
J ꢁ 7.6 Hz, 2H), 7.54–7.60 (tt, J ꢁ 1.2, 7.2 Hz, 1H), 8.03–
8.06 (dd, J ꢁ 1.2, 8.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 18.20, 21.79, 23.97, 32.82, 36.23, 38.51, 51.64,
73.54, 75.04, 75.94, 78.06, 81.34, 85.95, 117.51, 128.47,
129.73, 130.17, 133.18, 134.09, 165.82, 173.93. TBDMS
D
Compound 9: TLC, EtOAc/hexane (1:1), Rf ꢁ 0.52; ½aꢂ23
ꢀ26.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 0.87
(t, J ꢁ 10.0 Hz, 3H), 1.19–1.39 (m, 6H), 1.59–1.70 (m,
4H), 2.00–2.20 (m, 6H), 2.27 (t, J ꢁ 10.0 Hz, 2H), 2.31–
2.58 (m, 4H), 3.64 (s, 3H), 3.82–3.86 (m, 1H), 4.30 (br s,
1H), 4.41 (dt, J ꢁ 9.2, 12.0 Hz, 1H), 5.24 (dt, J ꢁ 7.2,
9.2 Hz, 1H), 5.29–5.53 (m, 5H), 7.41–7.46 (m, 2H), 7.52–
7.57 (m, 1H), 7.99–8.03 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 14.22, 22.70, 24.81, 26.81, 27.44, 27.56, 29.36,
29.53, 31.65, 33.57, 37.35, 51.67, 72.97, 75.61, 77.86,
83.01, 124.55, 125.01, 128.56, 129.76, 130.45, 131.89,
132.90, 133.15, 166.09, 174.24.
D
ether of 3: TLC, MeOH/CH2Cl2 (1:1), Rf ꢁ 0.87; ½aꢂ23
ꢀ24.1 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3) d
0.01 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H), 1.68 (apparent p,
J ꢁ 7.2 Hz, 2H), 1.85 (ddd, J ꢁ 3.6, 5.2, 12.8 Hz, 1H),
1.98–2.21 (m, 5H), 2.30 (t, J ꢁ 7.6 Hz, 2H), 2.51–2.63 (m,
2H), 3.59 (s, 3H), 3.74 (dt, J ꢁ 4.0, 6.4 Hz, 1H), 4.00 (dt,
J ꢁ 3.6, 7.2 Hz, 1H), 4.37 (dt, J ꢁ 6.4, 8.0 Hz, 1H), 4.80–
4.97 (m, 2H), 5.19 (apparent q, J ꢁ 6.0 Hz, 1H,), 5.63–5.74
(m, 1H), 7.45 (apparent t, J ꢁ 8.0 Hz, 2H), 7.57 (apparent
t, J ꢁ 7.2 Hz, 1H), 8.02–8.05 (apparent dd, J ꢁ 1.6,
7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) d ꢀ4.58,
ꢀ4.41, 18.08, 18.29, 21.82, 24.06, 25.90, 32.84, 36.62,
38.18, 51.60, 73.76, 75.25, 76.02, 78.11, 81.35, 85.87,
117.35, 128.49, 129.83, 130.39, 133.15, 134.36, 165.80,
173.74.
D
Compound 10: TLC, MeOH/CH2Cl2 (1:9), Rf ꢁ 0.28; ½aꢂ23
ꢀ12.4 (c 1.10, CHCl3); 1H NMR (400 MHz, CDCl3) d
0.88 (t, J ꢁ 6.8 Hz, 3H), 1.22–1.40 (m, 8H), 1.71 (apparent
p, J ꢁ 7.2 Hz, 2H), 1.93 (dd, J ꢁ 6.0, 13.2 Hz, 1H), 2.24–
2.22 (m, 7H), 2.35 (t, J ꢁ 7.2 Hz, 2H), 2.38–2.49 (m, 2H),
3.84–3.94 (m, 2H), 4.19–4.24 (m, 1H), 4.33 (t, J ꢁ 3.2 Hz,
1H), 5.36–5.55 (m, 4H); 13C NMR (75 MHz, CDCl3) d
14.25, 22.75, 24.71, 26.71, 27.59, 29.44, 29.88, 31.01,
31.70, 33.65, 34.78, 72.33, 73.05, 80.09, 83.42, 124.65,
126.33, 131.48, 132.95, 179.00; MS (AP-LC) m/z 354 (M+,
100%).
D
D
Compound 4: ½aꢂ23 ꢀ19.6 (c 1.0, CHCl3); 1H NMR
Compound 11: TLC, MeOH/CH2Cl2 (1:9), Rf ꢁ 0.29; ½aꢂ23
1
(400 MHz, CDCl3) d 1.71 (apparent p, J ꢁ 7.2 Hz, 2H),
2.02 (ddd, J ꢁ 1.6, 6.8, 13.2 Hz, 1H), 2.09 (td, J ꢁ 4.4,
8.4 Hz, 1H), 2.14–2.19 (m, 2H), 2.28–2.43 (m, 4H), 2.57–
2.70 (m, 2H), 3.64 (s, 3H), 3.85 (td, J ꢁ 2.8, 6.4 Hz, 1H),
4.30 (br s, 1H), 4.50 (dt, J ꢁ 6.0, 8.8 Hz, 1H), 5.01–5.12
(m, 2H),5.24 (q, J ꢁ 6.0 Hz, 1H,),5.78–5,81 (m, 1H), 7.45
(apparent t, J ꢁ 7.6 Hz, 2H), 7.57 (apparent tt, J ꢁ 1.2,
7.2 Hz, 1H), 8.02–8.05 (apparent dd, J ꢁ 1.2, 7.6 Hz, 2H);
13C NMR (75 MHz, CDCl3) d 21.92, 24.09, 25.94, 32.88,
33.99, 37.80, 51.64, 73.30, 74.16, 76.08, 77.66, 81.32, 83.33,
116.67, 128.54, 129.85, 130.42, 133.18, 135.40, 165.95,
173.79.
16.9 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3) d 0.89
(t, J ꢁ 6.8 Hz, 3H), 1.22–1.40 (m, 7H), 1.62– 1.78 (m, 2H)
1.92–2.30 (m, 10H), 2.35 (t, J ꢁ 6.8 Hz, 2H), 3.85–3.90 (m,
1H), 4.03 (t, J ꢁ 7.2 Hz, 1H), 4.07 (d, J ꢁ 5.6 Hz, 1H),
4.15 (dt, J ꢁ 2.8, 9.2 Hz, 1H), 5.34–5.55 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 14.25, 22.74, 24.66, 26.68,
27.58, 29.42, 31.31, 31.69, 31.89,32.82, 33.60, 72.20, 74.48,
80.54, 87.13, 124.47, 125.99, 131.89, 132.88, 178.69; MS
(AP-LC) m/z 354 (M+, 100%).
D
Compound 13: TLC, 3% MeOH/CH2Cl2, Rf ꢁ 0.26; ½aꢂ23
1.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.68 (s,
1H), 1.75 (apparent p, J ꢁ 7.2 Hz, 2H), 1.90–2.00 (m, 3H),
2.16–2.21 (m, 2H), 2.33– 2.41 (m, 3H), 2.59–2.74 (m, 2H),
3.65 (s, 3H), 3.86 (td, J ꢁ 2.8, 6.4 Hz, 1H), 4.12 (apparent
q, J ꢁ 2.8 Hz, 1H), 4.70 (td, J ꢁ 4.0, 8.4 Hz, 1H), 5.07–
5.14 (m, 2H), 5.19 (td, J ꢁ 4.0, 6.8 Hz, 1H), 5.82–5.94 (m,
1H), 7.42 (apparent t, J ꢁ 7.6 Hz, 2H), 7.55–7.60 (m, 1H),
8.06–8.09 (m, 2H); 13C NMR (75 MHz, CDCl3) d 18.32,
21.81, 24.07, 32.95, 36.51, 38.64, 51.76, 73.58, 75.28,
76.24, 77.47, 81.38, 85.85, 117.62, 128.57, 129.94, 130.17,
133.29, 134.38, 166.17, 174.00.
D
Compound 6: TLC, EtOAc/hexane (1:4), Rf ꢁ 0.40; ½aꢂ23
ꢀ23.0 (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3) d
0.87 (t, J ꢁ 7.2 Hz, 3H), 1.16–1.32 (m, 6H), 1.61–1.72 (m,
3H), 1.88–1.98 (m, 4H), 2.03–2.24 (m, 5H), 2.28 (t,
J ꢁ 7.2 Hz, 2H), 2.41–2.55 (m, 2H), 3.65 (s, 3H), 3.76–
3.81 (m, 1H), 4.10 (dt, J ꢁ 2.8, 5.6 Hz, 1H), 4.31 (dt,
J ꢁ 6.0, 8.8 Hz, 1H), 5.27–5.51 (m, 5H), 7.44 (apparent t,
J ꢁ 7.6 Hz, 2H), 7.56 (apparent t, J ꢁ 7.6 Hz, 1H), 8.01–
8.04 (m, 2H); 13C NMR (75 MHz, CDCl3) d 14.25, 22.74,
24.84, 26.86, 27.52, 29.39, 29.58, 31.64, 32.12, 33.62, 36.16,
51.71, 74.88, 75.51, 78.67, 86.48, 124.24, 125.04, 128.56,
129.79, 130.53, 131.93, 133.02, 133.15, 166.02, 174.29.
D
Compound 14: ½aꢂ23 11.9 (c 0.9, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.87 (t, J ꢁ 7.1 Hz, 3H), 1.16–1.38
(m, 6H), 1.65 (quintet, J ꢁ 7.3 Hz, 2H), 1.88–2.18(m, 6H),
2.23–2.41 (m, 4H), 2.54 (t, J ꢁ 6.3, Hz, 2H), 3.65 (s, 3H),
3.81 (ddd, J ꢁ 3.2, 6.2, 7.6 Hz, 1H), 4.05–4.09 (m, 1H),
4.37 (dt, J ꢁ 3.9, 7.0 Hz, 1H), 5.17 (dt, J ꢁ 3.9, 6.6 Hz,
1H), 5.40–5.56 (m, 4H), 7.40–7.47 (m, 2H), 7.53–7.60 (m,
1H), 8.04–8.08 (m, 2H); 13C NMR (75 MHz, CDC13) d
14.23, 22.73, 24.84, 26.81, 27.63, 29.45, 29.54, 31.67,
D
Compound 7: TLC, EtOAc, Rf ꢁ 0.18; ½aꢂ23 ꢀ26.5 (c 1.03,
CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.88 (t,
J ꢁ 6.8 Hz, 3H), 1.22–1.39 (m, 6H), 1.70 (q, J ꢁ 7.2 Hz,
2H), 1.78 (ddd, J ꢁ 4.0, 6.0, 13.2 Hz, 1H), 2.03 (apparent
q, J ꢁ 7.2 Hz, 2H), 2.08–2.16 (m, 3H), 2.17– 2.24 (m, 2H),
2.28 (t, J ꢁ 7.2 Hz, 2H), 2.35 (t, J ꢁ 7.2 Hz, 2H), 3.82–3.86

2638
J. R. Falck et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2634–2638
32.18, 33.63, 36.57, 51.69, 74.79, 75.46, 77.98, 86.26,
124.49, 125.20, 128.56, 129.91, 130.38, 132.08, 132.93,
133.18, 166.36, 174.31.
Compound 17: TLC, 3% MeOH/CH2Cl2, Rf ꢁ 0.32;
D
½aꢂ23 10.5 (c 0.72, CHCl3); 1H NMR (400 MHz, CDCl3)
d 1.76–1.78 (m, 3H), 1.97 (ddd, J ꢁ 4.8, 9.2, 13.6 Hz,
1H), 2.12 (dd, J ꢁ 6.8, 13.2 Hz, 1H), 2.15–2.21 (m, 2H),
2.33–2.53 (m, 4H), 2.59–2.74 (m, 2H), 3.66 (s, 3H),
3.86 (td, J ꢁ 2.4, 6.8 Hz, 1H), 4.28 (apparent s, 1H),
4.59–4.64 (m, 1H), 5.07–5.21 (m, 3H), 5.81–5.94 (m,
1H), 7.45 (apparent t, J ꢁ 7.6 Hz, 2H), 7.55–7.60 (m,
1H), 8.04–8.07 (m, 2H); 13C NMR (75 MHz, CDCl3) d
18.37, 21.92, 24.13, 29.91, 32.98, 33.77, 37.54, 51.78,
73.19, 74.34, 76.22, 81.51, 82.50, 117.30, 128.62, 129.97,
130.25, 133.30, 134.76, 166.27, 173.95.
D
Compound 15: ½aꢂ23 ꢀ10.0 (c 0.7, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.88 (t, J ꢁ 7.0 Hz, 3H), 1.24–1.40
(m, 6H), 1.70 (quintet, J ꢁ 7.0 Hz, 2H), 1.85 (apparent ddd,
J ꢁ 2.8, 5.9, 13.1 Hz, 1H), 1.93–2.06 (m, 3H), 2.12 (apparent
q, J ꢁ 5.7 Hz, 2H), 2.22–2.30 (m, 4H), 2.36 (t, J ꢁ 7.3 Hz,
2H), 3.47 (apparent q, J ꢁ 6.1 Hz, 1H), 3.83 (dt, J ꢁ 10.4,
3.0 Hz, 1H), 4.04–4.13 (m 2H), 5.36–5.56 (m, 4H); 13C
NMR (75 MHz, CDC13) d 14.26, 22.75, 24.57, 26.64, 27.64,
29.43, 31.71, 32.11, 32.22, 33.31, 36.98, 73.72, 75.96, 80.56,
86.14, 124.20, 126.51, 131.23, 133.35, 178.66.
18. Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem.
Commun. 1973, 553.
19. Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.;
Capdevila, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4759.
20. Durand, T.; Guy, A.; Vidal, J.-P.; Rossi, J.-C. J. Org.
Chem. 2002, 67, 3615.
21. Falck, J. R.; Krishna, U. M.; Reddy, Y. K.; Kumar, P. S.;
Reddy, K. M.; Hittner, S. B.; Deeter, C.; Sharma, K. K.;
Gauthier, K. M.; Campbell, W. B. Am. J. Physiol. 2003,
284, H337.
22. Campbell, W. B.; Gebremedhin, D.; Pratt, P. F.; Harder,
D. R. Circ. Res. 1996, 78, 415.
D
Compound 16: ½aꢂ23 25.0 (c 0.68, CHCl3); 1H NMR
(400 MHz, CDCl3) d 0.88 (t, J ꢁ 6.7 Hz, 3H), 1.25–1.40
(m, 6H), 1.72 (quintet, J ꢁ 7.4 Hz, 2H), 1.83 (apparent dd,
J ꢁ 14.0, 3.0 Hz, 1H), 2.07 (q, J ꢁ 7.0 Hz, 2H), 2.14 (q,
J ꢁ 6.7 Hz, 2H), 2.28-2.52 (m, 7H), 3.54 (ddd, J ꢁ 10.4, 5.5,
2.4 Hz, 1H), 3.65 (dt, J ꢁ 14.0, 2.8 Hz, 1H), 4.01 (td,
J ꢁ 9.8, 2.8 Hz, 1H), 4.07 (dd, J ꢁ 5.5, 2.8 Hz, 1H), 5.40–
5.55 (m, 4H); 13C NMR (75 MHz, CDC13) d 14.28, 22.80,
24.62, 26.66, 27.30, 27.56, 29.55, 31.74, 32.28, 33.35, 38.33,
71.67, 73.51, 78.99, 84.13, 125.25, 126.61, 132.04, 132.62,
178.58.