M. Gebauer / Bioorg. Med. Chem. 15 (2007) 2414–2420
2419
1.62 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.85 (s, 3H, CH3),
2.00–2.09 (m, 4H, 2CH2), 2.18 (m, 4H, 2CH2), 3.45 (d,
2H, a-CH2), 5.08 (m, 2H, C@CH), 5.47 (t, 1H, C@CH),
7.25–7.31 (m, 2H, CH), 7.52 (m, 1H, CH), 7.77 (dd, 1H,
CH); HRMS [EI] 367.22715 C24H31O3 (M+H+) requires
367.22732.
(12.94 g, 0.0391 mol) was added from a syringe over
10 min. Stirring was continued for 10 min at 80 ꢁC.
The hot reaction mixture was poured onto a mixture
of toluene (300 mL) and 2 M HCl (200 mL), mixed
and the phases separated. The organic phase was
washed with water (200 mL), dried over MgSO4, the sol-
vent evaporated and the residue chromatographed of
ethylacetate (16% ethylacetate/84% heptane). Two prod-
ucts were isolated. First eluting from the column was
4.73 g (29.4%) of 4-O-oleyl-coumarin: mp 32–34 ꢁC
(from n-heptane). Product 23 eluted second (263 mg,
1.6%) and was obtained as a white solid: mp 76–77 ꢁC
(from n-heptane). 1H NMR (CDCl3) d 0.87 (d, 3H,
CH3), 1.20–1.34 (m, 22H, 11CH2), 1.60 (m, 2H, CH2),
1.67 (s, 2H, CH2), 1.98 (m, 2H, CH2), 2.63 (t, 2H,
a-CH2), 5.30–5.36 (m, 2H, HC@CH), 7.29–7.32 (m,
2H, 2CH), 7.52 (m, 1H, CH), 7.89 (dd, 1H, CH); HRMS
[EI] 412.29762 C27H40O3 (M+H+) requires 412.29775.
4.9. 3-all-trans-Geranylgeranyl-4-hydroxy-2H-1-benzo-
pyran-2-one (20)
To 4-hydroxycoumarin sodium salt (1.02 g, 4.82 mmol)
was added all-trans-geranylgeranyl bromide (1.213 g,
3.44 mmol) as described for the synthesis of 19. The
crude product was chromatographed (20% ethylace-
tate/80% heptane) to give 180 mg (12%) of 20 as a waxy
1
white solid: mp 44–45 ꢁC. H NMR (CDCl3) d 1.58 (s,
3H, CH3), 1.60 (s, 3H, CH3), 1.63 (s, 3H, CH3), 1.67
(s, 3H, CH3), 1.85 (s, 3H, CH3), 1.95–2.10 (m, 8H,
4CH2), 2.18 (m, 4H, 2CH2), 3.45 (d, 2H, CH2), 5.08–
5.12 (m, 3H, C@CH), 5.47 (t, 1H, C@CH), 7.25–7.31
(m, 2H, CH), 7.52 (m, 1H, CH), 7.77 (dd, 1H, CH).
HRMS [EI] 435.28959 C29H39O3 (M+H+) requires
435.28992.
Acknowledgments
I thank Foundation Daw Park and the Veterans Heart
Clinic of the Repatriation General Hospital for their
financial support. I thank Peter Stockham (gift of bro-
difacoum), Larry Hicks, Dr. Steven Blanksby, Dr. Keith
Fisher (MS services); Dr. Eva Stupans, Kathryn Corbett
(rat liver microsomes); Dr. Carolyn Muscat, Dr. Geoff
Crisp (Assistance with synthesis); Dr. Wilf Armarego
(Assistance with manuscript).
4.10. 3-trans,trans-Farnesyl-6,7-dimethyl-4-hydroxy-2H-
1-benzopyran-2-one (21)
To 6,7-dimethyl-4-hydroxycoumarin sodium salt (3.30 g,
15.6 mmol) was added farnesyl bromide (2.20 g,
7.7 mmol) as described for the synthesis of 19. The crude
product was chromatographed (ethylacetate 16%/n-hep-
tane 84%) to yield 219 mg (7.2%) of 21 as a white solid:
1
Supplementary data
mp 92–93 ꢁC. H NMR (CDCl3) d 1.58 (s, 3H, CH3),
1.62 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.84 (s, 3H, CH3),
2.01 (m, 2H, CH2), 2.07 (m, 2H, CH2), 2.18 (m, 4H,
2CH2), 2.30 (s, 3H, ring CH3), 2.34 (s, 3H, ring CH3),
3.42 (d, 2H, a-CH2), 5.08 (tq, 1H, C@CH), 5.10 (tq,
1H, C@CH), 5.46 (tq, 1H, C@CH), 7.07 (s, 1H, OH),
7.33 (s, 1H, CH), 7.48 (s, 1H, CH); HRMS [EI]
395.25883 C26H35O3 (M+H+) requires 395.25862.
Supplementary data associated with this article can be
References and notes
1. Hirsh, J.; Dalen, J. E.; Anderson, D. R.; Poller, L.; Bussey,
H.; Ansell, J.; Deykin, D. Chest 2001, 119, 8S–21S.
2. Bell, R. G.; Sadowski, J. T.; Matschiner, J. T. Biochem-
istry 1972, 11, 1959–1961.
4.11. 3-trans,trans-Farnesyl-2-hydroxy-1,4-naphthoqui-
none (22)
3. Thijssen, H. H. W.; Baas, G. M. Biochem. Pharmacol.
1989, 38, 1115–1120.
4. Sadler, J. E. Nature 2004, 427, 493–494.
5. Fasco, M. J.; Principe, L. M.; Walsh, W. A.; Friedman, P.
A. Biochemistry 1983, 22, 5655–5660.
To 2-hydroxy-1,4-naphthoquinone sodium salt (10.65 g,
54.3 mmol) was added farnesyl bromide (5.1 g,
17.9 mmol) as described for the synthesis of 19. The
crude product was chromatographed (ethylacetate
15%/n-heptane 85%) to give 61 mg (1%) of 22 as a yellow
6. Zytkovicz, T. H.; Nelsestuen, G. L. J. Biol. Chem. 1975,
250, 2968–2972.
1
solid: mp 68–69 ꢁC. H NMR (CDCl3) d 1.55 (s, 3H,
CH3), 1.56 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.79 (s, 3H,
CH3), 1.90–2.09 (m, 8H, 4CH2), 3.32 (d, 2H, a-CH2),
5.03 (tq, 1H, C@CH), 5.06 (tq, 1H, C@CH), 5.21 (tq,
1H, C@CH), 7.28 (s, 1H, OH), 7.67 (t, 1H, CH), 7.74
(t, 1H, CH), 8.06 (d, 1H, CH), 8.13 (d, 1H, CH); HRMS
[EI] 379.22732 C25H31O3 (M+H+) requires 379.22763.
7. Nelsestuen, G. L.; Shah, A. M.; Harvey, S. B. Vitam.
Horm. 2000, 58, 355–389.
8. Nelsestuen, G. L. J. Biol. Chem. 1976, 251, 5648–5656.
9. Friedman, P. A.; Rosenberg, R. D.; Hauschka, P. V.; Fitz-
James, A. A. Biochim. Biophys. Acta 1977, 494, 271–276.
10. Campbell, H. A.; Link, K. P. J. Biol. Chem. 1941, 138,
21–35.
11. Overman, R. S.; Stahmann, M. A.; Huebner, C. F.;
Sullivan, W. R.; Spero, L.; Doherty, D. G.; Ikawa, M.;
Graf, L.; Roseman, S.; Link, K. P. J. Biol. Chem. 1944,
153, 5–24.
12. Holmes, R. W.; Love, J. JAMA 1952, 148, 935.
13. Valle, M. G.; Appendino, G.; Nano, G. M.; Picci, V.
Phytochemistry 1987, 26, 253–256.
4.12. 3-Oleyl-4-hydroxy-2H-1-benzopyran-2-one (23)
DMSO (200 mL) was heated to 80 ꢁC under nitrogen
and finely powdered 4-hydroxycoumarin sodium salt
(22.58 g) added in portions allowing each to dissolve
before adding the next portion. Oleyl bromide