Figure 2. Known precursors of lomatin and khellactone.
be achieved in the epoxidation of cis-chromene structures
using chiral iminium salt catalysts,18 and we report herein
the highly enantioselective synthesis of (-)-(3′S)-lomatin 4
and (+)-(3′S,4′R)-trans-khellactone 6 using such an enan-
tioselective epoxidation of seselin, followed by reductive or
hydrolytic ring opening of the resulting epoxide.
Figure 1. Naturally occurring pyranocoumarins.
North has reported a simple synthesis of chromenes from
commercially available starting materials, in which, for
6, isolated from the aerial parts of Ligusticum elatum10 and
Peucedanum japonicum.11 Seselin 1 and xanthyetin 2 have
shown cytotoxic activity against Vero monkey cells, with
IC50 values of 12 µg/mL and >20 µg/mL,12 while selenidin
3 has antisuppressant properties toward leukotriene C4
production,3 and (+)-decursinol 5 exerts anticancer activity
against prostate cancer PC3 cells.13 (+)-trans-Khellactone
6 has cytotoxic activity against P-388 lymphocytic leukemia
systems (ED50 2.8 µg/mL).11
To our knowledge, lomatin has been previously prepared
only by achiral synthesis, using osthenol 7,14 2,4-dihydroxy-
benzaldehyde,15 visnadin (provismine) 8,16 and seselin 18
as starting materials, although the enantiomers of lomatin
have been resolved.8 Racemic trans-khellactone has been
prepared from seselin 1 using m-CPBA followed by saponi-
fication.5 (+)-trans-Khellactone 6 has been isolated alongside
the cis isomer in a 1:1 ratio from the alkaline hydrolysis of
a number of dihydropyranocoumarins, such as peujaponisin
9, (-)-visnadin 8, and (+)-anomalin 10, all diesters of (-)-
cis-khellactone 11, itself isolated from Peucedanum japoni-
cum,17 through epimerization at the benzylic position (Figure
2). We have shown that high levels of enantioselectivity can
(18) Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org.
Lett. 2005, 7, 375.
(19) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.; Real, S. D.;
Chen, H. Y. J. Org. Chem. 1995, 60, 3397.
(20) Ma, T.; Liu, L.; Xue, H.; Li, L.; Han, C.; Wang, L.; Chen, Z.; Liu,
G. J. Med. Chem. 2008, 51, 1432.
(21) Seselin 1.28 Thermal method: 7-Hydroxycoumarin (1.0 g, 6.17
mmol) was dissolved in p-xylene (20 mL). 1,1-Diethoxy-3-methyl-2-butene
(1.47 mL, 7.40 mmol) and 3-picoline (0.15 mL, 1.50 mmol) were added,
and the reaction mixture was heated under reflux for 24 h. Dichloromethane
(20 mL) was added to the reaction mixture, the solution was filtered through
a pad of silica gel and Celite, and the pad was rinsed with ethyl acetate (3
× 20 mL). The combined organic solvents were removed under reduced
pressure, and the residue was purified by column chromatography on silica
gel using ethyl acetate/toluene (1:1) as eluent to give seselin 1 as a yellow
solid (1.03 g, 73%). Microwave-assisted method: 7-Hydroxycoumarin (0.1
g, 0.62 mmol) and 1,1-diethoxy-3-methylbut-2-ene (0.13 mL, 0.74 mmol)
were dissolved in 3-picoline (0.50 mL, 5.0 mmol). The mixture was
submitted to microwave irradiation (300 W max, 100 °C, 2 × 10 min).
Dichloromethane (5 mL) was added to the reaction mixture, the solution
was filtered through a pad of silica gel and Celite, and the pad was rinsed
with ethyl acetate (3 × 5 mL). The combined organic solvents were removed
under reduced pressure, and the residue was purified by column chroma-
tography on silica gel using ethyl acetate/toluene (1:1) as eluent to give
seselin 1 as a yellow solid (0.132 g, 94%): mp 119-120 °C (lit.28 117-120
°C); νmax (film/cm-1) 2976, 2361, 1734, 1597, 1485, 1152; δH (400 MHz;
CDCl3) 1.45 (6H, s, 2 × CH3), 5.71 (1H, d, J ) 10 Hz), 6.20 (1H, d, J )
9.5 Hz), 6.70 (1H, d, J ) 8.5 Hz), 6.86 (1H, d, J ) 10 Hz), 7.20 (1H, d,
J ) 8.5 Hz), 7.59 (1H, d, J ) 9.5 Hz); δC (100 MHz; CDCl3) 28.3 (2 ×
CH3), 53.4, 109.4, 112.7, 113.7, 115.1, 120.2, 127.9, 130.9, 144.1, 150.2,
156.4, 161.2.
(6) Lee, Y. R.; Lee, W. K.; Noh, S. K.; Lyoo, W. S. Synthesis 2006,
853.
(22) Stereochemical assignment based on published structures of (-)-
lomatin8 and (+)-khellactone.17,30
(7) Ju, Y.; Still, C. C.; Sacalis, J. N.; Li, J.; Ho, C. T. Phytother. Res.
2001, 15, 441.
(23) (+)-(3′S,4′S)-Seselin Epoxide 12.6,29 Seselin 1 (0.50 g, 2.19 mmol)
was dissolved in chloroform (30 mL) and the solution cooled to -30 °C.
Sulfone catalyst 13 (0.16 g, 0.22 mmol) and TPPP (2.0 g, 4.38 mmol) were
added, and the mixture was stirred at -30 °C for 24 h. Diethyl ether (50
mL) was added to the mixture and the resulting cloudy solution filtered
through Celite. The solvents were removed under reduced pressure, and
the residue was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate/triethylamine (3:1:0.1) as eluent to give (+)-
(3′S,4′S)-seselin epoxide 12 as a colorless solid (0.348 g, 65%) of 97% ee
(HPLC conditions/hexane/2-propanol (90:10), oven temp 20 °C, column
Eurocel 01 250 × 4.6 mm, 5 µm particle size, flow rate 1 mL/min): mp
143-144 °C (lit.29 mp 144-146 °C); RD +7.2 (c 0.1 CHCl3); νmax (film/
cm-1) 2950, 2256, 1729, 1698, 1587, 1423, 1120; δH (400 MHz; CDCl3)
1.24 (3H, s, CH3), 1.53 (3H, s, CH3), 3.49 (1H, d, J ) 6.0 Hz), 4.53 (1H,
d, J ) 6.0 Hz), 6.19 (1H, d, J ) 12.7 Hz), 6.65 (1H, d, J ) 11.5 Hz), 7.24
(1H, d, J ) 11.7 Hz), 7.55 (1H, d, J ) 12.7 Hz); δC (100 MHz; CDCl3)
23.1 (CH3), 25.8 (CH3), 44.2, 62.1, 75.0, 108.4, 113.1, 113.8, 115.8, 129.4,
144.2, 155.1, 156.2, 161.2.
(8) Leandros, S. A.; Sofia, M.; Gilbert, G.; Francois, T.; Michel, K.
Heterocycles 1992, 121.
(9) Lee, J. H.; Bang, H. B.; Han, S. Y.; Jun, J.-G. Tetrahedron Lett.
2007, 48, 2889.
(10) Kapoor, S. K.; Kohli, J. M.; Sharma, Y. N.; Zaman, A. Phytochem-
istry 1972, 11, 477.
(11) Duh, C.-Y.; Wang, S.-K.; Wu, Y.-C. Phytochemistry 1991, 30,
2812.
(12) Gunatilaka, A.; Kingston, D. J. Nat. Prod. 1994, 57, 518.
(13) Song, G. Y.; Lee, J.-H.; Cho, M.; Park, B-S.; Kim, D.-E.; Oh, S.
Mol. Pharmacol. 2007, 72, 1599.
(14) Bohlmann, F.; Franke, H. Chem. Ber. 1971, 104, 3229. Murray,
R. D. H.; Sutcliffe, M.; McCabe, P. H. Tetrahedron 1971, 27, 4901.
(15) Steck, W. Can. J. Chem. 1971, 49, 1197.
(16) Mustafa, A.; Starkovsky, N. A.; Salama, T. I. J. Org. Chem. 1961,
26, 890.
(17) Ikeshiro, Y.; Mase, I.; Tomita, Y. Phytochemistry 1992, 31, 4303.
(24) Optical rotation matched the known data for (-)-(3′S)-lomatin.8
1992
Org. Lett., Vol. 11, No. 9, 2009