Total Synthesis of Psoralidin
atmosphere, DMF (one drop) and oxalyl chloride (0.18 mL, 2.04
mmol) were added. The mixture was stirred for 3 h at rt, and then
the solvent was removed under vacuum to yield acid chloride 7,
which was directly used for the next reaction without further
purification.
achieved by heating a mixture of 22, Grubbs second-generation
catalyst, and 2-methyl-2-butene in CH2Cl2 in a sealed tube
microwave reactor at 100 °C for 15 min. The reaction produced
1 in 73% yield along with compound 24 as a minor side product.
All spectroscopic data of the synthetic compound matched those
of the natural product (Table 1 in Supporting Information) except
for the melting point, which was significantly higher for the
synthetic compound than reported for the natural product. Since
there was no ambiguity about the structure of the synthetic
compound, we assumed that the melting point of the natural
product was lowered by minor impurities.
A solution of compound 6 (430 mg, 2.1 mmol) in THF (5 mL)
was added at -78 °C to a solution of LDA, prepared from n-BuLi
(2.5 M in THF, 1.1 mL, 2.72 mmol) and i-Pr2NH (0.38 mL, 2.72
mmol) in THF (6 mL) at 0 °C under N2 atmosphere. This produced
a yellowish colored anion that was stirred at -78 °C for 45 min,
and then a solution of crude acid chloride 7 in THF (10 mL) was
added dropwise. The reaction mixture was stirred at the same
temperature for another 45 min and then at room temperature for
4 h. The reaction was quenched by the addition of 10% HCl (10
mL), THF was removed in vacuum, and the water layer was
extracted with ethyl acetate (2 × 50 mL). The organic layer was
washed with water (2 × 20 mL) and brine (20 mL), dried (Na2SO4),
and concentrated. The crude product was purified by column
chromatography to yield 5 (495 mg, 82%) as a yellowish oily
compound. Rf ) 0.3 (50% ethyl acetate in hexane); νmax (CHCl3)
cm-1 2359, 2341, 1738, 1666, 1604, 1507, 1463, 1270, 1211, 1029.
1H NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.01 (d, 1H, J ) 8.0
Hz), 6.41 (s, 1H), 6.40 (d, 1H, J ) 8.0 Hz), 6.30 (s, 1H), 5.91 (s,
1H), 5.22 (t, 1H, J ) 7.5 Hz), 3.82 (s, 3H), 3.76 (s, 3H), 3.75 (s,
3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.18 (d, 2H, J ) 7.5 Hz), 1.68 (s,
3H), 1.64 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ 193.0 (C), 171.1
(C), 162.6 (C), 160.3 (C), 159.6 (C), 157.9 (C), 132.7 (CH), 132.3
(CH), 130.3 (CH), 122.6 (C), 122.0 (C), 118.2 (C), 115.9 (C), 104.1
(CH), 98.5 (CH), 94.2 (CH), 57.3 (CH3), 55.6 (CH3), 55.5 (CH3),
55.4 (CH3), 55.3 (CH3), 52.2 (CH), 27.6 (CH2), 25.9 (CH3), 17.8
(CH3). HRMS (EI+) m/z 442.1993 ([M]+ C25H30O7, requires
442.1992).
Conclusions
In summary, we achieved the first total synthesis of psoralidin
1 in a convergent and highly regioselective manner. The
synthetic scheme described here is straightforward and efficient.
The longest linear sequence is only five steps starting with
commercially available resorcinol. The process is readily
adaptable and flexible as substitutions can be introduced in both
the phenyl acetate and the allyl benzoyl chloride starter
molecules to furnish numerous analogues for SAR studies.
Further structural diversification could be achieved on the level
of the concluding Grubbs reaction. Biological assays to deter-
mine and compare the efficacy of 16, 22, and 23 with that of 1,
as well as syntheses of various regioisomers, are in progress.
Experimental Section31
Psoralidin 1. Grubbs second-generation catalyst (3 mg, 0.0035
mmol) was added to a degassed solution of 22 (20 mg, 0.06 mmol)
in CH2Cl2 (10 mL) and 2-methyl-2-butene (2 mL). The solution
was heated in a sealed tube at 100 °C for 15 min by a microwave
reactor (Biotage Initiator 2.0, standard configuration, temperature
control, external IR temperature sensor, fixed hold time). CH2Cl2
was removed in vacuum, and the mixture was purified by reverse
1-Bromo-2,4-dimethoxy-5-(3-methyl-but-2-enyl)-benzene (10).
Compound 9 (3.10 g, 10.47 mmol) was added to a solution of
i-PrMgCl (1 M in THF, 13 mL, 13 mmol) at -10 °C under N2
atmosphere. After 45 min of stirring, prenyl bromide (1.3 mL, 11.5
mmol) was added dropwise, and the mixture was allowed to stir at
the same temperature for 30 min and then at rt for 2 h. The reaction
was quenched by the addition of 10% HCl (15 mL). THF was
removed in vacuum, and the mixture was extracted with ethyl
acetate (2 × 75 mL). The organic layer was washed with water (2
× 30 mL) and brine (20 mL), dried (Na2SO4), filtered, and
concentrated. The resulting crude compound was purified by column
chromatography to yield 10 (1.94 g, 65%) as a colorless liquid along
with 550 mg of unreacted starting material 9. Rf ) 0.5 (5% ethyl
acetate in hexane); νmax (CHCl3) cm-1 1599, 1500, 1463, 1295,
18
phase semipreparative HPLC (symmetry C, 7 µm, solvent gradient
9:1 CH3CN:H2O) to get compound 1 (16 mg, 73%) as a white solid
along with a minor amount of side product 24 (1 mg, 5%). Rf )
0.4 (50% ethyl acetate in hexane); mp >400 °C (lit.1 315 °C); νmax
1
(film) cm-1 1719, 1629, 1597, 1419, 1370, 1260, 1092. H NMR
(DMSO-d6, 500 MHz) δ 7.68 (d, 1H, J ) 8.0 Hz), 7.62 (s, 1H),
7.17 (d, 1H, J ) 2.0 Hz), 6.94 (dd, 1H, J ) 8.0, 2.0 Hz), 6.93 (s,
1H), 5.35 (t, 1H, J ) 7.5 Hz), 3.32 (d, 2H, J ) 7.5 Hz), 1.74 (s,
3H), 1.70 (s, 3H). 13C NMR (DMSO-d6, 125 MHz) δ 159.6 (C),
159.0 (C), 157.8 (C), 157.0 (C), 156.0 (C), 152.9 (C), 132.6 (C),
126.5 (C), 121.8 (CH), 121.0 (CH), 120.6 (CH), 114.7 (C), 114.0
(CH), 103.8 (C), 102.4 (CH), 102.0 (C), 98.8 (CH), 27.6 (CH2),
25.7 (CH3), 17.7 (CH3). HRMS (EI+) m/z 336.1008 ([M]+
C20H16O5, requires 336.0998).
(E)-2-(But-2-enyl)-3,9-dihydroxy-6H-benzofuro[3,2-c]chro-
men-6-one (24). Rf ) 0.35 (50% ethyl acetate in hexane); mp >400
°C; νmax (film) cm-1 1718, 1637, 1629, 1267, 1213, 1093. 1H NMR
(DMSO-d6, 500 MHz) δ 7.68 (d, 1H, J ) 8.5 Hz), 7.64 (s, 1H),
7.17 (d, 1H, J ) 2.0 Hz), 6.94 (dd, 1H, J ) 8.5, 2.0 Hz), 6.90 (s,
1H), 5.70-5.50 (m, 2H), 1.67 (d, 3H, J ) 6.0 Hz). 13C NMR
(DMSO-d6, 125 MHz) δ 159.6 (C), 157.8 (C), 157.0 (C), 155.9
(C), 153.1 (C), 128.7 (CH), 126.3 (CH), 126.2 (CH), 125.3 (C),
121.3 (C), 120.5 (CH), 118.6 (C), 114.7 (CH), 113.9 (CH), 102.4
(C), 98.7 (CH), 31.9 (CH2), 17.8 (CH3). HRMS (EI+) m/z 322.0847
([M]+ C19H14O5, requires 322.0841).
1
1208, 1029. H NMR (CDCl3, 500 MHz) δ 7.21 (s, 1H), 6.44 (s,
1H), 5.21 (t, 1H, J ) 7.0 Hz), 3.87 (s, 3H), 3.82 (s, 3H), 3.19 (d,
2H, J ) 7.0 Hz), 1.72 (s, 3H), 1.67 (s, 3H). 13C NMR (CDCl3, 125
MHz) δ 157.5 (C), 154.8 (C), 133.1 (C), 133.0 (CH), 124.0 (C),
122.2 (CH), 101.6 (C), 96.8 (CH), 56.6 (CH3), 55.9 (CH3), 27.6
(CH2), 26.0 (CH3), 17.9 (CH3). HRMS (EI+) m/z 284.0414 ([M]+
C13H17O2Br, requires 284.0412).
2,4-Dimethoxy-5-(3-methyl-but-2-enyl)-benzoic acid (11). n-
BuLi (2.5 M in THF, 2.1 mL, 5.34 mmol) was added dropwise to
a stirred solution of 10 (1.27 g, 4.45 mmol) in THF (15 mL) at
-78 °C under N2 atmosphere. After 30 min, CO2 gas was passed
through the solution for 45 min, and then it was allowed to warm
up to rt. THF was removed in vacuum, and the mixture was treated
with saturated NaHCO3 solution (30 mL). The water layer was
washed with ethyl acetate (2 × 20 mL) and then acidified with
conc. HCl. The mixture was extracted with ethyl acetate (2 × 75
mL). The organic layer was washed with water (2 × 30 mL), brine
(30 mL), dried (Na2SO4), filtered, and concentrated. Recrystalli-
zation from ethyl acetate produced 11 (930 mg, 84%) as a white
solid. Rf ) 0.1 (50% ethyl acetate in hexane); mp: 98-99 °C; νmax
(film): cm-1 1719, 1616, 1442, 1278,1168, 1020. 1H NMR (CDCl3,
500 MHz) δ 7.77 (s, 1H), 6.41 (s, 1H), 5.16 (t, 1H, J ) 7.0 Hz),
3.97 (s, 3H), 3.84 (s, 3H), 3.14 (d, 2H, J ) 7.0 Hz), 1.64 (s, 3H),
Methyl-3-[2,4-dimethoxy-5-(3-methyl-but-2-enyl)-phenyl]-2-
(2,4-dimethoxy-phenyl)-3-oxo-propionate (5). To a stirred solution
of compound 11 (340 mg, 1.36 mmol) in CH2Cl2 (8 mL) under N2
(30) Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 112, 1125–1132.
(31) For general experimental methods, see Supporting Information.
J. Org. Chem. Vol. 74, No. 7, 2009 2753